ARSR Vol 14 Pfaus - CiteSeerX

What Can Animal Models Tell Us About Human Sexual Response? James G. Pfaus

Tod E. Kippin

Genaro Coria-Avila

Center for Studies in Neurobiology Research Group Center for Studies in Behavioral Neurobiology Department of Anatomy Behavioral Neurobiology Department of Psychology & Cell Biology Department of Psychology Concordia University University of Toronto Concordia University In all species, sexual behavior is directed by a complex interplay between steroid hormone actions in the brain that give rise to sexual arousability and experience with sexual reward that gives rise to expectations of competent sexual activity, including sexual arousal, desire, and performance. Sexual experience allows animals to form instrumental and Pavlovian associations that predict sexual outcome and thereby directs the strength of sexual responding. Although the study of animal sexual behavior by neuroendocrinologists has traditionally been concerned with mechanisms of copulatory responding, more recent use of conditioning and preference paradigms, and a focus on environmental circumstances and experience, has revealed behaviors and processes that resemble human sexual responses. In this paper, we review behavioral paradigms used with rodents and other species that are analogous or homologous to human sexual arousal, desire, reward, and inhibition. The extent to which these behavioral paradigms offer predictive validity and practicality as preclinical tools and models is discussed. Identification of common neurochemical and neuroanatomical substrates of sexual responding between animals and humans suggests that the evolution of sexual behavior has been highly conserved and indicates that animal models of human sexual response can be used successfully as preclinical tools. Key Words: conditioning, expectancy, female, hormone, male, monoamines, neuropeptides, rodent.

The validity of interspecific generalization can never exceed the reliability of intraspecific analysis; and the latter is an indispensable antecedent of the former (p. 113). —Frank A. Beach (1979) Preparation of this paper and the studies reported from our laboratory were supported by grants from the Natural Sciences and Engineering Research Council of Canada (OGP0138878), Canadian Institutes for Health Research (MT-13125), U.S. National Institute on Drug Abuse (R21-DA11898), Fonds pour la Formation de Chercheurs et l’Aide à la Recherche du Québec (CE-98), and CONACyT of México (GAC-128099). The authors are indebted to Drs. Anders Ågmo, John Bancroft, Michael Baum, Ray Blanchard, Mary Erskine, Walter Everaerd, Barry Everitt, Chris Fibiger, Irwin Goldstein, Julia Heiman, Elaine Hull, Jake Jacobs, Erick Janssen, Ellen Laan, Jorge Manzo, Peg McCarthy, Martha McClintock, Cindy Meston, Pablo Pacheco, Raul Paredes, Tony Phillips, Ray Rosen, Ben Sachs, Annette Shadiack, Jane Stewart, Paul Vasey, and Ian Whishaw for many fruitful discussions that helped formulate the ideas expressed in this paper. Correspondence concerning this article should be addressed to James G. Pfaus, PhD, Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, 7141 Sherbrooke St. W. Montréal, QC. H4B 1R6, Canada. ([email protected])

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J. PFAUS, T. KIPPIN, & G. CORIA-AVILA

Understanding human sexual behavior requires continued research and a hefty dose of patience and creativity. We must balance the simplicity of DSM-like definitions of normal and abnormal arousal, desire, performance, and orgasm with the bewildering array of exceptions to those definitions that characterize sexual function and dysfunction in real people. All too often our questions are obscured by scientific blinders and constrained by research review committees, with certain moral limitations imposed by ethics review boards and government agencies pressured to enforce “community standards.” There is much that we simply cannot do, either because of ethical concern, impracticality, or the lack of sufficient technology. This is most obvious when we ask questions about the neurobiology of sexual behavior. Although we can view human brain activation in sexual circumstances or monitor the sexual behavior of individuals with specified brain damage or following drug treatments, it is difficult to study these phenomena experimentally. Most people will not knowingly allow themselves to be rendered sexually dysfunctional by some experimental manipulation, and ethics review boards generally have a hard time allowing researchers to monitor human copulatory behavior firsthand. Despite this, we have made real progress in the past decade in understanding the neuroanatomical and neurochemical mechanisms of erection, ejaculation, and other sexual responses, and in the design of rational pharmacological treatments for certain sexual dysfunctions. We have begun to examine the mechanisms that underlie desire, and how sexual stimulation and reward impact on attractiveness and mate choice. Progress in these areas could not have been made without the help of animal models. The comparative approach to the study of sexual behavior was championed by Beach, who issued a “call to arms” in his 1950 presidential address to the American Psychological Association, in a delightful treatise called “The Snark was a Boojum” (Beach, 1950). His call was heeded by those in the fledgling science of behavioral neuroendocrinology, but at the expense of a unified approach to the study of sexuality. By the early 1990s it was as if two camps had emerged: clinicians who studied people and neuroendocrinologists who studied animals. Those camps rarely shared their insights at scientific meetings. And why bother? After all, human copulatory behavior doesn’t really resemble copulatory behavior in animals. There is no human counterpart to lordosis (at least not as an unambiguous, estrogen-dependent postural display of sexual receptivity in females), and human sexual behavior is so shaped by experience and learning that it seems to defy hormone actions that are critical to the display of animal sexual behavior. But insights into the human experience could indeed be derived from ani-

ANIMAL MODELS OF HUMAN SEXUAL RESPONSE

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mals. The links started forming around the study of sexual pharmacology. For example, the dopamine receptor agonist apomorphine induces erection in rats and men (Lal et al., 1987; Melis, Argiolas, & Gessa, 1987), whereas the dopamine antagonist haloperidol reduces sexual arousal and desire in rats and men (Petrie, 1985; Pfaus & Phillips, 1991). Such results allowed researchers to make a predictive link between the sexual responses of male rats and men (e.g., Barfield, 1993; Everitt & Bancroft, 1991; Pfaus, 1996) and gave rise to an important theoretical implication that certain brain systems had been conserved in evolution to subserve similar or identical functions among species. One interpretation of Beach’s argument was that a true understanding of the neurobiological or behavioral rules that underlie sexual responding required us to study how well they fit across species. If they did, then animals could be used as models to study aspects of human sexual behavior that otherwise could not be studied experimentally in humans. If they did not, then they represented either interesting examples of biological diversity or evolutionary dead-ends. Of course, either possibility required a full account of what animals do, or can do if asked the proper questions. Conceiving of Commonalities All organisms that engage in sexual behavior share a common set of principles and end-points that define the behavior, along with particular neural mechanisms that make it successful. First, we must be able to respond to hormonal and neurochemical changes that signal our own sexual desire and arousal. This ability underlies our moment-tomoment level of sexual arousability (as conceived by Whalen, 1966) and defines a large part of the internal state that is commonly referred to as “sex drive.” The rest requires a complex mix of instinct, learning, and feedback with a neural organization that allows us to interact with external sexual incentives. We must be able to identify external stimuli that predict where potential sex partners can be found, seek out, solicit, court, or otherwise work to obtain sex partners, distinguish external cues and behavioral patterns of potential sex partners from those that are not sexually receptive, and pursue sex partners once sexual contact has been made. Neural mechanisms exist that allow sexual responding to become habitual or automated with practice, and such processes may underlie the ability of sexually experienced animals to be less affected by treatments that disrupt sexual responding in sexually naive animals (e.g., Pfaus & Wilkins, 1995). Similarly, neural mechanisms exist that allow the stimulation received during sexual contact to be perceived as rewarding. Such reward alters subsequent behavior, for example, by

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contributing to the formation of preferences for salient stimuli associated with positive sexual reinforcement (Pfaus, Kippin, & Centeno, 2001). Many of these aspects of sexual responding go well beyond the traditional focus on copulation or penile reflexes. Although some appetitive and preparatory responses that animals make prior to copulation are not specific to sexual behavior, they can be considered “sexual” if they are conditioned using sexual reward as the positive reinforcer. This is as true for bar pressing in male rats (e.g., Everitt, Fray, Kostarczyk, Taylor, & Stacey, 1987) as it is for giving flowers and remembering birthdays in men. For all animals, sexual behavior occurs as a sequence or “cascade” of behavioral events. Beach (1956) recognized the heuristic value of separating sexual behavior into respective appetitive and consummatory phases. Essentially, this scheme followed from the work of early ethologists, such as Craig (1918), and experimental psychologists, such as Woodworth (1918), who defined appetitive (or “preparatory”) behaviors as those which bring an animal from distal to proximal and into contact with goal objects or incentives. In contrast, consummatory behaviors are performed once an animal is in direct contact with the incentive (i.e., to “consummate” the goal). Consummatory behaviors tend to be species-specific, sexually differentiated, and stereotyped, whereas appetitive behaviors are more flexible. Indeed, survival often depends on an animal’s ability to learn a variety of strategies to obtain goals in different appetitive circumstances. We have found it useful heuristically to conceive of appetitive and consummatory behaviors as two overlapping Venn diagrams (e.g., Pfaus, 1996, 1999) in which the behavioral stream moves from appetitive to consummatory incentive sequences (see Figure 1). The intersection of the diagrams defines precopulatory behaviors made once animals come into contact with potential sex partners. The diagrams are overlapping, rather than discontinuous, because the division between the two phases is rarely fixed. Some responses, such as solicitation, can be placed into both phases, especially if sexual interaction comes in bouts. We would, therefore, define solicitation as a precopulatory behavior that acts as a transition from appetitive to consummatory. It is also essential to place the behaviors into a comparative context: Are they homologous or analogous to human sexual responses? Homologies Versus Analogies Homologies are typically defined in biology as tissues that correspond in evolutionary origin, structure, and function; for example, the flippers of a seal and the arms of a human being. However, homologies come in degrees. We may regard brain dopamine systems among different mam-


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mals as homologous because cell bodies originate and axons terminate in similar brain regions (e.g., ventral tegmental area to nucleus accumbens). In addition, drugs that activate dopamine receptors (e.g., apomorphine) or block the reuptake of dopamine (e.g., amphetamine or cocaine) produce psychomotor stimulation in many mammalian species, thus we may regard the function of this neurochemical system as homologous at that level of analysis. We may also define tissues with different function, such as the labia and scrotum, as homologous structures because they differentiate from the same primordial gonads.

Figure 1. Incentive sequences for human and rat sexual behavior (modified from Pfaus, 1996, 1999). The behavioral stream moves from left to right, through appetitive, precopulatory, and consummatory phases of behavior. This conforms to the movement of animals from distal to proximal to interactive with respect to the sexual incentive. Three types of appetitive responding reflect relative degrees of learning and necessity. “Preparatory” behaviors are learned responses that animals must make in order to acquire the incentive (e.g., operant behaviors, pursuit, etc.). “Anticipatory” behaviors, such as excitement, are learned responses that occur in anticipation of an incentive, but are not necessary to obtain it. Unlearned appetitive responses also exist that are instinctual (e.g., unconditioned anogenital investigation). These aspects of behavior also occur once copulatory contact has been made, especially if copulation occurs in bouts (as it does in rats). The PEI is the Postejaculatory Interval, or refratory period between ejaculation and the first intromission of the next copulatory interaction.

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Regarding behavior, homologies are usually easy to define because they have the same endpoints and are typically controlled by similar neural systems. Erections in rats and men are a good example: A large number of drugs, situations, and brain lesions alter the latency to obtain an erection and the duration of erection similarly across species. Analogies are less straightforward and require a degree of creativity in interpretation, inference, and design. What distinguishes analogies from homologies is the idea that things or events are dissimilar in form, yet may serve the same endpoint. In biology, this is usually taken to mean that the organ or structure is similar in function, but not necessarily in evolutionary origin. For example, the gills of a fish and the lungs of a mammal both remove oxygen from water or air, but cannot remove it from both media. However, analogous tissues may have similar neural control. With regard to behavior, something done by an animal may not appear similar to its human counterpart, despite serving a similar endpoint and being dependent on identical neural systems. Solicitation in female rats is a good example. During copulation, female rats control the initiation and pacing of copulation by soliciting mounts from males. A female makes a headwise orientation to the male and then runs away, forcing the male to chase her (e.g., McClintock, 1984). If the male is sluggish or nonresponsive, the female may increase the strength of her solicitations, to the point of kicking the male in the head before the runaway or even mounting the male if he does not respond to previous enticements (Afonso & Pfaus, 2003; Beach, 1968). Of course, such behavior would not be interpreted as sexual solicitation in most human cultures. However, solicitation in all species indicates a willingness or desire to copulate, and high levels of solicitation in females, or analogous courtship behaviors in males, suggest that the animals are highly motivated to copulate. At a strictly behavioral level of analysis, it does not matter whether the motivation to do so is driven by a primary desire for sexual gratification, offspring, conflict resolution, or other social rewards. Contrast solicitation with lordosis: the arching of the back characteristic of sexual receptivity in many mammalian females. As mentioned above, there is no human counterpart to this, except perhaps spreading one’s legs to allow penetration to occur (although doing so is not an estrogen-dependent spinal reflex). Thus, solicitation in rats, and not necessarily lordosis, might be the most “analogous rat model” of sexual desire in women. The validity of any homologous or analogous animal model can only be determined in situations that test whether a treatment that modifies behavior in the animal does so in humans. Analogies may exist that bear no resemblance whatsoever to the phenomenon in question, but


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that can nonetheless serve as a model system. For example, lordosis behavior depends critically on molecular and intracellular changes induced by estrogen in the brain and spinal cord (Pfaff, 1980, 2001). Such changes come under the general rubric of plasticity and growth, and are mined regularly by molecular biologists to examine the proteinsynthetic effects of estrogen in cells of other tissues. Conversely, although an organ, structure, or function may be homologous in form at one level of analysis, the neural and behavioral mechanisms that control them may be dissimilar enough to render them unsuitable as model systems. For example, some mammals are “spontaneous” ovulators, whereas others are “reflex” ovulators. In the former, such as in female macaques or humans, preovulatory maturation of follicles and ovulation occur by the actions of ovarian steroids and pituitary peptides; the presence of males or copulatory stimulation is not a prerequisite. In the latter, such as in female rabbits, cats, or camels, the presence of males or copulatory stimulation is almost always required. Although there is no strict boundary between spontaneous and reflex ovulation, it is clear that the latter is not a good model of the former, even if some vestigial holdovers occur (e.g., increased sperm retention and transport in women who have orgasms after ejaculation as opposed to those who do not; Baker & Bellis, 1995; Singh, Meyer, Zambarano, & Hurlbert, 1998). What is Required of a Good Animal Model? Predictive validity is the most important requisite of an appropriate animal model. In addition to this, animal models should be simple and practical enough to have “high throughput,” meaning the ability to have experiments conducted relatively quickly. Issues of sample size and ease of testing and analysis are key. For example, testing the sexual effects of alcohol in male dogs may reveal processes similar to those in men (e.g., the ability of low doses of alcohol to increase the ejaculation latency in male dogs that led to the suggestion by Gantt (1952) that a couple of glasses of wine could be used as a quick remedy against premature ejaculation), but such experiments are cumbersome from an experimental testing and animal housing standpoint and, indeed, might have a difficult time passing an animal ethics review by today’s standards. Throughput in numbers. Because testing large animals is simply not practical except in field studies, many researchers use smaller animals, such as rats, rabbits, ferrets, gerbils, hamsters, voles, mice, snakes, lizards, or birds, to examine the neural and hormonal control of sexual behavior. These animals can be tested in large numbers at the same time and do not present a challenge for animal housing in a colony room. Although some, like certain transgenic mice, require constant monitoring,

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this is not an overriding obstacle to their use as research subjects. Optimal testing environments. Testing small animals means that suitable chambers and testing environments need to be constructed. Attention has to be paid to the ecological validity of those testing environments. Some animals, like rats, are very social and will copulate under a variety of circumstances regardless of the presence of a human experimenter (Calhoun, 1962). The testing environment also needs to be optimized for each animal. For example, female rats like to pace the rate of copulation. Providing them with chambers that allow such behavior to occur (e.g., the preference chambers described by Emery, 1986; the pacing chambers described by Erskine, 1989, and Paredes & Alonso, 1997; or the bilevel chambers described by Mendelson & Pfaus, 1989, Pfaus, Mendelson, & Phillips, 1990, and Pfaus, Smith & Coopersmith, 1999; shown in Figures 2 and 3), gives researchers the ability to

Figure 2. Bilevel chambers used to study appetitive and consummatory measures of copulation in rats. Depicted is a female soliciting a male (top left), then allowing him to investigate her anogenital region (top right), followed by a runaway to the top level, during which the male pursues her (bottom left), leading to lordosis, which allows the male to mount and gain vaginal penetration (bottom right). The entire bout of copulation took 4 sec. Vaginal penetration is followed by an abrupt dismount, after which the male grooms his penis and anogenital regions. The male ejaculates after several copulatory bouts with intromission.


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Figure 3. Pacing chambers used to study the ability of female rats to control the sexual interaction and the impact of such control on sexual reward (in both males and females). Each chamber is bisected by a Plexiglas divider that contains either 1 or 4 holes of dimensions that only the female can pass through. Females typically exit from the male’s side after a bout of copulation. In addition to traditional measures of copulation, the latency to return to the male’s side following different copulatory stimulation (e.g., mount, intromission, or ejaculation) can be assessed.

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detect certain appetitive behaviors in both female and male rats in an unambiguous manner. Likewise, if the experimenter wishes to study appetitive responses made to acquire a sex partner, then the testing environment should contain some kind of operant apparatus upon which the animal must work to obtain sexual reinforcement (e.g., as described in Everitt et al., 1987). Each experimental question dictates the proper treatments and testing environment, so the rate-limiting factor in generating the appropriate animal model is really the inspired intuition of the experimenter (see Ågmo & Ellingsen, 2003). What Animals Make Good Models?

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Any animal “system” in which the homology or analogy has predictive validity to human responses or physiological processes (and can be replicated) is a good model. If the model is practical from an experimental standpoint, then it will likely be used more than models that are cumbersome. And the more information that is gathered from a particular model, the more the model will be used because it has a large literature associated with it. Rats continue to be the most frequently used animals in the study of sexual behavior. There are many reasons for this, the most obvious being that they are practical (e.g., small, easy to handle, and quite social), and they have a large literature associated with them. Rats also resemble humans in many analogous and homologous ways. Certain tissues and neuroendocrine systems in rats are strikingly similar to our own (e.g., the physiological control of erection or uterine tissue growth following estrogen treatment). As social animals, rats have evolved a level of behavioral plasticity that allows them to adapt to a variety of ecological niches (Barnett, 1963; Calhoun, 1962; Dewsbury, 1975). Like humans, their patterns of copulatory behavior can be described as “opportunistic,” and they will copulate in a variety of circumstances, in dyads, triads, or large groups (Beach, 1956; Dewsbury, 1975; Madlafousek & Hlinák, 1978; McClintock, 1984; Stone, 1922). Beach (1938) noted that male and female rats will copulate in virtually any type of testing chamber. Thus, rat sexual behavior has been examined experimentally in groups (e.g., McClintock 1984), in mate-choice paradigms (e.g., Emery, 1986; Kippin, Talianakis, Schattmann, Bartholomew, & Pfaus, 1998), and in traditional dyadic mating situations in a variety of unilevel or bilevel chambers (e.g., Erskine, 1989; Larsson, 1956; Pfaus, Mendelson, et al., 1990, Pfaus et al., 1999). The use of different testing situations sometimes results in different patterns of copulatory behavior. Rather than such differences being considered an experimental annoyance, they stand as examples of the profound behavioral plasticity of rats in different circumstances,


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examples of the way that rats are able to alter their behavior to meet the demands of different contexts, much like humans do. Other animals, notably hamsters, gerbils, mice, voles, rabbits, ferrets, and quail, have also been used in some of the paradigms discussed later in this article. All are viable animal models of human sexual response so long as the paradigms employed render homologous or analogous behaviors that ultimately have predictive validity in controlled clinical trials of human sexual response. Depicted in Tables 1 and 2 are measures of rodent sexual behavior that can be used in models of human sexual behavior. A theoretical discussion of these measures as motivational variables has been made previously (Ågmo, 1999; Pfaus, 1996, 1999). The present discussion is of their utility as models. In Table 3, current rodent models of human sexual behavior are depicted. For simplicity’s sake, they have been divided into general headings of sexual arousal, desire, reward, and inhibition. In reality, all four dimensions interact considerably, making their separation more conceptual than real. Models of Sexual Arousal Physiological sexual arousal in both humans and other animals can be defined as increased autonomic activation that prepares the body for sexual activity. This includes both parasympathetic blood flow to genital and erectile tissues, in particular the clitoris, labia, vaginal epithelium, and penis, and sympathetic blood flow from the heart to striated and smooth muscle that participate in sexual responses. Sexual arousal also includes a central component that increases neural “tone” or preparedness to respond to sexual incentives. This latter concept was defined as “arousability” by Whalen (1966) and may form around an intricate interaction of hormone priming and noradrenergic activity in different regions of the brain. Both peripheral and central arousal may be detected as part of the perception of subjective sexual arousal, and both clearly lead to changes in responsiveness in genital tissues and control certain copulatory responses, such as the latency to orgasm or ejaculation (with shorter latencies indicating an increase in arousal). There is a considerable degree of similarity between male rats and men in terms of the neuroanatomical, neuroendocrine, and neurochemical regulation of penile erection and ejaculation (see Andersson & Wagner, 1995; Meisel & Sachs, 1994; Rosen & Sachs, 2000, for comprehensive reviews). Penile erections in men can be either “physiological” or “psychogenic” in response to parasympathetic arousal. They can be studied using mercury-in-rubber strain gauges either during the night (to gain an unbiased measure of physiological erectile capability) or in response to different types of erotic

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Table 1 Measures of Appetitive Sexual Behavior in Rodents Sexual Excitement Grooming (counts in response to a potential sex partner) Anogenital investigation (counts, latencies, duration of bout) Motor activation (conditioned level changing, wheel-running, activity meters) Preparatory Sexual Behaviors Instrumental responses Operant responses for primary or secondary sexual reinforcers Maze running Obstruction boxes Crossing electrified grids Sexual attractivity (e.g., scent marking, approach) Courtship behaviors Preference tests Unconditioned or conditioned partner preference Conditioned place preference Coolidge effect (response to novel versus familiar partner) Sexual Arousal (males) Penile reflex tests Noncontact erections Copulatory Responses (females) Sexual proceptivity Solicitations Hops and darts Pacing Defensive behaviors Copulatory Responses (males) Pursuit Postejaculatory refractory period Sexual exhaustion

or somatosensory stimuli (to measure psychogenic arousal). Latency to erection (tumescence), percentage of full erection, and duration of erection can be studied following the administration of drugs that either enhance or delay parasympathetic arousal. Such studies are important diagnostically in distinguishing psychological from physiological erectile dysfunction, or in determining spared erectile capability in men with spinal cord injury. Ejaculation has been more difficult to study objectively in men and has thus been the subject of far fewer studies. Typically, subjects masturbate in the presence of different types of erotic stimulation following an experimental treatment. Ejaculation latencies are recorded along with physiological measurements of ejaculate volume, sperm motility, or psychological measurements of orgasm intensity (e.g., Mah & Binik, 2002; Rowland, Strassberg, de Gouveia Brazao, & Slob, 2000). Subjective sexual


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Table 2 Measures of Consummatory Sexual Behavior in Rodents Females Sexual receptivity Lordosis (quotients, reflex magnitudes, in rats) Lateral tail displacement in hamsters Males Mounts (latency, number before ejaculation) Intromissions (latency, number before ejaculation, interval between each or “hit rate”) Ejaculations (latency, number in a timed test or before exhaustion)

arousal, or the ability of people to describe or monitor their own sexual arousal, is difficult if not impossible to determine in animals. We must use components of sexual desire, specifically behavioral excitation in response to changes in genital blood flow, to make inferences about subjective arousal in animals. Penile Erections In rats, penile erections can be studied in isolation to obtain measures of physiological arousal (summarized in Meisel & Sachs, 1994) or in response to different types of sexually arousing stimuli (e.g., noncontact erections in response to estrous odors) to obtain measures of psychogenic arousal (Sachs, 1995; Sachs, Akasofu, Citron, Daniels, & Natoli, 1994). Penile reflex tests. In typical penile reflex tests, male rats are placed supine in a tube with their penile sheaths held back and the penis retracted. The penis then shows a characteristic pattern of tumescence and detumescence accompanied by “quick flips” (quivers following full erection) and “cups” (a flaring of the glans penis thought to be analogous to ejaculation). Latency to erection and the frequency of these different reflexes are counted following an experimental treatment (e.g., systemic or central drug administration, brain lesions, or lesions of different nerves that innervate the pelvic ganglia). Many treatments that enhance penile erection in men (e.g., sildenafil, apomorphine, prostaglandin E1, oxytocin, α2-adrenergic receptor antagonists, such as yohimbine, idazoxan and imiloxan, and vasodilators that act through nitric oxide substrates, such as nitroglycerine, sodium nitroprusside, and linsidomine) enhance penile erection in rats (reviewed in McKenna 1999; Meisel & Sachs, 1994). Erectile responses to these drugs are also studied by monitoring intracavernosal pressure with electrodes (e.g., Andersson et al., 1999; Bernabe, Rampin, Sachs, & Giuliano, 1999). Conversely, drugs that reduce sexual arousal in men (e.g., dopamine antagonists such as haloperidol [Crenshaw & Goldberg, 1996] also

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Table 3 Paradigms That Can Be Used as Rodent Models of Human Sexual Behavior Sexual Arousal Males Penile reflex tests (physiological erectile function; responses to somatosensory stimulation) Noncontact erections (“psychogenic” erectile function; responses to primary or secondary conditioned sexual cues) Copulatory measures Latency to mount, intromit or ejaculate (shorter latency = greater arousal) Enforced interval effect (model of premature ejaculation) Coolidge effect (increased arousal by changing sexual stimuli) Sexual Desire Females and males Excitement (motor responses in anticipation of sexual activity or in response to hormonal stimulation) Instrumental responding (desire to obtain a sex partner) Sexual preference paradigms (desire to obtain unconditioned or conditioned sexual incentives) Copulatory measures Males Pursuit (desire to obtain sex partner) Females Solicitation, hops and darts (desire to initiate sexual activity) Pacing (desire to regulate copulatory contact; increased pacing = decreased desire for copulatory contact) Lordosis (receptivity to vaginal penetration) Lateral tail displacement in hamsters (receptivity to vaginal penetration) Sexual Reward Females and males (to examine what aspect of sexual responding is rewarding, e.g., copulatory stimulation vs. ejaculation in males, or the ability to control sexual interaction in females) Operant responding for primary or secondary sexual reinforcers Conditioned place preference Unconditioned or conditioned partner preference Conditioned copulatory behavior (e.g., copulatory responses in places paired with sexual or other rewards, or in the presence or absence of conditioned incentive cues) Sexual Inhibition Females Copulatory behavior after several ejaculatory series Estrus termination Tests using ovariectomized females primed with estrogen alone Males Primary sexual inhibition (using access to nonreceptive females) Second order sexual inhibition (using odors or other stimuli paired with access to nonreceptive females). Recovery from sexual exhaustion


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reduce penile reflexes in rats (Pehek, Thompson, Eaton, Bazzett, & Hull, 1988). However, selective activation of different dopamine receptors in the medial preoptic area alters autonomic arousal differently, with selective agonist actions on D1 receptors facilitating erections and inhibiting seminal emissions in male rats, and selective actions on D2 receptors having the opposite effect (Hull et al., 1989). This suggests that the erectogenic actions of apomorphine in rats occur through its binding to D2 receptors in this or other brain regions. “Psychogenic” erections. Noncontact erections in rats are studied in the presence of an inaccessible receptive female behind a mesh screen, or behind a series of walls with an air circulation system that brings the estrous odors to the male’s compartment. Erections in response to these salient sexual cues are viewed as a model of psychogenic erection because they do not require direct somatosensory stimulation to be induced. The neurochemical and hormonal mechanisms that control their expression have been studied in detail (e.g., nitric oxide release in the paraventricular hypothalamus, Melis, Succu, Spano, & Argiolas, 2000; dopamine in the medial preoptic area, Adachi et al., 2003; peripheral and central actions of androgens, Manzo, Cruz, Hernandez, Pacheco, & Sachs, 1999). Drugs that enhance noncontact erections also induce a “penile erection and yawning syndrome” in rats in the absence of sexual stimulation (Bertolini, Gessa, & Ferrari, 1974; Doherty & Wisler, 1994; Melis & Argiolas, 2002). It remains to be studied whether this “syndrome” is related neurochemically to psychogenic erection in rats, or whether it stems from a more general activation of the autonomic nervous system. On the other hand, general autonomic activation by drugs or environmental circumstances may be translated into sexual arousal in the presence of a sexual incentive. This is reminiscent of the idea put forth by the ancient Roman poet Ovid, in Ars Amatoria (1930; www.sacredtexts.com/cla/ovid/lboo/) that, under the right circumstances and occasion setting, high levels of general arousal can be manipulated into sexual arousal (see the discussion later in this article). Such an effect is also consistent with the notion by Meston and colleagues (Meston, 2000; Meston & Gorzalka, 1996) that sympathetic arousal provides a necessary background for the perception of sexual arousal. Copulatory Responses in Males That Indicate Arousal Ejaculations in rats can be studied much the same way they are studied in humans, with the latency from first mount or intromission to ejaculation being the key variables. Male rats typically ejaculate following several penile intromissions and can ejaculate several times before becoming sexually exhausted, at which time the male no longer responds to estrous odors

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or female solicitations (Beach & Jordan, 1956b). During successive ejaculatory series, the refractory period or postejaculatory interval between each ejaculation and the subsequent resumption of copulation increases progressively (Larsson, 1956). Penile intromission requires erection, and ejaculation typically requires sensory feedback from the penis that accumulates with multiple intromissions. The number of intromissions before ejaculation, the number of ejaculations achieved in a timed test, and the length of the postejaculatory interval are all dependent on autonomic arousal and can be enhanced or disrupted by drugs that have similar effects on copulatory performance in men (see Bitran & Hull, 1987; Dornan & Malsbury, 1989; Meisel & Sachs, 1994; Pfaus & Gorzalka, 1987, for selective reviews). For example, drugs that delay or abolish orgasm in men (e.g., selective serotonin reuptake inhibitors such as fluoxetine) increase the ejaculation latencies and reduce the total number of ejaculations in rats (Frank, Hendricks, & Olson, 2000; Yells, Prendergast, Hendricks, & Nakamura, 1994). As in men, the reduced ability to ejaculate is more pronounced in rats following long-term daily administration (Cantor, Binik, & Pfaus, 1999). Acute alcohol intoxication also delays ejaculation in men (Malatesta, Pollack, Wilbanks, & Adams, 1979) and in rats (Dewsbury, 1967; Pfaus & Pinel, 1989). Although tolerance to this effect appears to accrue contingently in rats (Pinel, Pfaus, & Christensen, 1991), it is not yet known if contingent or conditional tolerance occurs in humans to alcohol’s sexual effects with long-term use. A short ejaculation latency in rats, ejaculation with fewer than normal pre-ejaculatory intromissions, or an increased number of ejaculations in a timed test or before sexual exhaustion sets in suggests an enhancement of sympathetic arousal. Although at first glance, faster ejaculation and/or ejaculation with fewer intromissions suggest that the male may be a more “proficient” copulator, such behavior in the wild would be less likely to get a female rat pregnant (e.g., Adler, 1969) and should be considered a disruption of normal copulatory responding. Such behavior is more reminiscent of premature ejaculation in humans, and can be induced by drugs that stimulate sympathetic arousal (e.g., cocaine; Ferrari & Giuliani, 1997) or by experiential conditions that increase sympathetic arousal in sexual circumstances. For example, Larsson (1956) observed that male rats would ejaculate faster, and with fewer intromissions, if the stimulus female were removed from the test chamber for periods up to 1 min between successive intromissions. Although Larsson’s “Enforced Interval Effect” could constitute a rat analogue model of premature ejaculation, it remains to be seen whether drugs that can counteract premature ejaculation in men, such as alcohol or fluoxetine, can increase the latency of male rats to ejaculate in this condition.


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Classically conditioned stimuli are also capable of increasing sexual arousal as reflected by copulatory rate measures. Zamble and his colleagues (Zamble, Hadad, Mitchell, & Cutmore, 1985; Zamble, Mitchell, & Findlay, 1986) used placement of male rats in a holding cage as a conditioned stimulus to signal noncopulatory exposure to a receptive female behind a wire-mesh screen on several training trials. On test trials, they found that placing the males into the holding cage prior to unrestricted copulation resulted in significantly shorter latencies to intromit and ejaculate than if the conditioned stimulus was omitted. Subsequent studies found that second-order conditioned stimuli (e.g., a plastic toy fish found in the holding cage) were effective in enhancing the same measures of arousal (Zamble et al., 1985), and such conditioning in sexually naive or sluggish males could increase the proportion of males that copulate on a subsequent test (Cutmore & Zamble, 1988). Hollis, Cadieux, and Colbert (1989) demonstrated that repeatedly pairing a light with noncontact exposure to a receptive female resulted in conditioning of sexual behavior in male gouramies, a type of Labyrinth fish. They found that males receiving the conditioning treatment displayed significantly lower latencies to initiate copulation and lower levels of aggression toward females when the conditioned stimulus was presented before access to a female. Similar results have been demonstrated by Domjan and colleagues in birds, notably Japanese quail. Male quail that received repeated exposure to females following the presentation of a conditioned stimulus light displayed significantly shorter latencies to initiate copulation when the stimulus was present compared to when it was absent (e.g., Domjan, O’Vary, & Greene, 1988). Pfaus, Talianakis, and Kippin (2003) recently found evidence that somatosensory stimuli can be used to condition sexual arousal in male rats. Males that received prior sexual experience with receptive females while wearing a rodent harness jacket displayed slower intromission and ejaculation latencies if tested without the jacket than with it on. A rat model of conditioned sexual arousal would be useful as an analogy of psychogenic copulatory sexual arousal, or perhaps even the development of certain fetishes. However, the ability of conditioned stimuli to “prime” sexual arousal may depend on the association of neutral stimuli with sexual reward in addition to arousal (see the subsequent discussion of this point). In fact, pairing stimuli with sexual arousal per se, without sexual reward, may result in counterconditioning, in which males show lower levels of arousal in the presence of such stimuli. Female Sexual Arousal Physiological sexual arousal in women has not received nearly the same experimental attention as in men, in part because genital blood

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flow in women has been assumed to follow the same physiological and psychological rules as in men (Barlow, 1986). Certainly, drugs or stressful circumstances that block erections in men also block vaginal and possibly clitoral blood volume in women. However, clinical results with sildenafil in women with sexual arousal disorders have been inconclusive (Basson, McInnes, Smith, Hodgson, & Koppiker, 2002; Berman et al., 2001; Rosen, 2000). There may be real differences between men and women in patterns of sexual arousal and in the types of psychogenic stimuli that elicit genital blood flow (e.g., Palace & Gorzalka, 1990; Rosen & Beck, 1988). For example, women are reported to experience cyclic fluctuations in arousability and desire, with peak incidents of female-initiated sexual activity coinciding with ovulation (Wallen, 1995). Indeed, event related potentials (ERPs) that correspond to attention and stimulus processing for working memory (e.g., the P3 amplitude) increase following the presentation of sexually arousing pictures, but not pictures of babies or body care products, to women during the ovulatory phase (Krug, Plihal, Fehm, & Born, 2000). The same pictures do not activate those ERP components during other phases of the menstrual cycle, or in women taking oral contraceptives (Krug, Pietrowsky, Fehm, & Born, 1994). Timing may thus be extremely important when studying sexual arousal in women relative to men. Such a relationship has been established for rats and other species. Female rats display sexual “heat” only during the periovulatory period of their estrous cycle, a state that can be induced in ovariectomized rats by sequential administration of estrogen and progesterone (Bolling & Blandau, 1939). In vivo experimental models of genital arousal in female New Zealand White rabbits have been developed by Traish, Goldstein, and their colleagues (e.g., Kim et al., 2003; Min et al., 2003; Munarriz, Kim, Kim, Traish, & Goldstein, 2003; Park et al., 1997; Traish, Kim, Min, Munarriz, & Goldstein, 2002; Traish, Kim, Munarriz, Moreland, & Goldstein, 2002). In these models, electrical stimulation of the pelvic nerve is applied that mimics the type of stimulation normally received by females during vaginal intromission and results in increased vaginal blood flow, vaginal wall pressure, vaginal length, clitoral intracavernosal pressure and blood flow, and decreased vaginal luminal pressure. Similar effects have been reported following pelvic nerve stimulation in female rats (Giuliano et al., 2001; Vachon, Simmerman, Zahran, & Carrier, 2000). In addition to vaginal and clitoral blood flow responses, vaginal smooth muscle preparations have been developed to examine the ability of different neurotransmitters to induce muscle contraction and relaxation. These studies have shown that ovariectomy diminishes vaginal blood flow, lubrication, and epithelial cell morphology, and that


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treatment with estradiol restores these measures of vaginal response. Moreover, the nitric oxide-cyclic GMP pathway appears to be critical for vaginal blood flow, as it is for penile blood flow. Treatment with androgens facilitates vaginal nitric oxide synthase activity, along with vaginal smooth muscle relaxation. Although it is not yet known how these vaginal responses are integrated with behavioral responses, Whalen and Lauber (1986) hypothesized that cyclic GMP was a common target for drugs that substitute for progesterone in the facilitation of lordosis in rats. Inhibition of the ability of nitric oxide to stimulate cyclic GMP in the rat brain results in a profound disruption of lordosis (Chu & Etgen, 1997), suggesting that the brain is an important target for nitric oxide/GMP stimulated activation of lordosis. However, it remains an intriguing possibility that increased vaginal blood flow could be perceived by females and might help stimulate behavioral measures of sexual arousal. Such a relationship could be examined following inhibition of peripheral nitric oxide-cyclic GMP. Models of Sexual Desire Desire has always been difficult to define, which is why it remains something of a “holy grail” in sex research (see Levine, 2003; Pfaus, 1999). In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; American Psychiatric Association, 2000), the diagnosis of Hypoactive Sexual Desire Disorder is given when “desire for and fantasy about sexual activity are chronically or recurrently deficient or absent.” By converse logic, then, sexual desire is the presence of desire for, and fantasy about, sexual activity. This definition appears coherent but is circular. How does desire manifest itself? Many clinicians and motivational theorists alike view desire as distinct from arousal in both animals and humans. This is apparent in the DSM’s categorization of arousal disorders distinct from desire disorders, a distinction that generally reflects blood flow to the genitals and erectile tissues versus a “psychological” sexual interest in which individuals “want” or “crave” sex (with wanting and craving defined here as in Robinson & Berridge, 1993, for drugs of abuse). In practice, however, desire may well be informed or even confirmed by the presence of autonomic and central responses that define arousal, and there is growing evidence that people regard desire and arousal as parts of one another, despite being given distinct definitions (e.g., Basson, 2001; Toledano & Pfaus, 2003). When an individual expresses sexual desire behaviorally, it follows that attention and behavior focus on obtaining some form of positive sexual reinforcement. This can occur alone in fantasies or together with others in goal-directed social and sexual behaviors. Thus,

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in addition to people stating colloquially that they feel “horny” (with or without corresponding arousal), desire encompasses the work people will perform to obtain sexual rewards, the excitement displayed in anticipation of such rewards, and the strength of the incentive value ascribed to a particular sexual stimulus. Like people, animals manifest sexual excitement behaviorally. They will increase their motor output in anticipation of copulation and work for the opportunity to copulate or to obtain primary or secondary (conditioned) sexual rewards associated with copulation. Animals will also choose between two or more sexual incentives based on the strength of the incentive cues and the animal’s own internal drive state. What characterizes these behaviors is that they occur before copulation: Courtship, operant responses, conditioned locomotion in anticipation of sex, time spent near a particular sexual incentive, or choices made between two or more incentives can all be considered analogies of anticipatory sexual desire. The strength of the behavior can be observed as increases or decreases, or can be tested by increasing the criterion level of responding that animals must attain before they are given access to rewards. Simply put, animals with more “desire” will display more robust behavior than animals with less desire. Desire can also be inferred from certain appetitive behaviors that occur during copulation. A growing body of evidence indicates that these aspects of sexual behavior are altered in a relatively selective fashion by certain drugs that are known to alter desire in humans. Anticipatory Motor Responses Male rats in bilevel chambers (see Figure 2) display an increase in level changing in anticipation of the arrival of a sexually receptive female (Pfaus, Mendelson, et al., 1990; van Furth & van Ree, 1996a, 1996b). Typically, males are placed into the testing chamber for a 5-min adaptation period prior to the placement of a receptive female. The anticipatory behaviors develop naturally over a few trials but do not develop if the chamber is baited with an ovariectomized (nonreceptive) female or another male. Dopamine receptor antagonists decrease the number of anticipatory level changes displayed by male rats in bilevel chambers at doses that do not alter copulatory responses once receptive females are placed into the chamber (Pfaus & Phillips, 1991). Interestingly, a loss of desire and interest in sex is a common complaint among patients taking these drugs as major tranquilizers (Crenshaw & Goldberg, 1996). Long-term use of the stimulant drug cocaine is also reported to decrease sexual desire in men (MacDonald, Waldorf, Reinarman, & Murphy, 1988; Siegel, 1982; Washton & Gold, 1984). We have


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recently found that long-term administration of cocaine to sexually active male rats decreases conditioned level changes progressively over time (Pfaus, Benibgui, DiPietro, Wilkins, & Schattmann, 2003). Instrumental Responding for Primary or Secondary Sexual Incentives All animals will work to obtain sexual rewards, and such behavior can be viewed as analogous to desire. Sexual rewards may come in the form of primary reinforcers (e.g., orgasm in humans; ejaculation in male rats or pacing in female rats), or secondary reinforcers, such as stimuli associated with sexual gratification (e.g., certain facial features, clothes, or smells in humans; certain odors or place cues in rats). In male rats, those behaviors have included performance in obstruction boxes (Jenkins, 1928; Moss, 1924; Stone, Barker & Tomlin, 1935; Warner 1927), straight-alley running (Beach & Jordan, 1956a; Sheffield, Wulff, & Backer, 1951; Ware, 1968), maze learning (Drewett, 1973; Eliasson & Meyerson, 1975; Hetta & Meyerson, 1978; Kagan, 1955; Meyerson & Lindstrom, 1973; Warner et al., 1991; Whalen, 1961), crossing of electrified grids (Moss, 1924), nose-poking, and other attempts to “get to” a potential sex partner behind a wire-mesh screen (Damsma, Pfaus, Wenkstern, Phillips, & Fibiger, 1992; Pfaus, Damsma, et al., 1990; Pfaus, Damsma, Wenkstern, & Fibiger, 1995), digging through sand (Anderson, 1938), bar-pressing for a sex partner (Beck, 1971, 1974, 1978; Beck & Chmielewska, 1976; French, Fitzpatrick, & Law, 1972; Jowaisas, Taylor, Dewsbury, & Malagodi, 1971; Larsson, 1956; Sachs, Macaione, & Fegy, 1974; Schwartz, 1956), or for light cues associated with the arrival of a sex partner (Everitt et al., 1987; Everitt & Stacey, 1987). Indeed, to gain access to receptive females male guinea pigs will learn to run an alley (Seward & Seward, 1940), male pigeons will learn to peck keys (Gilbertson, 1975), and male stickleback fish will learn to swim through rings (Sevenster, 1973). Some appetitive instrumental sexual responses are expressed easily, without much prior experience (e.g., nose-pokes, digging, obstruction box performance, crossing electrified grids), whereas others require some degree of training (maze learning, bar pressing). Those behaviors can be reduced following castration, indicating that gonadal steroid actions in the brain are necessary for their development and/or maintenance, or following lesions of certain steroid-concentrating brain regions (e.g., basolateral amygdala [Everitt et al., 1987; Nissen 1929]). They can also be reduced after a devaluation of the reward offered by the incentive the male is working for (e.g., switching from receptive female to no female, an extinction procedure), or following infusions of dopamine antagonists to the nucleus accumbens (Everitt, 1990; Mendelson &

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Pfaus, 1989). Restoration of bar pressing in male rats with lesions of the basolateral amygdala can be made following infusions of amphetamine to the nucleus accumbens, indicating that mesolimbic dopamine release is critical for the expression of that behavior, and suggesting that the extensive glutamate projections from the basolateral amygdala to the nucleus accumbens modulate dopamine release (Everitt, 1990). Dopamine antagonists administered systemically to male rats reduce running speed in a runway that leads to a goal box containing a sexually receptive female (López & Ettenberg, 2001). Antagonists infused to the medial preoptic area of the hypothalamus disrupt maze learning for sexual reinforcement in male rats (Warner et al., 1991). It is likely that different dopamine terminal regions play a role in different types of unconditioned and conditioned sexual activity. Although many of these paradigms have been in the literature for over 50 years, they have not been mined extensively by sex researchers to study the effects of drugs that activate or inhibit other neurotransmitter systems. Likewise, they have been applied sparingly to females. Bermant (1961) and Bermant and Westbrook (1966) reported that female rats would bar-press for access to gonadally intact, sexually active males. More recently, Matthews et al. (1997) reported that access to intromissions from a male that were made contingent on poking a lever with the nose increased the incidents of nose-poking in sexually receptive female rats. Contingent access to male bedding or emulsified preputial gland did not support increases in behavior, indicating that the copulatory stimulation was rewarding. The paradigm used by Matthews et al. ensured that females could control or “pace” the rate of copulation, a characteristic of copulatory interaction that female rats find rewarding (see the subsequent discussion of this point). Becker and colleagues (Becker, Rudick, & Jenkins, 2001; Jenkins & Becker, 2003; Mermelstein & Becker, 1995) found increased dopamine release in the striatum and nucleus accumbens of females that had to press a lever to gain access to a male, or run back and forth from behind an opaque barrier, relative to females that did not. Indeed, lesions of the striatum reduced the efficiency of females to pace the copulatory interactions, whereas lesions of the nucleus accumbens resulted in females that avoided sexual contact (Jenkins & Becker, 2001). Sexual Preference Paradigms Sexual desire can be inferred from the strength of preference made toward particular features of a person or conspecific, or toward a place in which potential sex partners have been found in the past. As with other instrumental responses, preferences are typically displayed prior


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to sexual interaction so that animals and people can focus their forward trajectories toward sexual incentives. In humans, preferences exist for gender, and within gender for certain individually defined physical features that people find attractive (shape of face, smile, eye or hair color, body type, etc). Preferences also exist for scents, for certain types of clothing, even for fetish objects. There are likely as many combinations of these as there are people, and the role of such preferences is to focus the attention of individuals on other individuals so that sexual interactions can occur. Some preferences are determined by particular cultures or epochs within a culture, whereas others are learned during a critical period of sexual behavior development, especially during an individual’s first sexual experiences. Some may be genetic. However, what is clear is that the association of particular features with sexual gratification entices people to seek out those features in future sexual interactions, even if those interactions are made at a distance or are part of a rich fantasy life. We would never deny that preferences exist in humans that are conditioned by experience; yet arguments continue to be made that the sexual preferences of animals (and even humans) are hard-wired for ultimate reproductive success and fitness, rather than more proximate rewards, such as sexual pleasure (e.g., Buss, 1994; Symons, 1979). Is this true? Certainly animals do not exist within a social organization that approximates human culture and, therefore, are not subject to moral restrictions or the whims of advertising executives. However, recent evidence indicates that animals do show preferences for specific features, many of which are learned during experience with sexual reward, rather than driven instinctually to maximize reproductive fitness. This latter dimension represents an exciting new foray into a level of animal behavior that approximates our own. Some preferences seem instinctual and hard-wired by hormonal influences on the brain. For example, numerous researchers have shown that male rats spend more time near sexually receptive compared to nonreceptive females (Edwards & Einhorn, 1986; Hetta & Meyerson, 1978; Merkx, 1983). Likewise, sexually receptive females spend more time near gonadally intact, sexually active males versus castrated, sexually inactive males (Gilman & Westbrook, 1978). Male rats also show unconditioned preferences for the odors of sexually receptive versus nonreceptive females (Bakker, van Ophemert, & Slob, 1996; Carr, Wylie, & Loeb, 1970; Stern 1970). These studies have been conducted in Y-mazes, T-mazes, radial-arm mazes, or open fields, that contain goal boxes baited with tethered receptive versus nonreceptive conspecifics (e.g., Gilman & Westbrook, 1978), different conspecifics behind wire-mesh screens (e.g., Ågmo, 2003a, 2003b; Bakker et al.,

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1996), or in which different anesthetized stimulus animals are contained at opposite ends (e.g., Landauer, Wiese, & Carr, 1977). Castration of male rats abolishes their preference to remain near a sexually receptive female, whereas replacement with testosterone restores the preference (Ågmo, 2003a). Moreover, intact, sexually experienced males display significant preferences for sexually receptive females versus nonreceptive females and for sexually receptive females versus males, but not for sexually nonreceptive females versus males. Those data suggest that amount of time spent near the receptive female is based on the intensity of her olfactory cues. Indeed, Ågmo reported that the intensity of preference for a live receptive female could be generated by bedding that contained estrous odors, suggesting that olfactory cues are important sensory determinants of incentive value in the rat. Estrous odors are known to induce dopamine release unconditionally in the nucleus accumbens of intact, sexually inexperienced male rats (Mitchell & Gratton, 1991, 1992; Wenkstern, Pfaus, & Fibiger, 1993), and such odors increase neural activation in several key brain regions known from lesion studies to be critical for male sexual behavior, including the medial preoptic area, bed nucleus of the stria terminalis, medial amygdala, nucleus accumbens, and ventral tegmental area (Bialy & Kaczmarek, 1996; Bressler & Baum, 1996; Kippin, Cain & Pfaus, 2003; Newman, Parfitt, & Kollack-Walker, 1997; Pfaus & Heeb, 1997, Swann & Fiber, 1997; Veening & Coolen, 1998). The studies of Mitchell and Gratton (1991, 1992) are of particular interest because they suggest that endogenous opioid release in the ventral tegmental area occurs in response to estrous odor cues, and this release in turn disinhibits ascending mesolimbic dopamine neurons. However, systemic treatment with a dopamine agonist or antagonist (amphetamine, cis-flupenthixol) or opioid agonist or antagonist (morphine, naloxone) did not alter the amount of time sexually experienced males spent near a sexually receptive versus nonreceptive female in an open field, except at higher doses that induced motor deficits (Ågmo, 2003a). Although Ågmo’s data suggest that dopamine and opioid systems are not necessary for the processing of unconditioned incentive cues, infusions of the dopamine antagonist cis-flupenthixol to the ventral tegmental area of male rats decreases the percentage of time spent near a sexually receptive female in an X-maze (Warner et al., 1991), and infusions of the dopamine antagonist haloperidol to the nucleus accumbens or medial preoptic area decreases conditioned level changing in bilevel chambers (Pfaus & Phillips, 1991). It is also known that sexually experienced males are relatively resistant to many treatments that disrupt sexual behavior in inexperienced males, including castration,


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penile anesthesia, novelty of a testing chamber, olfactory deprivation, and age (Gray, Smith, Dorsa, & Davidson, 1981; Lisk & Heiman, 1980; Lodder, 1975; Pfaus et al., 2001; Pfaus & Wilkins, 1995; Thor & Flannelly, 1977). It is not clear whether experience may have buffered Ågmo’s males from the effects of dopaminergic or opioid drugs. The kinds of studies outlined above are considered “pure” measures of preference because they are not confounded with copulation. However, that fact leads to the question of what is actually being studied. Meisel and Sachs (1994) noted that, in the absence of the opportunity to engage in sexual behavior, the choice to spend time near one conspecific over another could reflect sexual preference but could also be measuring social affiliation, opportunity to engage in aggression, curiosity, or a reaction to other incentive aspects of the stimulus animal that have nothing to do with sexual behavior. This concern was partially addressed in the study mentioned above by Ågmo (2003a): Sexually experienced males displayed selective preferences for sexually receptive females but had no preference when the choice was between sexually nonreceptive females and other males. Indeed, although these kind of preferences are displayed by sexually naive males, they are not as strong as those displayed by sexually experienced males (Carr, Loeb, & Wylie, 1966), indicating that sexual experience increases the incentive value of sex-related odors in the rat. Repeated exposure to estrous odors is known to sensitize mesolimbic dopamine release (Mitchell & Gratton, 1992), and intermittent exposure to amphetamine, which also sensitizes mesolimbic dopamine release, facilitates copulatory behavior in sexually naive male rats (Fiorino & Phillips, 1999). Some preferences are not instinctual, in the sense of being hardwired, but rather reflect a process of Pavlovian conditioning in which neutral stimuli associated with sexual reward become conditioned sexual incentives. Such conditioned preferences can be assessed along with copulation in sequence. For example, Domjan and colleagues have examined conditioned preferences in the seasonally monogamous Japanese quail. Male Japanese quail respond differentially to females based on the presence of stimuli previously paired with copulation. Nash and Domjan (1991) allowed male quail to copulate with females of two strains of quail that have different plumage color (brown versus blond). Subsequently, males chose to spend more time in the proximity of females whose color was the same as that of females with whom they had copulated previously. Similarly, males allowed to copulate with females that were adorned with bright orange feathers subsequently spent more time near, and engaged in more sexual activity with, females similarly adorned compared to unadorned females. Moreover,

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males trained with adorned females attempted to copulate with a taxidermic model of a female quail, but only when it was adorned with the same color feathers (Domjan et al., 1988). Domjan and Hall (1986) also demonstrated that males would stay in the vicinity of a window in their home cage through which they could see a sexually receptive female during a precopulatory period. However, this behavior developed only if the males had the opportunity to copulate with the female after the precopulatory period. A variant of this procedure, similar to that used to study anticipatory motor responding in rats, was used by Balthazart and colleagues to study the role of hormones and brain dopamine systems in conditioned sexual behavior in quail. Male quail were placed into a chamber that contained a window and sliding door at one end through which the male could see a sexually receptive female. After a 10-min period, the sliding door opened, and the animals could interact freely (Balthazart, Reid, Absil, Foidart, & Ball, 1995). As in Domjan and Hall (1986) and Mendelson and Pfaus (1989), only males that copulated with the females during this period developed the behavior, in this case, a preference to stay close to the window in the precopulatory period of subsequent tests. Castrated males did not develop this conditioned proximity behavior, nor did males that did not copulate. Castration also reduced the time spent near the window in males trained prior to castration, and subsequent replacement with testosterone or estradiol restored the behavior. Subsequently, Castagna, Ball, and Balthazart (1997) reported that nomifensine, a dopamine re-uptake inhibitor, decreased the appetitive social proximity response but increased the frequency of mount attempts. In contrast, amfonelic acid, a compound that enhances dopaminergic tone, increased aspects of both appetitive and consummatory sexual behaviors. Thus, brain dopamine systems in birds and mammals seem to have analogous functions in the control of appetitive or conditioned sexual behaviors. We have developed a model to examine the role of associative learning on sexual partner preferences in male and female rats during sexual interaction. Kippin et al. (1998) trained male rats to associate a neutral odor (almond or lemon extract) with copulation to ejaculation in either bilevel or pacing chambers (see Figures 2 and 3). The odor was dabbed around the back of the female’s neck and anogenital area, two regions that the male reliably places his nose during copulation. Males in several control groups were either not exposed to the odor or had the odor randomly paired with sexually receptive and nonreceptive females. On a final test, each male was presented with two receptive females in a large open field (see Figure 4, top). One female was scented with the odor, whereas the other was left unscented. The males were allowed to


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copulate freely with both females for 30 min. Males in the control groups did not show a preference for either female for first mount, intromission, or ejaculation, or for the total number of mounts, intromissions, or ejaculations displayed throughout the test. In contrast, although males in the paired group did not show a preference of female for mounts or intromissions, they chose the scented female for their first ejaculation, and displayed significantly more ejaculations overall with that female compared to the unscented female (see Figure 5). Thus, a

Figure 4. Open field partner preference paradigm. Top—Males are placed into the open field for 5 min, after which two receptive females, one bearing a conditioned cue (e.g., odor) and one without the conditioned cue are presented at opposite corners. Latency and frequency measures for mounts, intromissions, and ejaculations are then calculated for each female during a 30-min test. Choice of female for first mount, intromission, or ejaculation, and the distribution of these measures across the test, are then determined for each male. Bottom—The same preference test for females. Females are placed into the open field that already contains two sexually vigorous males, one bearing the conditioned cue and one without the cue. Because males tested in pairs with a single female will crawl over one another, they must wear rodent jackets that are tethered to opposite corners of the open field by a spring. Females can then “sample” both males, or display a preference for a single male by staying in his vicinity. Latency and frequency measures for mounts, intromissions, and ejaculations are calculated for each male, along with proceptive measures of solicitation and hops and darts, and defensive responses. Choice of male for first mount, intromission, or ejaculation, and the distribution of these measures across the test, are then determined for each female.

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Figure 5. Partner preference of male rats for female rats either bearing an odor cue (e.g., almond) that was paired with sexual reward (i.e., ejaculation and the central state it induced during postejaculatory interval), explicitly unpaired with reward, or randomly paired. Note that males in the paired group copulate indiscriminately but ejaculate preferentially with the female bearing the conditioned cue. However, males in the unpaired or random groups do not display an ejaculatory preference for the female. Data are adapted from Kippin et al. (1998) and reprinted with permission. *p < 0.05.


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simple odor-conditioning paradigm reversed what is typically considered a hard-wired biological predisposition in the polygamous male rat to prefer a novel partner over a familiar partner (Symons, 1979). In subsequent studies, we identified the postejaculatory interval, rather than ejaculation per se, as the critical unconditioned stimulus for the development of this preference (Kippin & Pfaus, 2001a). Significant conditioning also occurred after the male’s very first ejaculation, although it was considerably stronger if the males had multiejaculatory trials with the scented female (Kippin, Samaha, Sotiropoulos, & Pfaus, 2001). Males were found to become “choosy” during their last few mounts before ejaculation (Kippin & Pfaus, 2001b), and males in the paired group were more likely to attempt to mount sexually nonreceptive females scented with the conditioned odor, indicating that the odor acquired conditioned excitatory properties. When presented alone, the conditioned odor activated regions of the brain associated with olfactory processing and reward, including the main olfactory bulb, main olfactory (piriform) cortex, basolateral amygdala, and core of the nucleus accumbens (Kippin, Cain, & Pfaus, 2003). Those findings suggest that estrous odors and sexually conditioned odors are processed by distinct pathways that may converge in the ventral striatum. We have found similar results in female rats (Coria-Avila, Haley, Manzo, Pacheco, & Pfaus, 2001). In those studies, the odor was paired with a different unconditioned stimulus: The ability of females to pace the copulatory contact. This was done using a pacing chamber similar to that described by Erskine (1989) and Paredes and Alonso (1997) in which a Plexiglas divider is placed in the middle of the chamber (see Figure 3). The bottom of the divider has one or more holes cut out that are small enough for the female to pass through, but too small for the male, thus the female can regulate her contact with the male simply by running from side to side. During training, females in the paired group received sequential access to scented males on one side of the divider or unscented males with no divider, on alternate testing days. Females in the explicitly unpaired group received the opposite order of experience. On the final test, each female was placed into an open field with two intact, sexually experienced males, both tethered to opposite sides of the open field (see Figure 4, bottom). One male was scented and the other was not. Females in both groups were significantly more likely to solicit and receive their first intromissions from the male paired with pacing. However, only females in the paired group show a significant preference to stay with that male for their first ejaculation; females in the unpaired group did not show a conditioned ejaculatory preference (see Figure 6). The selective copulation and mating behavior on the part

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Figure 6. Partner preference of female rats for male rats either bearing an odor cue (e.g., almond) that was paired with sexual reward (i.e., the ability of females to pace the copulatory contact in pacing chambers bisected by the 4-hole divider) or unpaired with reward. Note that females in both the paired and unpaired group receive their first intromission from the male paired with pacing (scented male in the paired group, unscented male in the unpaired group). However, only females in the paired group subsequently solicit and receive their first ejaculation preferentially from the scented male. Females in the unpaired group did not display any copulatory or ejaculatory preference after their first intromission. Data are from Coria et al. (2002). * p < 0.05>


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of females in the paired group would be expected to assure paternity (Coria-Avila, Pfaus, Hernandez, Manzo, & Pacheco, in press). Implications of this are discussed below. Desire in Copulatory Measures Sexual desire can also be inferred from certain unconditioned copulatory measures. For example, the rate at which female rats will solicit and pace their copulatory contact with males, and the willingness of males to chase females, can be considered analogues of desire (and possibly arousal). These measures can be recorded unambiguously in bilevel chambers, pacing chambers, mazes, or choice boxes (e.g., Ågmo, 2003a, 2003b). Solicitations by the female usually result in mounts and intromissions by the male. Following intromission, the female runs away in order to “pace” the rate of copulation. In an open field or in bilevel chambers, the male typically chases her until she stops again and holds a lordosis crouch, allowing him to mount. If the male stops chasing, then she will have to solicit to initiate another bout of copulation. Essentially, pacing refers to the amount of temporal distance the female keeps from the male between bouts of copulatory activity. This measure is inversely related to her degree of sexual interest; for example, the timing between intromissions increases with successive intromissions, and increases dramatically following several ejaculations (Pfaus et al., 1999). Rates of pacing are also much larger in ovariectomized female rats primed with estrogen but not progesterone, relative to females primed with both hormones. To the extent that solicitation and pacing reflect inversely a general desire for sexual contact, then experimental treatments that increase solicitations and/or keep pacing durations low, may increase desire in women. For example, ovariectomized female rats primed with estrogen and progesterone, or estrogen alone, and administered the melanocortin agonist PT-141, display a dramatic and selective increase in solicitations (Pfaus, Shadiack, van Soest, Tse, & Molinoff, 2003). Although in recent Phase I clinical trials, this drug was shown to increase vaginal arousal in women viewing a femalecentric erotic film (A. Shadiack, personal communication, September 26, 2002), it remains to be tested whether this drug will increase their desire for sex in appropriate circumstances, or as measured by paperand-pencil tests of sexual arousal and desire. If so, then solicitation in female rats can be considered an analogue of sexual desire in women. Another feminine copulatory behavior that is taken as a measure of the willingness to have sex is lordosis, the arching of the back displayed by female rats (and other species) that indicates their sexual “receptivity” (Beach, 1976). More is known about the hormonal, neurochemical,

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and neuroanatomical control of lordosis than any other mammalian sexual behavior (Pfaff, 1980; Pfaff et al., 1994). This reflex is dependent on estrogen, although treating ovariectomized females with estrogen alone produces only a moderate activation of the reflex in response to flank stimulation by the male. Full receptivity depends on additional activation by progesterone. Indeed, so does the full expression of proceptive behaviors like solicitation, and the normally low expression of pacing (Beach, 1976; Pfaus et al., 1999). Drugs that bind to D1 dopamine receptors, α1 adrenergic receptors, oxytocin receptors, opioid receptors, or GABA receptors in certain hypothalamic brain regions can increase lordosis in ovariectomized rats primed with estrogen alone (e.g., see Kow, Mobbs, & Pfaff, 1994; Pfaff, 1999, for reviews). These substances may work on neurochemical substrates normally activated by progesterone or could work via cell-signalling cascades that activate progesterone receptors (e.g., as has been described by Mani, Allen, Clark, Blaustein, & O’Malley, 1994, for dopamine in the ventromedial hypothalamus). If these drugs also enhance solicitations and delay the increase in pacing normally observed at the beginning of estrus termination, they might stand as suitable candidates for the treatment of hypoactive sexual desire disorder. In males, the willingness to mount, intromit, and pursue females can be used as analogues of male desire. Several drugs are known to decrease mount and intromission latencies in sexually naive or sluggish male rats, including the opioid receptor antagonist naloxone (Gessa, Paglietti, & Quarantotti, 1979; McIntosh, Vallano, & Barfield, 1980; Pfaus & Gorzalka, 1987). Although chasing behavior displayed by male rats in open fields or bilevel chambers has not been studied in detail, it was noted that dopamine antagonists reduced this behavior in bilevel chambers at doses that did not alter the initiation of copulation (Pfaus & Phillips, 1991). Models of Sexual Reward Like the expression of sexual desire, sexual reward has many faces and states of being. This alone makes it difficult to define what is and is not rewarding for any person or within a culture. Moreover, sexual behavior may occur for reasons that have nothing to do with sexual gratification per se. But using sexual reward as a general concept presents us with a more pervasive problem—its association in psychology with positive reinforcement. Positive reinforcers are traditionally considered events or stimuli that increase the probability of subsequent behavior (e.g., Ferster & Skinner, 1957). Small food pellets are positive reinforcers to hungry rats because they increase instrumental responding. Playing with one’s


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hair or sideways glances during a bout of flirting would also be considered positive reinforcers if they increase the degree of responding between the flirting pair (Perper, 1985). Now consider satiety. All behaviors have a beginning, middle, and end, and satiety mechanisms place negative feedback on behavior by activating inhibitory neural pathways. Satiety mechanisms are absolutely critical for any regulatory behavior (e.g., Toates, 1992). Is satiety rewarding? In the short term, consuming a large meal or copulating to sexual exhaustion decreases responding for food or sexual incentives. Fortunately, meals can be broken up into small bits that maintain operant responding for them. Sex partners cannot. This was the reason that Everitt et al. (1987) used a stimulus light that predicted the arrival of a sex partner. The light acted as a conditioned reinforcer that could be presented for brief periods, and doing so supported relatively high rates of operant responding. If positive reinforcement equals reward, then satiety cannot be rewarding because it suppresses ongoing behavior. It is easy to see how theories of human sexual reward can be hindered by conflicting definitions of reward, reinforcement, and satiety: Flirtations are unambiguously rewarding if they lead to more behavioral output. However, orgasms would be rewarding only if they lead to more sexual activity; they could not be considered rewarding if they induce a period of sexual refractoriness. In any motivational system, reward should be considered a dynamic function with an inverted U-shaped relationship to ongoing behavior: Low rewards do not sustain behavior, moderate to ideal rewards do, and high rewards induce the inhibitory feedback that characterizes satiety. With regard to sexual behavior, rewards that sustain sexual arousal and desire might be considered low-to-moderate, whereas high rewards, such as orgasm, might be those that induce a period of sexual refractoriness. The reward value of satiety may also depend on the time frame. Although sexual satiety decreases sexual responding in the short term, the reward associated with it in male and female rats is necessary for the conditioning of sexual preferences in the long term. A final note of caution: In the study of feeding, satiety lies on a continuum to aversion where continued food ingestion after one is full leads to emesis. Likewise, continued genital stimulation after orgasm can be experienced as aversive in both men and women (Masters, Johnson, & Kolodny, 1983), although the nature of the sensation is obviously different. Responding for Sexual Reinforcers How do we infer sexual reward in animals? There are at least three ways. The first involves assessments of operant or instrumental responding for a particular sexual reinforcer. Anything an animal must

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do to get closer to, or to obtain, the reward can be assessed in this manner. In rats, this would include behaviors such as nose-poking through a wire-mesh screen, navigating obstruction boxes or complex mazes, or bar-pressing for first- or second-order reinforcers. The inference here is simple (albeit circular): If the animal will work for it, it must be reinforcing. But Meisel and Sachs’ (1994) caveat for understanding preference without copulation also applies here: Without knowing what animals will actually do with the reinforcer once they obtain it, it is difficult to know exactly what the motivation was behind the responding and hence difficult to specify what was rewarding about the stimulus in the first place. Consider male rats with bilateral lesions of the medial preoptic area. Those rats display normal or even elevated rates of anogenital investigation of a receptive female and will pursue females if solicited (Everitt et al., 1987; Heimer & Larsson, 1967). They will even bar-press at high rates to obtain second-order sexual reinforcers (Everitt & Stacey, 1987). However, they cannot translate that arousal and desire into copulation. The female is clearly a reinforcer, but the males cannot do the one thing required to “prove” that it is sexual. Reward in Copulatory Measures The second way to infer sexual reward is based on copulatory activity. Indeed, solicitation and pacing in female rats, and courting, chasing, or other copulatory rate measures in male rats, can all be construed as indices of the reward value of the stimulus animal. These behaviors are also operants in the sense that animals must perform them in order to achieve the goal of copulatory interaction/sexual stimulation. Beach (1956) originally proposed that two separate but interactive sexual mechanisms existed in male rats, an Arousal Mechanism (AM) and Copulatory Mechanism (CM). The AM integrated distal olfactory, auditory, and visual cues from receptive females. When the cue strength became sufficiently intense, the AM activated the CM to initiate copulatory responding (mounts and intromissions). The CM then integrated somatosensory stimulation from the penis with each vaginal intromission, leading eventually to ejaculation. Given the fact that sexually naive males can show preferences for receptive females and that they are responsive to sex odors from receptive females, the first unconditioned reinforcer in the cascade of sexual reinforcers would be sex odors. The goal would be getting to them. In Beach’s terms, this would be the primary function of the AM. But what about copulation? Whalen (1961) asked what the necessary stimulation must be for the development of copulatory behavior. The answer was penile stimulation. Whalen varied whether males achieved mounts without intromission, intromissions


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without ejaculation, or intromissions with ejaculation, with sexually receptive females. On a final test, males were allowed to copulate to ejaculation with receptive females. Many rats that achieved only mounts during their sexual experience trials did not copulate, whereas rats that achieved intromissions with or without ejaculation were able to copulate to ejaculation normally. Thus, exposure to sex odors alone was not sufficient to crystallize patterns of copulation; sensory feedback from penile stimulation was necessary. This makes penile stimulation a second goal or reinforcer in the cascade (and the first of the CM). Related to penile stimulation is the fact that the male is chasing a moving target: A soliciting and pacing female generates much excitement for the male during copulation. As mentioned above, the female often directs the behavior of the male by forcing him to chase her. Pacing behavior in bilevel chambers typically increases dramatically as the male approaches ejaculation, in a natural expression of Larsson’s “Enforced Interval Effect” (Pfaus et al., 1999). This increased pacing almost always results in the male ejaculating. Everitt (1990) reported that sexually vigorous male rats given subthreshold neurochemical lesions of the mesolimbic dopamine system initiated copulation normally with sexually receptive and proceptive females. However, if the females were treated with the dopamine receptor antagonist flupenthixol (which has the effect of prolonging the time spent in lordosis and eliminating proceptive solicitation and pacing), the males took significantly longer to initiate copulation. The next copulatory goal or reinforcer is ejaculation. López, Olster, and Ettenberg (1999) asked whether sexually naive rats would show decreased run times in a straight-arm runway if their prior copulatory experience was intromissions with or without ejaculation. Only rats that achieved ejaculation showed decreased run times. Thus, it would seem that a cascade of reinforcing events, from perception of sex odors to chasing receptive females to penile stimulation during mounting to ejaculation, is necessary for the normal display of appetitive and consummatory sexual responses. However, ejaculation itself may not be the final endpoint in the cascade of copulatory reinforcers for male rats. In the odor-conditioning studies mentioned previously, the postejaculatory refractory period was identified as the necessary unconditioned stimulus for the development of the preference in the paired groups (Kippin & Pfaus, 2001a). Ejaculatory preferences developed only if males were allowed to be in close proximity of the odor during the postejaculatory period. If the females were removed immediately after ejaculation, no preference developed. Moreover, if males were allowed to achieve only five intromissions without ejaculation prior to the removal of the

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scented female, they displayed the opposite preference in the final choice test and ejaculated preferentially with the unscented female (despite having never had access to an unscented receptive female before). Finally, a small but significant ejaculatory preference developed if males copulated with an unscented female but had her replaced with a scented female during the postejaculatory refractory period. Thus, ejaculation induces a powerful reward state that occurs during the postejaculatory interval. Experience with an ejaculatory sexual reward can also alter the incentive properties of an unconditionally aversive odor (cadaverine) applied to the neck and anogenital region of female rats (Pfaus et al., 2001). During conditioning trials, male rats copulated with cadaverinescented females. Subsequently, when males were given a final openfield test with two receptive females, one scented with cadaverine and one unscented, males in the paired group did not show any preference for either female. In contrast, males in the unpaired group copulated exclusively with the unscented female, despite aggressive solicitations and interceptions by the scented female. Indeed, in a final test, males in the paired group would approach and chew on a wooden dowel scented with cadaverine, whereas males in the unpaired group, or in a cadaverine-alone preexposure group, would avoid contact with the dowel, or would bury the dowel in bedding. Pairing an aversive stimulus with drug reward has been shown previously to induce taste preferences for initially nonpreferred flavors (e.g., a bitter taste paired with the consequences of morphine in rats; Zellner, Berridge, Grill, & Ternes, 1983). The same basic phenomenon, pairing sexual reward with a highly arousing circumstance—whether aversive or appetitive, painful or pleasurable—may underlie the development of certain human sex behavior preferences or fetishes (see Krafft-Ebing, 1928). Conditioned Place Preference Contextual factors, such as settings, are important components of positive sexual experiences for both men and women (e.g., Basson, 2001; Hoon, 1984; Kinsey, Pomeroy, & Martin, 1948; Kinsey, Pomeroy, Martin, & Gebhard, 1953; McCarthy, 1977). Salient cues in the environment may be associated with sexual reward in such a way that they increase arousal or desire directly in their presence. Accordingly, the third way to infer sexual reward is to examine responses made toward contextual cues paired with sexual reward. With animals, this can be done using the conditioned place preference (CPP) paradigm. Animals often display a preference to remain in a context that has been paired consistently with access to a reward (e.g., drugs of abuse, highly palatable foods, a


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mate) over a context that has not. This type of CPP is typically demonstrated in an apparatus with two distinctive compartments that are connected to either side of a third neutral compartment (Figure 7). During training, the compartments are paired differentially with unconditional stimuli, (e.g., one side is paired with a sex partner, food, or a rewarding drug, and the other side is paired with either nothing or a control manipulation). On the final test, the subject is placed into the neutral compartment with the two doors on either side opened to allow free access to either compartment (Figure 7). CPP is said to have developed if the subject spends significantly more time in the reward-paired compartment than the other compartment. Stimuli or events that are capable of supporting CPP are referred to as “rewards” rather than “reinforcers,” because the subject has never been required to move into the paired compartment to experience them. Thus, CPP is not reinforced, per se, because it is displayed spontaneously on the final test.

Figure 7. Conditioned place preference (CPP) apparatus. Animals are placed into one distinctive side of the CPP box following a particular type of sexual stimulation, and into the other distinctive side following a different type of stimulation (or no stimulation). On a final test, the animal is placed into the start compartment between the two sides. The doors are raised and the animal is then allowed free access to both sides. The amount of time spent on either side is recorded automatically by photobeams connected to a computer. A particular stimulus is considered rewarding if the animal spends significantly more time in the side associated with it compared to the other side associated with a control stimulus.

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However, the increased time spent in the side paired with reward is clearly conditional upon the Pavlovian association of those contextual cues with the reward state. In male rats, sexual CPPs have been established using two different conditioning procedures. In one procedure, copulation to ejaculation is allowed to occur within one of the distinctive environments, and this environment is subsequently preferred over one in which no copulation occurred (Everitt, 1990). CPPs developed by this procedure are referred to as “copulatory CPPs.” Copulatory CPPs can be maintained by intromissions alone, whereas prevention of intromission disrupts a previously established CPP (Hughes, Everitt, & Herbert, 1990). In a second procedure, male rats are allowed to copulate to ejaculation in a separate testing chamber, and are then transferred immediately to one distinctive compartment of the CPP apparatus. As with the first testing procedure, the other distinctive compartment is paired on intermediate days with a control condition (usually no copulation). Following such training, the compartment paired with copulation is preferred over the other compartment (e.g., Ågmo & Berenfeld, 1988). A CPP induced by this procedure is referred to as a “postejaculatory CPP.” Demonstrations of postejaculatory CPPs might appear puzzling at first glance because the conditioned stimulus (i.e., the distinctive environment) is presented after the unconditioned stimulus (copulation to ejaculation), in what learning theorists call “backward conditioning” (that would not be expected to yield conditional responding to the environment). However, if the neural reward state induced by ejaculation is the unconditional stimulus, then the pairing of environmental cues with it is simultaneous. Thus postejaculatory CPP can be accounted for by the rules of Pavlovian conditioning. CPPs have also been demonstrated in female rats and hamsters. Oldenburger, Everitt, and de Jonge, (1992) found that when copulation occurred within one of the distinctive compartments of a CPP apparatus, female rats showed only a weak CPP. Conversely, Paredes and Alonso (1997) and Paredes and Vazquez (1999) demonstrated a robust CPP in female rats that depended on whether the females were able to pace the rate of copulation without having to employ defensive behaviors. This was accomplished using the pacing chambers described above, in which a plexiglas divider bisects the chamber (e.g., Figure 3). The divider contains one or more holes that only the female can pass through. This allows her to pace the rate of copulation by moving freely from side to side. Like males, females acquired a strong preference for a distinctive environment only if they were placed into the CPP box immediately after paced copulation. No preference was found if the cop-


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ulation was unpaced prior to placement in the CPP box (meaning that it had occurred in the same pacing chamber but without the divider). Thus, for a female rat, CPP develops only if she has been able to control the initiation and rate of copulation freely without having to use defensive behaviors. Although a sexually vigorous male rat is a clear unconditioned stimulus for approach and solicitation in female rats (e.g., Ågmo, 1999), contextual cues associated with pacing elicit a conditioned sexual reward state in those females. However, these results may also indicate the presence of an unconditional aversive state during unpaced copulation. To examine this possibility, Afonso, Woehrling, and Pfaus (2003) allowed female rats to copulate in two paced conditions using Plexiglas dividers that had either four holes or one hole (see Figure 3). This was done to eliminate the possibility of an “aversive” state resulting from unpaced copulation. Trials were conducted sequentially at 4day intervals, and each pacing condition was paired with one of the distinctive sides of a CPP apparatus, in a counterbalanced fashion. Control groups contrasted the four-hole condition with no divider, or the one-hole condition with no divider (as was done by Paredes and colleagues). Control females developed significant CPP for either the onehole or four-hole condition, relative to unpaced copulation with no divider. Those control data replicate the findings of Paredes and colleagues, and indicate that both the four-hole and one-hole condition are rewarding relative to the unpaced (no divider) condition. However, they do not rule out the possibility that the real distinction being made is between an aversive condition (unpaced copulation) and a rewarding condition (paced copulation). This was addressed in the group allowed to contrast the four-hole versus one-hole condition. In this group, females developed significant CPP for the four-hole condition, relative to the one-hole condition, suggesting strongly that copulatory CPP reflects a true sexual reward state in females. Similarly, Jenkins and Becker (2003) found that female rats developed significant CPP for paced relative to unpaced mating, but also for unpaced mating in which the experimenter removed the male for a period that approximated the female’s imposed interintromission interval, relative to unpaced mating in which male removal did not occur. Thus, female rats develop CPP for sex at their own preferred intervals. Taken together with the results of Matthews et al. (1997), these data suggest that reward comes from the sexual stimulation that females receive, namely mounts with intromission, so long as that stimulation occurs at the desired time intervals. What about males? Martinez and Paredes (2001) found that males developed significant CPP if they had unrestricted access to females (as occurs in pacing chambers without a barrier). This was the opposite pref-

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erence to the one developed by females in their studies. However, we recently found that males exposed to the four-hole versus one-hole condition developed a preference for the one-hole condition (Pfaus & Doyle, 2003). At first glance, our data seem contradictory with those of Martinez and Paredes. However, males in the one-hole condition ejaculated with significantly fewer intromissions relative to the four-hole condition, perhaps owing to an “Enforced Interval Effect” due to the relatively restricted access they had to the female. This result gives rise to the possibility that sexual reward is “more” rewarding if it is accompanied by higher levels of arousal. This did not happen in the Martinez and Paredes study, in which the number of intromissions was relatively equivalent in all conditions. As with females, the type of sexual stimulation received is critical to the reward value of the copulatory contact in males. Although both copulatory and postejaculatory CPP procedures produce effects of similar magnitude in male rats, there are differences in the underlying neurobiology. The opioid receptor antagonist naloxone disrupts both copulatory and postejaculatory CPPs, but in different ways. Ågmo and Berenfeld (1990) found that the development of postejaculatory CPP was blocked by injections of naloxone prior to each training session. Conversely, the development of a copulatory CPP was unaffected by naloxone prior to each training session (Mehrara & Baum, 1990). However, once a copulatory CPP had developed, its expression was blocked by naloxone injections prior to the final test (Hughes et al., 1990; Mehrara & Baum, 1990). There is also evidence that the site of action of naloxone is different for these effects. Ågmo and Gomez (1993) found that naloxone’s disruption of the development of postejaculatory CPP occurred following infusions into the medial preoptic area, whereas infusions of naloxone into this brain region did not disrupt the expression of a copulatory CPP (Hughes et al., 1990). In females, naloxone blocked the acquisition of a pacing-related CPP, suggesting that common opioid systems in the brain of male and female rats is activated by sex-related cues (Paredes & Martinez, 2001). As with approach behaviors toward sex-related odors, castration disrupts the expression of a copulatory CPP on the first postoperative test in male rats (Hughes et al., 1990; Miller & Baum, 1987), and acquisition of a copulatory CPP was blocked by naloxone in castrated, but not gonadally intact, male rats (Mehrara & Baum, 1990). Endocrine responses have also been detected in male rats following exposure to contextual stimuli associated with copulation. Kamel, Mock, Wright, and Frankel (1975) reported that serum testosterone, luteinizing hormone, and prolactin levels were elevated after 45 min of exposure to an arena in which prior copulation occurred. Interestingly, a wintergreen odor paired with copulation to ejaculation was able to elevate serum


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testosterone and luteinizing hormone levels relative to the same odor not paired with sexual reward (Graham & Desjardins, 1980). Dopamine antagonists have not been reported to alter the development or expression of copulatory CPPs in either male or female rats, or postejaculatory CPPs in male rats (Ågmo & Berenfeld, 1990; Portillo, Garcia-Horsman, Camacho, & Paredes, 2001). In contrast, Meisel, Joppa, and Rowe (1996) found that the development of a copulatory CPP in female hamsters was blocked by injections of the D2-receptor antagonists sulpiride or raclopride prior to each training session. To summarize, sexual reward appears to involve the activation of brain opioid systems. In some cases, odor or contextual stimuli associated with sexual reward activate mesolimbic dopamine pathways (either to increase attention or drive goal-directed behaviors). Likewise, stimuli associated with sexual reward also activate pituitary and gonadal hormone release in male rats. Models of Sexual Inhibition In an elegant reinterpretation of Pavlov (1927), Gray (1971, 1975) proposed that all behavioral tendencies (both learned and unlearned) are governed by two general systems in the brain, one excitatory and the other inhibitory. This was applied originally to fear but subsequently to the development of anxiety (Gray, 1982). Bancroft and Janssen (2000) advanced this concept further by proposing a theoretical model of dual control of male sexual response in which the net expression of sexual behavior is based on the influence of excitatory and inhibitory mechanisms in the brain. As in Gray’s theory, this model stressed the adaptive nature of both excitatory and inhibitory processes. For example, the adaptive nature of sexual excitement would drive individuals to seek out sex partners for reproductive or reward purposes. The adaptive nature of sexual inhibition would guard against situations that threaten the individual, including chronically stressful life events. The propensity for sexual excitement, especially inhibition, was seen as an individual tendency: “For the majority, the presence of a fairly typical level of inhibition proneness is adaptive, helping to keep the individual out of trouble. Those whose propensity for central inhibition of sexual response is too high have increased vulnerability to sexual (e.g., erectile) dysfunction. For those whose inhibitory propensity is too low, an increased likelihood of engaging in high risk sexual behavior may result.” (Bancroft & Janssen, 2000, p. 571). Indeed, the study of sexual inhibition is also critical if we are to understand how certain events or “prosexual” drugs (e.g., alcohol, cocaine) induce sexual disinhibition. Responsiveness to inhibition is easy to categorize behaviorally: Individuals either will or will not do something. The presence of inhibition

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would be inferred if the individual wanted to do something but did not, owing to an obvious unconditional threat or a conditioned cultural proscription against the activity (complete with the possibility of getting caught). This last point, however, raises some interesting issues regarding the arousing nature of inhibition. Central excitation and inhibition both activate the autonomic nervous system. Typically, threatening stimuli activate the sympathetic arm, increasing blood flow and oxygen uptake to muscles and organs that need it. General activation of the sympathetic nervous system, as might happen if one meets a bear in the woods, turns off blood flow to the genitals. Selective activation of both sympathetic and parasympathetic nervous systems occurs in response to sexual stimuli, with the sympathetic nervous system increasing blood flow from the heart and the parasympathetic nervous system increasing blood flow to the genitals. A small degree of stress or threat (i.e., something “naughty” or even painful) can be arousing, especially for individuals with low levels of arousability. Translated to a sexual situation, such arousal could be directed into sexual activity, perhaps to the point in some individuals that it becomes a necessary antecedent. In Ars Amatoria (1930) Ovid suggested that anger, fear, even short-lived terror, can be preludes to sex specifically because they “stir passion” or arousal. The stimuli that evoke excitation and inhibition may be different for different individuals and what inhibits one person may actually excite another. Such individual differences must be considered in addition to differences in arousability and propensity for inhibition. How could such phenomena be studied in animals? Although punishment with shock can suppress a variety of appetitive and consummatory behaviors in rats (Mackintosh, 1974), such punishment has never been reported to induce sexual inhibition in males (Beach & Fowler, 1959; Hayward, 1957; Zimbardo, 1958). In fact, shock, short-term pain (e.g., tail-pinch), or neutral stimuli paired with them, actually stimulate mounting in sexually sluggish or inactive male rats (Barfield & Sachs, 1968; Caggiula, 1972; Crowley, Popolaw, & Ward, 1973), and reduce the number of intromissions required for ejaculation in sexually active males (Beach & Fowler, 1959; Sachs & Barfield, 1976). As mentioned above, both male and female rats will readily cross electrified grids to gain access to sexually receptive partners (Moss, 1924). Thus, punishment with shock or pain is not workable. Indeed, arousal is a necessary antecedent to sexual activity in both male and female rats. Drugs that decrease the activity of the sympathetic nervous system (e.g., α2 adrenergic receptor agonists like clonidine) decrease sexual responding in both male and female rats (Clark, Smith & Davidson, 1985; Meston, Moe, & Gorzalka, 1996).


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More reliable methods of punishment have been used. Rodents live in a predominantly olfactory world, and pairing estrous odors with gastrointestinal distress (induced by contingent injections of lithium chloride that make animals sick) induces a conditioned odor aversion in males rats and hamsters that translates to avoidance of female vaginal secretions (Zahorik & Johnson,1976), increased mount and intromission latencies (Johnston, Zahorik, Immler, & Zakon, 1978), decreased proportion of males that ejaculate (Peters, 1983), or avoidance of copulation altogether (Peters, 1983; however see Lawrence & Keifer, 1987). This effect occurs if conditioning took place when the males were juveniles (Koch & Peters, 1987), and conditioned males utter distress vocalizations in the presence of vaginal secretions (Peters, Koch, Blythe, & Sufka, 1988). Lawrence and Keifer (1987) demonstrated robust conditioned odor aversions using a second-order pairing of almond odor with lithium chloride injections. This conditioning paradigm led males to avoid copulation with almond-scented receptive females. That this conditioning was specific to the neutral odor was demonstrated by Ågmo (2002). Conditioned males in that study were allowed to copulate with females scented with capelin oil (a “fishy” smelling oil extracted from capelin, a fatty fish found off the coast of Iceland) to 1 ejaculation, after which they were injected with lithium chloride. Subsequently, those males avoided copulating with capelin-scented females, although they continued to copulate normally with unscented females. Moreover, in subsequent partner preference tests conditioned males avoided being near capelin oil-scented receptive females, indicating that their approach behavior was inhibited. Taken together with the results of our studies on appetitive odor conditioning, these results indicate that neutral odors can become “good” or “bad” depending on their consequences. When are animals in the wild exposed to circumstances in which they must inhibit their sexual responses? Interestingly, adult male rats in the wild are rarely observed to attempt copulation with sexually nonreceptive females (Barnett, 1963; Calhoun, 1962). This is in marked contrast to most laboratory settings in which males will attempt to copulate with nonreceptive females placed into chambers in which the males have copulated previously with sexually receptive females. We have shown that training sexually active male rats to differentiate between sexually receptive and nonreceptive females on alternating test trials leads quickly to a substantial reduction in the proportion of males that attempt to copulate with nonreceptive females (Pfaus & Pinel, 1989). The aversive stimuli provided by the nonreceptive females include a thwarting of attempted copulations due to the female’s lack of receptivity, along with aggressive and defensive behaviors (e.g., boxing,

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biting, kicking) when the male attempts to mount. By virtue of the females being nonreceptive, these behaviors are paired with a lack of estrous odors. Males learn quickly to differentiate the presence of estrous odors with proceptive and receptive behaviors, and the lack of estrous odors with thwarted sexual advances and female aggression (which can be severe). In the wild, such conditioning may occur normally during adolescence. As juveniles, male and female rats mount almost anything, including one another. As the expression of this behavior transitions into adult forms, males likely attempt to mount adult females that are not in heat. Of course, those females teach the males not to try it again. We have shown that low-to-moderate doses of alcohol can release sexual behavior from inhibition induced by pairing males with sexually nonreceptive females (Pfaus & Pinel, 1989). After learning to suppress their copulatory advances toward sexually nonreceptive females, males were treated with low to moderate doses of alcohol. Low doses of alcohol that increase the mount, intromission, and ejaculation latencies when males are paired with sexually receptive females, increased the proportion of males that attempted to mount the nonreceptive females. Moreover, many of those males ejaculated, despite never gaining vaginal penetration. However, if the alcohol dose was high enough to induce motor disruption, the males did not attempt any copulation with the nonreceptive females. These findings are of interest for several reasons, most notably because alcohol intoxication figures in high-risk sexual activity (Castilla, Barrio, Belza, & de la Fuente, 1999; Lowry et al., 1994; McCusker et al., 1990; Steele & Josephs, 1990; Woody et al., 1999) and is one of the strongest antecedent predictors of men actually carrying out a rape (Rada, 1975; Ranieri-Collins, 1995; Ullman & Brecklin, 2000; Wild, Graham, & Rehm, 1998). In contrast, cocaine intoxication did not release sexual behavior from primary inhibition (Pfaus et al., 2003). We have also shown that neutral odors paired with access to sexually nonreceptive females, or with sexual activity restricted to intromission without ejaculation, can inhibit mate choice in male rats (Kippin & Pfaus, 2001; Kippin et al., 1998). Although those conditions were used as controls in our previous studies of appetitive odor conditioning, in both cases males chose to ejaculate preferentially with the unscented, rather than scented, females during the final choice test. This indicates that, despite the presence of estrous odors and vigorous proceptive behaviors of both females during the final choice test, the neutral odor had acquired sufficient aversive properties to deter the male from ejaculating with a receptive female bearing it. We have recently found that alcohol does not alter the expression of this aversive conditioning, but a


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low dose of cocaine can eliminate the preference for the unscented female (Pfaus et al., 2003). Given the fact that cocaine use is also implicated in uninhibited or risky sexual behavior, these data suggest that alcohol and cocaine disrupt different types of sexual inhibition. Finally, situational stressors and sexual exhaustion can be used as models of sexual inhibition in male rats. Sexually naive males are extremely sensitive to novel environments, and a high proportion of naive males will not copulate in a novel environment, despite intense proceptive behaviors displayed by receptive females (Pfaus & Wilkins, 1995). In fact, many of these males never copulate and, in the past, have been discarded as research subjects by many laboratories. However, in our study, the effect of novelty was attenuated by systemic administration of the opioid receptor antagonist naloxone or by preexposure of males to the sex chamber. Novel environments are stressors that induce naloxone-reversible analgesia (Izquierdo & McGaugh, 1987). In turn, naloxone-reversible analgesia is taken to indicate the release of endogenous opioids. Thus, the release of endogenous opioids in response to being placed into a novel environment disrupts copulation in sexually naive male rats, as if they had been administered morphine exogenously. Like treatment with naloxone, preexposure to the chamber lessened the novelty effect naturally, allowing males to copulate. However, sexual approach and copulatory behaviors were not disrupted in sexually experienced male rats placed into a novel environment, indicating that the males had acquired sufficient knowledge of the female as an appetitive sexual incentive to offset the induction of opioid release. This paradigm could be used as a model of situational anxiety in sexually naive males. If male rats are allowed to copulate to sexual exhaustion, they display reduced responsiveness to female solicitations and many will not copulate to ejaculation for 24 to 48 hrs (Beach & Jordan, 1956b; Larsson, 1956). This inhibition is due to neurochemical events that underlie sexual satiety, and can be partly or fully reversed with several drugs, notably the α 2 -adrenergic receptor antagonist yohimbine (which increases noradrenergic tone), the 5-HT-1A agonist 8-OH-DPAT (which decreases serotonin release), and the opioid receptor antagonists naloxone or naltrexone (which block the binding of endogenous opioids) (Rodriguez-Manzo & Fernandez-Guasti, 1994, 1995a, 1995b). This suggests that increased release of serotonin and endogenous opioids, and decreased release of noradrenaline, somewhere in the brain underlies the neurochemical state of sexual satiety. Interestingly, the generation of sexual satiety can be delayed by changing the stimulus female for every ejaculatory series (i.e., by inducing a “Coolidge effect”; RodriguezManzo, 1999).

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Sexual inhibition in female rats has not yet been explored, although circumstances in which females are either not receptive (e.g., with lowlevel estrogen priming) or are losing their receptivity (e.g., during estrus termination) might be good places to start. Animal Models: A Synthesis Animals possess appetitive and consummatory aspects of sexual behavior that are homologous and analogous to our own and that are controlled by similar or identical neurochemical and hormonal systems. They experience sexual arousal, desire, reward, and inhibition. Males are excited by females that require some form of courtship or pursuit, and will work hard to obtain even small sexual rewards. Females like to control the initiation and rate of sexual contact. Sexual behavior in males is strengthened with experience, making them less vulnerable to treatments that disrupt sexual responding. The same may occur in females. From an evolutionary perspective, sexual behavior appears to have similar processes and endpoints for all mammalian species and perhaps for all species that engage in it. If the process and endpoints of sexual response are the same (even if the outward expression of appetitive behaviors or copulation is speciesspecific), then animals can indeed be used as models of human sexual response, provided the homology or analogy is specified unambiguously and that treatments or experiences have similar effects between the species, giving the animal model predictive validity. This requires that we understand the particular behaviors of both species as best we can, which in turn requires that we be careful and creative in how we ask our scientific questions. For example, it was once believed that male rats lack the cognitive capacity and sophisticated cultural conditioning for sexual inhibition, thereby making them unsuitable models for the disinhibitory effects of alcohol (e.g., Wilson, 1977). Yet they clearly learn not to attempt copulation with sexually nonreceptive females and show disinhibition under the influence of low doses of alcohol. It was also believed that female rats did not “enjoy” copulation because it took them longer to return to a male following intromission or ejaculation, relative to precopulatory interaction or mounts without intromission. However, Paredes and colleagues provided an important glimpse of what female rats really like about sex: their ability to control its occurrence and rate. If they have control over the initiation and rate of sexual interaction, then female rats will develop copulatory CPPs; if not, then CPPs do not develop despite the fact that females still copulate and are sexually receptive. For male rats, the reward state induced by ejaculation and/or its aftermath is critical for the development of CPP


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and partner preference. Larsson (1956) reported that some enforced intervals between intromissions were optimal for ejaculation, whereas others that were too long (e.g., greater than 5 min) led to an inhibition of sexual activity. It may be that male rats also require a form of “control” with regard to female accessibility (as suggested by Martinez & Paredes, 2001). This can be expressed naturally in chasing or pursuit, or in other behaviors that maximize the desired rate of genital contact and stimulation. Control is an important aspect of sexual function in both men and women, and problems with locus of control may form an important part of the etiology of different sexual disorders (McCullough & Fine, 1999). Female rats display proceptive and receptive sexual behaviors only during their periovulatory period, or if they are ovariectomized and given appropriate replacement with estrogen and progesterone. Although female primates, including humans, can have sex throughout their ovulatory cycles, they display increased female-initiated solicitation and sexual activity during their periovulatory periods (Wallen, 1982, 1995). Making the conceptual connection between animal and human sexual behaviors is the primary challenge for researchers. Subsequent testing of those connections is easier but equally important. We believe that animal models will continue to be indispensable for studies of the neurobiology of sexual behavior. We need the knowledge that lesion and drug studies, neurochemical and neuroanatomical analyses, and molecular approaches provide in animals to guide our emerging work in the neuroanatomy of sexual responding in humans using functional magnetic resonance imaging or positron emission tomography. We need animal models to further understand the hormonal processes that lead to changes in sexual arousability (e.g., following hormone replacement therapy in postmenopausal or hypogonadal individuals). The kind of invasive and direct studies of brain or organ function in animals simply cannot be conducted in human subjects. Animal models will also continue to inform us about basic behavioral mechanisms. For example, a role for learning in animal sexual behavior has important implications for our understanding of human sexual response. This is especially true concerning the development of extreme forms of sexual desire, including paraphilias or deviant sexual practices. Paraphilias are thought to develop through conditioning processes (e.g., Abel & Blanchard, 1974; Laws & Marshall, 1991; McGuire, Carlisle, & Young, 1965), and conditioning techniques are often employed to reduce or eliminate these preferences. Common techniques include directed masturbation (in which subjects masturbate to nondeviant sexual themes), satiation (in which subjects masturbate well past the first orgasm to deviant sexual themes), and masturbatory recondi-

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tioning (in which subjects masturbate to nondeviant themes followed by fantasizing to deviant themes) (Brownell, Hayes, & Barlow, 1977; Marquis, 1970; Marshall, 1979). Unfortunately, the effectiveness of those techniques is quite limited (Johnston, Hudson, & Marshall, 1992; Laws & Marshall, 1991). Our finding that pairing a stimulus with sexual reward (e.g., during the postejaculatory refractory period in male rats) increases the incentive value of sex partners bearing that stimulus suggests that directed masturbation should be followed by exposure (either real or fantasized) to nondeviant stimuli. This may explain the weak effects of satiation and masturbatory reconditioning. Our finding that a stimulus paired with sexual frustration (e.g., sexual stimulation that does not accompany sexual reward) or with lack of sexual stimulation in a sexual context (e.g., with a sexually nonreceptive partner) decreases the incentive value of sex partners bearing that stimulus suggest new venues for conditioning of sexual preferences in clinical treatment. Pairing deviant stimuli with sexual frustration or with diminished sexual stimulation or reward may enhance the therapeutic effectiveness of directed masturbation. It is also possible that attraction to more “normal” physical attributes (e.g., a certain body type, shape of face, eye and hair color, etc.) is produced by conditioning, especially during an individual’s early sexual experience. Many factors appear to be related to the attractiveness of a mate in humans, including physical, personality, and social features (see Buss & Schmidt, 1993; Townsend & Levy, 1990). As denoted in the Incentive Sequence Model, the process of sexual interaction begins at a distance. Physical attributes are essentially incentive cues, and those that are found attractive are likely to pull an individual toward them. If mesolimbic dopamine release is activated in response to such cues (as it is in response to estrous or conditioned odors in male rats), then attentional mechanisms will be focused onto those cues in a way that inhibits attention to other cues and other possibilities for interaction. Selectivity for certain sets of physical cues forms our distal partner preferences. The movement from distal to proximal to interactive is thus directed by this first set of choices about attractive features. How might such preferences develop? Given that the development of partner preference in rats depends on sexual reward, we may hypothesize that partner preference in humans develops during masturbation or actual copulation, with salient features of real or fantasized partners becoming preferred by their association with sexual reward or gratification. The development of preferences during copulation would explain the anecdotal evidence that individuals often pursue new partners with some features similar to previous partners (e.g., Stendahl, 1821/1959).


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Even following past abuse, partners with similar features are often sought after despite the aversive consequences. Preferences developed during masturbation may also contribute to the adherence to cultural values. The features of fantasized partners could be comprised of culturally valued characteristics. When these are paired with sexual reward, preferences would be established or strengthened. This can explain not only the status quo of physical preferences within a culture, but also how those cultural preferences can change from era to era. Accordingly, the “evolved psychological mechanism” that guides copulatory preferences, according to Buss (1994), may in fact be learning. Learning also provides an efficient mechanism to guide behavior toward stimuli that are predictive of fertility and reproductive success. Sexually imprinted maternal stimuli may be excellent predictors of fertility. Classically conditioned stimuli paired with sexual reward are also likely to be excellent predictors of receptivity. Moreover, the relative impact of imprinted and conditioned stimuli in sexual preferences in humans may be magnified in comparison to the rat because sexual status (i.e., menstrual cycle) is masked in women (Alexander & Noonan, 1979). In an incentive motivation analysis, sexually imprinted and conditioned stimuli would be expected to have more powerful influences in the absence of direct knowledge of reproductive status. This would indeed be the case in heterosexual men for whom the reproductive status of women can not be determined directly. Accordingly, copulatory attempts may be appropriately or inappropriately directed toward or away from women based largely upon learned stimuli rather than actual reproductive status. Our finding that the male’s first ejaculation and postejaculatory interval were sufficient for the induction of partner preference (e.g., Kippin et al., 1998) suggests that a “critical period” for the development of conditioned sexual responses might exist in other mammalian species. Stimuli associated with the initial experience of sexual arousal and/or gratification may become conditioned, such that they are designated subsequently as attractive and preferred. Even if some stimuli are innately preferred, others could be added by experience, which would maintain a degree of diversity in features that are considered attractive within a single human social system or culture. There are domains of human sexual experience and response that animal models cannot inform us about. Although animals clearly possess cognitive abilities, at least from a conditioning standpoint, we will never know their “thoughts” and “feelings” about sex, nor will we be certain that the occasion setters we give them mean anything outside the restricted domains of our laboratories. Our ability to alter their sexual activity by manipulating environmental variables means that their

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brains are sensitive to such manipulation. This kind of plasticity probably exists in the brains of all animals that display sexual behavior and may underlie the diversity in sexual behavior and responding that all animals possess, both individually and between species. However, the particular expression of this plasticity in behavior or cognitive processes may well depend on a particular animal’s behavioral and cognitive capacity, and what it is given in a laboratory or societal group to respond to. Essentially, the problem is one of level of analysis: at the level of the basic response “rule” or physiological process we may be able to make logical and predictable jumps from animals to humans. At the level of emotional processing or outward expression of behavior, the rules may not be interchangeable. Therefore, we would certainly argue that cultural influences on human sexual behavior will continue to depend on studies of its unique expression in humans. However, we can use animal models as analogies to make predictions about the impact of certain cultural variables on sexual expression, so long as we can pare the question down to the basic rules of expression. For example, engaging in risky sex may be proscribed by a culture, but doing so may increase autonomic arousal, leading to increased sexual reward. In turn, highly rewarding sex may become the preferred mode of expression for an individual, leading to a relative inability to engage in sexual activity that is less rewarding. At one level, this tells us about the basic conditioning processes that form part of the reason why people engage in risky sex. After that, the basic “rule” must be extended into the realm of human experience: alone it cannot account for certain events that are common referents for sexual desire or reward, such as why certain fantasies or actions are more arousing than others. Humans must be asked to get those answers. Likewise, homosexuality has been viewed as a uniquely human characteristic (Dixson, 1998; Wallen & Parsons, 1997), and it is clear that homosexual orientation in humans has social expressions beyond copulatory choice (e.g., Herdt, 1998). However, homosexual behavior exists in many species (Bagemihl, 1999), and even as a preferred mode of sexual expression (e.g., as in female Japanese macaques during the breeding season; Vasey, 2002). The caveat here is that animal models reveal basic behavioral and neural mechanisms. Which part of an animal’s sexual response is unique to the animal, and which is the basic rule that can be applied to humans are the key variables to determine. Although studies of human and animal sexual behavior have advanced independently, their convergence is long overdue. More and more animal models of human sexual response are being used productively by clinical sex researchers and neuroendocrinologists to study the neuroanatomy, neurochemistry, and pharmacology of sexual behavior. The cross-


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