Role of Nitric Oxide on Motor Behavior - CiteSeerX

C 2005) Cellular and Molecular Neurobiology, Vol. 25, No. 2, April 2005 ( DOI: 10.1007/s10571-005-3065-8

Role of Nitric Oxide on Motor Behavior 1 ˜ 2 M. Bermudez-Echeverry, ´ E. A. Del Bel,1,5 F. S. Guimaraes, M. Z. Gomes,1,3 1,3 1 3 A. Schiaveto-de-Souza, F. E. Padovan-Neto, V. Tumas, A. P. Barion-Cavalcanti,1,4 M. Lazzarini,1,4 L. P. Nucci-da-Silva,1 and D. de Paula-Souza1

Received June 15, 2004; accepted July 27, 2004 SUMMARY 1. The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. 2. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), NG -nitro-L-arginine methylester (L-NAME), NG monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. 3. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfa1 adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. 4. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. 5. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NOproducing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. 6. Finally, recent studies using experimental Parkinson’s disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may 1 Department

˜ Preto, MEF Physiology, School of Odontology, Medical School, Campus USP, Ribeirao SP Brazil. 2 Department of Pharmacology, Medical School, Campus USP, Ribeirao ˜ Preto, SP Brazil. 3 Department of Physiology Medical School, Campus USP, Ribeirao ˜ Preto, SP Brazil. 4 Department of Neurology, Medical School, Campus USP, Ribeirao ˜ Preto, SP Brazil. 5 To whom correspondence should be addressed at Department MEF-Physiology, School of Odontology, ˜ Preto, SP, Brazil 14049-904; e-mail: [email protected]. Campus USP, Ribeirao 371 C 2005 Springer Science+Business Media, Inc. 0272-4340/05/0400-0371/0

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Del Bel et al. be a key participant on physiological and pathophysiological processes in the nigrostriatal system. KEY WORDS: catalepsy; L-NOARG; 7-NIO; nitric oxide synthase; L-arginine; haloperidol; tolerance; dopamine; NADPH-diaphorase; intracerebral injection; anxiogenic; anxiolytic; Parkinson.

INTRODUCTION Nitric Oxide (NO) is an “atypical neurotransmitter” that is synthesized from Larginine by the enzymes nitric oxide synthases (NOS) (Forstermann et al., 1991; Bredt and Snyder, 1992; Bredt, 1999). This enzyme exists in several forms (Dawson et al., 1991; Forstermann et al., 1991). Neuronal NOS is a constitutive, cytosolic, Ca2+ /Calmodulin-dependent enzyme (Bredt and Snyder, 1990; Klatt et al., 1992) that occurs only in neuronal cell bodies, dendrites, and axons and (Bredt et al., 1990) presents discrete localization in brain structures (Vincent and Kimura, 1992; Barjavel and Bhargava, 1995). The same cerebral neurons stain for NOS and NADPH diaphorase (NADPH-d, (Dawson et al., 1991; Hope et al., 1991) and purified brain NOS has NADPH-d activity (Bredt and Snyder, 1990; Schmidt et al., 1992). Systemic application of L-arginine analogues such as NG -nitro-L-arginine (L-NOARG-Dwyer et al., 1991) has been shown to produce an in vivo (Carreau et al., 1994; Iadecola et al., 1994) and in vitro (Traystman et al., 1995) time-dependent irreversible inhibition of brain NOS. Manipulations of NO formation modify many brain physiological and/or pathological conditions, such as long-term potentiation in hippocampus (Bohme et al., 1991; O’Dell et al., 1991), long-term depression in cerebellum (Shibuki and Okada, 1991; Linden and Connor, 1992), neurotoxicity/neuroprotection (Buisson et al., 1993; Choi, 1993; Lipton et al., 1993; Castagnoli et al., 1999), epilepsy (Mollace et al., 1991; Mollace et al., 1991; Del Bel et al., 1997), chronic effects of opiates (Kolesnikov et al., 1992), nociception (Babbedge et al., 1993a,b; Coderre, 1993), synaptic plasticity (Bohme et al., 1991; O’Dell et al., 1991), enhancement of neurotransmitter release (Meffert et al., 1994), regulation of gene expression (Johnston and Morris, 1994), and anxiety (De Oliveira et al., 2001; Guimaraes et al., 1994; Starr and Starr, 1995; Volke et al., 1995). Among regions with significant levels of NOS/NADPH-d there are sites involved in modulation of defensive responses, such as the amygdala, hypothalamus, ˜ et al., 1994). NADPH-d/NOS and dorsolateral central gray (Graeff, 1990; Guimaraes neurons are also detected in the cortex, striatum (CaudatePutamen), pedunculopontine tegmental nucleus, substantia nigra compacta (Vincent and Kimura, 1992), regions involved in motor control (Fig. 1). Striatal NO tone regulates the basal activity and responsiveness of dopamine (DA) neurons to cortical and striatal inputs (Sandor et al., 1995; West and Galloway, 1998; West et al., 2002). Therefore, striatal NO signaling may play an important role in the integration of information transmitted to basal ganglia output centers via corticostriatal and striatal efferent pathways (West et al., 2002). Although the influence of NO on striatal neuronal activity remains to be thoroughly characterized, evidence has accumulated suggesting that NO signaling may mediate and/or regulate multiple aspects of striatal neurotransmission (West and Galloway, 1998; West et al., 2002).

Nitric Oxide and Motor Function

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Fig. 1. NADPH-dNOS-positive neurons located in the Striatal circuitry regions: CaudadePutamen (Striatum) and pedunculopontine tegmental nuclei (PPTg). The reaction for NADPH-d were performed using the method employed by Vincent and Kimura (1992), with modifications. Mices were anethesized i.p. with 25% urethane and perfused through the left ventricle with 50 mL of 0.9% saline followed by 100 mL 4% paraformaldehyde and 0.1 M phosphate buffer solution. The brains were removed, soaked for 2 h in 4% paraformaldehyde, 0.1 M phosphate buffer solution and overnight in 30% sucrose 0.1 M phosphate buffer solution, frozen in liquid nitrogen, and then stored at −70◦ C. Thirty micrometer coronal brain sections were then cut with a cryostat. NADPH-d activity was demonstrated by incubating sections (free-floating) in 0.1 M phosphate buffer, pH 7.4, containing 0.3% Triton-X100, 0.1 mg/mL nitrobluetetrazolium and 1.0 mg/mL ß-NADPH at 37◦ C for 30–60 min in the dark. The sections were then dipped for 10 min in phosphate buffer, dried, rinsed in distilled water, dried again and slices were mounted on slides for microscopic observation. NOS-immunocytochemistry: The reaction of NOS were performed using the method employed by Oliveira et al. (2001). The animals were processed as described above. Afterwards, 30 µm coronal sections were processed for NOS immunohistochemistry. Briefly, tissue sections were successively washed and incubated for 24 h with the primary NOS antibody (1:2000, Cambridge Research Biochemicals). Sections were then processed by the avidin-biotin immunoperoxidase method (Vectastain ABC kit, Vector Lab.) and NOS presence revealed by addition of the chromogen 3,3 -diaminobenzidine (DAB, Sigma) and hydrogen peroxide. The slices were mounted on slides and coverslipped for microscopic observations.

NITRIC OXIDE: INVOLVEMENT IN ANXIETY OR MOTOR BEHAVIOR? Although studies employing systemically injected NOS inhibitors suggest that the L-arginine/NO pathway could modulate exploratory behavior and/or anxiety, several contradictory results have been obtained. For example, NOS inhibitors decreased the anxiolytic effect of chlordiazepoxide and nitrous oxide (NO2 ) in mice

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(Quock and Nguyen, 1992; Caton et al., 1994), and decreased open arm exploration of an elevated plus maze (De Oliveira et al., 1997a; Vale et al., 1998). Opposite results, however, were found by other studies (Volke et al., 1995; Faria et al., 1997; Yildiz et al., 2000), pointing to an anxiogenic action of NO in the central nervous system (CNS) of rats. For example, Volke et al. (1995) and Faria et al. (1997), showed that NG -nitro-L-arginine methylester (L-NAME) has an anxiolytic effect in the elevated plus maze. In the former study, however, doses higher than 10 mg/kg were not effective. One possibility to explain these contradictory studies could be an interference with locomotor activity. NOS inhibitor compounds reduce spontaneous locomotor activity (Sandi et al., 1995; Dzoljic et al., 1997; Del Bel et al., 2002) and hyperlocomotion induced by phencyclidine (Noda et al., 1995) or by DA agonists (Abekawa et al., 1994; Starr and Starr, 1995). To further investigate the role of NO in anxiety and motor behavior, we (De Oliveira et al., 1997b) verified the effects of NG -nitro-L-arginine (L-NOARG, 5– 120 mg/kg i.p.) in the elevated plus maze. Acute systemic injections of the drug in rats decrease open arm exploration in the plus maze, usually interpreted as an anxiogenic effect. The acute effect of L-NOARG was attenuated dose-dependently by i.c.v. pretreatment with L-arginine. These findings suggest that L-NOARG effect in the elevated plus maze involves a decrease in NO formation in the CNS. The decreased maze exploration induced by acute L-NOARG treatment suffered rapid tolerance, totally disappearing after 4 days of drug administration. A general confounding element in the interpretation of results obtained with NOS inhibitors is the drug effects on blood pressure. Acute administration of L-NOARG causes an increase in systemic blood pressure (Rosa et al., 1994). Some studies have suggested an influence of blood pressure on anxiety (Onstott et al., 1993). Nevertheless, although increased levels of blood pressure are maintained after 4 days of L-NOARG treatment (Onstott et al., 1993), the drug is no longer able to modify exploratory indexes in the elevated plus maze (De Oliveira et al., 1997a). In addition, Faria et al. (1997) describes that two-kidney one-clip hypertension failed to change the behavior of rats in the elevated plus maze. In the same way, Rosa et al. (1994), showed that hypertension per se does not affect the level of fear in spontaneously hypertensive rats submitted to the elevated plus maze. Therefore, it seems unlikely that increased blood pressure, per se, could explain the effect of acute L-NOARG administration. In our study the drug also decreased the number of enclosed arm entries, an index usually related to general exploratory activity. The “anxiogenic” effect obtained, therefore, should be seem with caution, since the doses employed were comparatively higher than the active doses of L-NAME that showed anxiolytic effects in other studies (Faria et al., 1997). A possible interference of NOS inhibitors on motor behavior could help to explain the inverted U-shaped dose-response curves found in several studies (Guimaraes et al., 1994; Volke et al., 1995).

NITRIC OXIDE SYNTHASE STRIATAL INTERNEURONES Striatal neurons receive a myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the


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most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide, and adenosine (Graybiel, 1990; Wichmann and DeLong, 1996). All these neurotransmitter systems interact with each other to regulate synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurons on this converging information dictates the final output of the striatum to the other basal ganglia structures. NADPH-d activity in the brain is not randomly distributed, and may be associated with functional properties of extrapyramidal areas. Vincent and Kimura (1992), using NADPH-d histochemical technique, demonstrated that NO Synthase is present in not only DA terminal regions such as the striatum (medium spiny neurons; Fig. 2) and nucleus accumbens, but also in the site of origin of DA cells, in the substantia nigra pars reticulata (A9) and ventral tegmental area (A10). Dendrites of substantia nigra pars compacta release dopamine at the vicinity of neurons in the substantia nigra pars reticulata (Cheramy et al., 1981; Wichmann and DeLong, 1996). The striatal NOS/NADPH-d positive neurons have been shown to contain more identified transmitters and cotransmitters than any other type of striatal neuron. In fact, they also colocalize with somatostatin and neuropeptide Y (Dawson et al., 1991; Vincent and Kimura, 1992) and can be identified in rat brain slices due to their electrophysiological, morphological and histochemical properties (Kawaguchi, 1993). NOS-positive interneurons represent 1–2% of striatal neurons and are spiny cells, 12–25 µm in diameter, with fusiform or polygonal somata (Fig. 2). In comparison with cholinergic cells, they have fewer dendritic branches but an extensive axonal arborization which forms a wider field (1000 µm vs. 600 µm). The medium spiny neurons are projection neurons, representing 95% of the total neuronal population in the striatum. Their function is profoundly influenced by the level of dopaminergic activity (Graybiel et al., 1989; Graybiel, 1990; Morris et al., 1997). The role of NOS-positive interneurons in the striatum is still controversial. At least two different functions have been postulated. NOS-positive cells might control local blood flow in the striatum by releasing NO acting directly on guanylate cyclase in the vascular smooth-muscle and causing vasodilatation (Kiss and Vizi, 2001). NO might also act as a transmitter to affect striatal activity, either through direct interactions with ligand-gated channels or by influencing, through the stimulation of second messenger systems, surrounding striatal projecting neurons. A well-established intracellular pathway activated by NO is the stimulation of soluble guanylyl cyclase. This enzyme causes an increase in intracellular concentration of cGMP and the consequent stimulation of cGMP-dependent protein kinase. Interestingly, striatal projecting neurons contain high concentrations of soluble guanylyl cyclase suggesting that they are potential targets for NO produced by NOS-positive cells (Ariano and Matus, 1981; Ariano et al., 1982; Ariano, 1983). The medium spiny neurons are among the first neurons to degenerate during the development of Huntington’s chorea (Graveland et al., 1985). There is a projection between basal ganglia and noncholinergic portion of the tegmental pedunculopontine nucleus, which may serve as a gateway for descending basal ganglia influences to spinal motor mechanisms (Lavoie and Parent, 1994; Inglis and Winn, 1995). Changes in discharge in basal ganglia output cells related to movement disorders will also affect their brain stem targets. This may conceivably contribute to the locomotor and

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Fig. 2. Triple photomicrographys from the same microscopic field showing neostriatal cells from adult rat brain, stained histochemically for NADPH-diaphorase. B and C are higher magnifications of A. The labeled neurons are neostriatal cells, with fewer dendritic spines, with fusiform or polygonal somata, considered interneurons (Kawaguchi, 1993). Further specifications as in Fig. 1.


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postural disturbances in Parkinson’s disease (Wichmann and DeLong, 1996). The tegmental pedunculopontine nucleus region has been shown to be overactive in parkinsonian animals, consistent with a major increase of basal ganglia input to this region (Mitchell et al., 1989).

NITRIC OXIDE AND MOTOR BEHAVIOR: THE CATALEPSY TEST Several pices of evidences suggest that NO play an important role in the control of motor behavior. Mice mutant for the neuronal NOS isoform have altered locomotor abilities (Kriegsfeld et al., 1999) and rats and mice treated with various NOS inhibitors show problems with fine motor control (Starr and Starr, 1995; Dzoljic et al., 1997; Araki et al., 2001; Dall’Igna et al., 2001; Uzbay, 2001; Del Bel et al., 2002). NO antagonizes the increase in locomotor activity found after dopamine agonists administration (Starr and Starr, 1995). Based on these findings we decided to test if NOS inhibitors would potentiate haloperidol-induced catalepsy in mice. Catalepsy is defined as a failure to correct an externally imposed posture. This test is widely used to evaluate motor effects of drugs, particularly those related to the extrapyramidal system (Sanberg et al., 1980; Sanberg et al., 1984; Hauber, 1998). Administration of dopamine antagonists, such as haloperidol, induces catalepsy in rodents (Koob et al., 1984; Osborne et al., 1994) and Parkinson’s symptoms in humans (Koffer et al., 1978; Sanberg et al., 1988). Systemic injections of L-NOARG and 7-nitroindazole (7NI), unspecific and specific inhibitors of neuronal NOS, respectively (Moore et al., 1993), induced catalepsy in mice (Fig. 3) and had an additive effect with haloperidol (Marras et al., 1995; Navarro et al., 1997; Del Bel et al., 1998; Araki et al., 2001; Cavas and Navarro, 2002; Del Bel et al., 2002). These effects were obtained with doses commonly used in the literature (Sandi et al., 1995; Starr and Starr, 1995; Greenberg et al., 1997) and were similar to those that significantly inhibit neuronal NOS (>10 mg kg−1 ) (Salter et al., 1995). The cataleptic effects were detected both in the hanging-bar and in the wire-ring tests (Del Bel et al., 2002) and the results in these two catalepsy tests were highly correlated. Similar to the effects obtained after systemic administration, catalepsy was also induced after intracerebroventricular (i.c.v. Del Bel et al., 2004) or intrastriatal injection of NOS inhibitors such as NG -monomethyl-L-arginine (L-NMMA), 7-NI, L-NOARG, L-NAME in rats (Fig. 4). The effect of i.c.v. injected L-NOARG was completely prevented by pretreatment with L-arginine but not by D-arginine. Both i.c.v. and intrastriatal injection of L-NOARG or L-NAME produced bell-shaped dose-response curves. These results confirm that interference with striatal formation of NO induces significant motor effects in rats.

OTHER MOTOR EFFECTS The acute effects of the NOS inhibitors L-NOARG and 7-NI on exploratory activity were analyzed in an open arena. L-NOARG and 7-NI decreased locomotion

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Fig. 3. Catalepsy induced by L-NOARG (Nrg, 40 mg/kg, n = 8–10 mice per group) administered i.p. 1 h before the test. Catalepsy was evaluated by placing the animal with both forelegs over a horizontal glass bar (diameter 0.5 cm) elevated 4.5 cm from the floor. The time (in s) during which the mouse maintained this position was recorded up to 300 s. Bars represent the means ± SEM. Asterisks indicate significant difference from saline (ANOVA followed by the Duncan test, P < 0.05). Aditional groups of animals received microinjections of saline + saline, L-arginine + saline or L-arginine + L-NOARG, and D-arginine + sal or D-arginine + L-NOARG. Bars represent the means ± SEM. Asterisks indicate significant difference from saline.

and rearing in the open arena (Del Bel et al., 2002). However, in addition to catalepsy, NOS inhibition could conceivably decrease exploratory activity by impairing movement coordination. This function can be measured by the footprint pattern test. It analyzes complex movements during locomotion by taking into account limb position or gait patterns (de Medinaceli et al., 1982; Goldberger et al., 1990; Clarke and Still, 1999). In this test standing support seems to be related to the integrity of the propriospinal system, controlled by both descending and segmental afferent input (Kunkel-Bagden et al., 1993). Drugs that produce ataxia in humans, such as ethanol or diazepam, decrease locomotor and rearing activity in rats (Hughes, 1993) and induce deficits in coordinated hind limb movements (Kulig et al., 1985). In studies employing a wheel-speed significant deficits in coordinated hind limb movement could be detected following the acute i.p. administration of diazepam and ethyl alcohol (Kulig et al., 1985). The footprint test analysis is a method to assess integrity of locomotion function, not only by examining ability to move but also by the quality of movement itself (Goldberger et al., 1990). It enables one to measure an animal’s individual limb rotation, base of support and stride length during overground locomotion. Generalized observations of locomotion are not sufficiently sensitive to assess pattern of locomotion deficit (Kunkel-Bagden et al., 1993). For example, there are experimental evidences indicating that an animal’s ability to cross a narrow beam


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Fig. 4. Catalepsy induced by L-NOARG (50 nmol), L-NAME (200 nmol), L-NMMA (100 nmol) and 7NIO (100 nmol) microinjected i.c.v. in rats (N = 8–10 animals per group). Rats were anesthetized and fixed in a stereotaxic frame. For i.c.v. injection a stainless steel guide cannula (0.7 mm OD) was implanted aimed at the right lateral ventricle (coordinates: AP = −1 mm from bregma, L = 1.6 mm, D = 3.5 mm). The cannulae were attached to the bones with stainless steel screws and acrylic cement. A stiletto inside the guide cannulas prevented obstruction. Five to seven days after the surgery i.c.v. injections were performed with a thin dental needle (0.3 mm OD) that was introduced through the guide cannula until its tip was 1.5 mm below the cannula end. A volume of 1 µL was injected in 1 min using a microsyringe (Hamilton). A polyethylene catheter (PE 10) was interposed between the upper end of the dental needle and the microsyringe. The movement of an air bubble inside the polyethylene catheter confirmed drug flow. Catalepsy was evaluated by placing the animal with both forelegs over a horizontal glass bar (diameter 0.5 cm) elevated 9.0 cm from the floor. The time (in s) during which the rat maintained this position was recorded up to 180 s. Bars represent the means ± SEM. Asterisks indicate significant difference from saline (ANOVA followed by the Duncan test, P < 0.05).

recovers after sensory motor cortex injury in terms of time to cross the beam, but when the animal’s movement patterns while crossing are analyzed the deficits are still detected (Keifer and Kalil, 1991). We showed that animals tested while walking under L-NOARG treatment do not show any modification in their locomotion pattern (Del Bel et al., 2002). Therefore, the reduced exploratory activity induced by L-NOARG does not relate to any gross impairment of locomotion pattern.

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TOLERANCE TO THE CATALEPTIC EFFECT Both the cataleptic effect (Marras et al., 1995; Del Bel et al., 1998) and the decrease in exploratory activity induced by acute doses of L-NOARG (Del Bel et al., 2002) suffered tolerance after 3 or 4 days of treatment. L-NOARG sub-chronic administration produced tolerance to L-NOARG and to haloperidol-induced catalepsy (Marras et al., 1995; Del Bel et al., 1998; Del Bel and Guimaraes, 2000, Fig. 5). Similar results were found with the more selective neuronal NOS inhibitor 7-NIO. This strengthens a possible relation between the haloperidol and NOS inhibitors effects. The mechanism involved in this rapid tolerance development is unknown. Although chronic treatment with haloperidol is also able to induce tolerance for its catalepsy-inducing effect, it usually needs 25 days of chronic treatment (Ezrin-Waters and Seeman, 1977; Sanberg et al., 1988). Accordingly, no tolerance was detected in our study after 4 days of haloperidol administration. Tolerance to neuroleptics has been attributed to compensatory mechanisms that would, at least in part, restore cerebral dopaminergic neurotransmission. According to one hypothesis, long-term neuroleptic treatment would lead to an increase in D2 receptor density (Iversen et al., 1980). A second hypothesis proposes that neurons located postsynaptically to the dopaminergic cells would adapt to chronic receptor blockade, as has already been shown in cholinergic neurons of the basal ganglia (Korf and Sebens, 1987).

Fig. 5. Effects of chronic treatment with saline (sal) or L-NOARG (Nrg, 40 mg/kg i.p., twice a day, during 4 days) on catalepsy induced by haloperidol (Hal, 1.0 mg/kg i.p.), or L-NOARG (40 mg/kg i.p.). Animals were tested 1 h after the last drug injection. L-NOARG subchronic administration produced tolerance to L-NOARG and to haloperidol-induced catalepsy. Asterisks indicate significant differences from nrg-HAL and nrg-NRG groups. Further specifications as in Fig. 3.


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According to a third hypothesis, tolerance to antipsychotic drugs would be the result of a higher affinity of the dopamine receptors towards agonist binding (Allikmets et al., 1981; Pycock et al., 1982). It is unknown, however, if similar mechanisms are involved in the tolerance to the haloperidol effect seen after only 4 days of L-NOARG treatment. It is possible that the development of this tolerance depends on plastic changes of the brain NOS system. Chronic treatment with L-NOARG increased the number of NADPH-d-positive cells in the dorsal part of the caudate and accumbens nuclei, as compared to haloperidol-treated animals, and in the pedunculopontine tegmental nucleus, as compared to saline-treated rats. In contrast, it decreases NADPH-d neuron number in the substantia nigra, pars compacta, an effect also found after chronic haloperidol treatment (Del Bel and Guimaraes, 2000). Several studies have shown that antagonism of NMDA-mediated transmission attenuates catalepsy induced by dopamine receptor antagonists such as haloperidol (Zarrindast et al., 1993; Morris et al., 1997). Since animals that became tolerant to L-NOARG are also tolerant to haloperidol effects, and NO has complex effects on N-methyl-D-aspartate (NMDA)-mediated neurotransmission, it is also possible that an influence of NO on dopamine neurotransmission is mediated by effects on NMDA neurotransmission.

MOTOR EFFECTS OF NOS INHBITORS: POSSIBLE MECHANISMS OF ACTION As suggested earlier, the mechanism of the locomotor effects of NOS inhibitors may involve interference with dopaminergic neurotransmission in the striatum (Morris et al., 1988, 1997). Whereas L-NOARG had an additive effect with haloperidol (Marras et al., 1995), apomorphine, a DA agonist, inhibits L-NOARG catalepsy (Table I). Although there are contradictory results (Silva et al., 1995) most

Table I.

Drug Effects on Catalepsy Induced by L-NOARG and Haloperidol

Treatment

L-NOARG Haloperidol

Atropine (Muscarinic antagonist)

−

−

Atropine-Methylnitrate Biperiden (Muscarinic antagonist)

0 −

Not done −

Apomorphin (DA agonist)

−

−

Ketanserin (5HT2A antagonist)

+

−

WAY 100135 (5HT1A parcial agonist)

+

±

Amantadine (NMDA antagonist)

±

−

Note. −: inhibition; +: activation; 0: no effect.

Reference Del Bel et al., 1998; Klemm, 1983; Klemm, 1985; Ushijima et al., 1997 Del Bel, unpublished results Oka et al., 1979; Del Bel et al., unpublished results Elliott et al., 1990; Del Bel et al., unpublished results Ninan and Kuilkarni, 1999; Nucci-da-Silva et al., 1999 Nucci-da Silva et al., 1999; Prinssen et al., 2002 Danysz et al. 1994; Moore et al., 1993; Papa et al., 1993; Yoshida et al., 1994; Del Bel, unpublished results

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studies suggest that, under physiological conditions, NO increases striatal dopamine by facilitating its release (Black et al., 1994; Stewart et al., 1996; Iravani et al., 1998; West and Galloway, 1998; West et al., 2002) and/or by decreasing its reuptake (Guevara-Guzman et al., 1994; Kiss and Vizi, 2001). The effects of NO may vary depending on several factors such as the functional state of the target neurons and the instant composition of the extracellular fluid. Small changes in NO local concentration may be a key factor in determining its biological effect (Contestabile, 2000). This may be related to the usual bell-shaped dose-response curves found with NOS inhibitors. For example, excessive production of NO may negatively modulate NMDA function (Contestabile, 2000) and a reduction in glutamate release induced by elevation of cGMP levels or administration of a NO donor has been described in rat nerve terminals (Sistiaga et al., 1997). There are suggestions that, at high concentrations, NOS inhibitors may be converted to L-arginine (Hecker et al., 1990) or interfere with endothelial NOS (Esplugues, 2002). Another possibility would be a dual effect of NO on dopamine or glutamatemediated neurotransmission in the striatum. An inhibitory, rather than facilitatory, role of NO on striatal dopamine release has been suggested by some studies (Silva et al., 1995, 2003). Glutamate mediated neurotransmission interacts with DA neurotransmission in the striatum and plays an important role in controlling motor behavior (Calabresi et al., 1997; West et al., 2002). For example, antagonism of NMDA receptors attenuates catalepsy induced by DA receptor antagonists such as haloperidol (Moore et al., 1993; Papa et al., 1993; Yoshida et al., 1994). NOS neurons in the striatum receive glutamate inputs and this enzyme is closely associated with NMDA receptors thought the postsynaptic protein PSD95 (Esplugues, 2002). Those neurons are proposed to act as detectors of glutamatergic activity, signaling glutamate-mediated activity to the environment. NO can inhibit monoamine reuptake, thus increasing the half-live of DA in the extracellular space (Kiss and Vizi, 2001). Electrophysiological study also showed that systemic administration of a neuronal NOS inhibitor increases the firing rate of a subpopulation of striatal cells, possibly output neurons (Sardo et al., 2002). NO has complex interactions with NMDA-mediated neurotransmission. It can mediate NMDA-induced increase in cGMP and facilitate glutamate release but antagonize NMDA receptors (Garthwaite, 1991; Hoyt et al., 1992; Manzoni et al., 1992; Lipton et al., 1993). It can also facilitate DA release via NMDA-receptor dependent and independent mechanisms (West et al., 2002). However, although NOmediated increase in striatal DA efflux is blocked by glutamate antagonists, these latter compounds failed to decrease basal DA efflux. This suggests that, although basal DA release in the striatum is not under the influence of endogenous glutamate, this neurotransmitter is important for NO-mediated facilitation of DA (Calabresi et al., 1997; West et al., 2002). Amantadine, originally used in the treatment and prophylaxis of influenza infection, has also proved to be beneficial in drug-induced Parkinsonism, Parkinson’s disease, traumatic head injury, dementia, multiple sclerosis, and cocaine withdrawal. Amantadine appears to act through several pharmacological mechanisms, none of which has been identified as the chief mode of action. It acts on dopaminergic, noradrenergic and serotonergic-mediated neurotransmission, blocks monoaminoxidase A and, trough uncompetitive channel blockade, inhibits


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glutamate NMDA receptor. It also seems to raise beta-endorphin/beta-lipotropin levels. The doses of amantadine and MK-801 that show anti-Parkinsonian-like activity in animals result in plasma levels that cause NMDA antagonism (Danysz et al., 1994). Amantadine in low (25 mg/kg), but not high (50 mg/kg), doses increased catalepsy induced by L-NOARG (Table I). In contrast, this drug produced dose-dependent inhibition of haloperidol-induced catalepsy (Danysz et al., 1994), suggesting that other mechanisms besides interference with dopamine-mediated neurotransmission are involved in the cataleptic effect of NOS inhibitors (West et al., 2002). Accordingly, we have recently showed that catalepsy induced by L-NOARG is modulated by drugs that modified serotonergic neurotransmission (Nucci-da-Silva et al., 1999; Table I). The cataleptogenic effect of L-NOARG was enhanced by pretreatment with (+)-N-tert-butyl-3-(4-[2-methoxyphenyl] piperazin-1-yl)-2-phenylpropanamide ((+)-WAY-100135), a 5-HT1A-selective receptor antagonist, or by ketanserin, a 5-HT2A receptor and α1 -adrenoceptor antagonist. Prazosin, an α1 adrenoceptor antagonist, and endo-N-(8-methyl-8-azabicyclo [3.2.1] oct-3yl)-2,3dihydro-3,3-dimethyl—indole—1-carboxamide HCl (BRL-46470A), a 5-HT3 receptor antagonist, did not interfere with L-NOARG-induced catalepsy. Ritanserin, a 5-HT2a and 5-HT2C receptor antagonist, tended to enhance the effect of L-NOARG. Anticholinergic drugs readily reverse neuroleptic-induced catalepsy in rats (Klemm, 1983, 1985; Ushijima et al., 1997). Atropine sulphate blocks L-NOARGinduced catalepsy in mice; this effect is probably centrally mediated, since no influence on NOS inhibitors-induced catalepsy was seen after i.p. injection of quaternary atropine (atropine methylnitrate, Table I), that does not cross the blood-brain barrier. Biperiden, an antiparkinsonian drug which has antimuscarinic and NMDA receptor antagonist properties, also blocks the cataleptic effect of NOS inhibitors or haloperidol (Oka et al., 1979). It is interesting that one of the principal groups of cholinergic neurons is located in the nucleus tegmental pedunculopontinus (Hirsch et al., 1987). This nucleus contain cholinergic cells that project to the extrapyramidal motor system. Virtually all cholinergic cells in this region express NOS mRNA (Sugaya and McKinney, 1994).

NITRIC OXIDE SYSTEM AND EXPERIMENTAL PARKINSON’S Parkinson’s disease (PD) is a neurological disorder that affects movement, balance, and fine motor control. These impairments are related to the progressive degeneration of DA neurons in the Substantia Nigra Compacta, with a concomitant reduction of striatal dopamine levels (Agid et al., 1987; Fahn, 1988). Animals in which this nigrostriatal pathway has been experimentally destroyed are considered useful preparations for PD study (Sugaya and McKinney, 1994). These preparations have clarified the anatomy, neurochemistry, and electrophysiology of dopaminergic neurons and their relationships with other associated brain nuclei. The nigrostriatal DA pathway consists of the A9 cell group, which is located in the substantia nigra pars compacta. The axons of these neurons run along the medial forebrain bundle to reach the dorsal neostriatum (caudate putamen nucleus).

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Electrolytic lesion of the Substantia Nigra will result in apomorphine-induced turning behavior. Although the precise mechanism and neuronal pathways mediating circling behavior in this model remain to be established, it may reflect an imbalance between dopaminergic mechanisms (Costall et al., 1976; Royland et al., 1999). After unilateral DA damage the homologous contralateral anatomical sites would become dominant, with turning behavior developing contralateral to the dominant side. Electrolytic lesions, however, induce nonspecific destruction of neuronal and glial cells, as well as connective tissue, in the vicinity to the electrode tip. It may, therefore, destroy other neuronal pathways in addition to the ascending nigrostriatal tract (Costall et al., 1976). The neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2, 3,6-tetrehydropyridine (MPTP) have been used in various mammalian species to produce experimental PD. In modeling experimental Parkinson a major advance was the introduction of the catecholamine neurotoxin 6-OHDA (Saner and Thoenen, 1971; Deumens et al., 2002). This molecule is transported into the cell bodies and fibers of both dopaminergic and noradrenergic neurons. It causes degeneration of nerve terminals and can affect cell body regions. Microinjection of 6-OHDA into the Medial Forebrain Bundle can cause a total destruction of Substantia Nigra Compacta and ventral tegmental area neurons (Ungerstedt, 1968). It results in a well-described syndrome that includes (i) near total depletion of DA in the ipsilateral CaudatePutamen; (ii) denervation supersensitivity of postsynaptic DA receptors in the ipsilateral CaudatePutamen; and (iii). a characteristic functional asymmetry, with quantifiable turning behavior contralateral to lesion side, in response to the direct DA agonist apomorphine (Ungerstedt, 1971a,b). Various factors, however, can influence 6-OHDA effects. For example, administration of the toxin into the Medial Forebrain Bundle, Substantia Nigra Compacta or Caudate Putamen can produce variable results regarding the extent of the lesion and the lesioned pathways (Iwamoto et al., 1976; Amalric et al., 1995; Barneoud et al., 1995; Gerlach and Riederer, 1996). Administration of 6-OHDA into the Medial Forebrain Bundle, the axon bundle that partly projects to the CaudatePutamen (Deumens et al., 2002), promotes almost complete lesions, with very few surviving DA neurons. This is an important point, since deficits induced by small lesions can probably be compensated by adaptive neural mechanisms. For example, small depletions of striatal DA after electrolytic lesion have been associated with lower intensity of ipsilateral circling to apomorphine (Costall and Naylor, 1975; Costall et al., 1976). More extensive lesions of the CaudatePutamen (>90% reduction in the CaudatePutamen DA fiber density) and Substantia Nigra Compacta (>50% depletion of dopaminergic neurons) are required to generate rotations demonstrable with low doses of apomorphine (Pycock, 1980). The etiology of Parkinson Disease is not known. However, biochemical data from human brain autopsy studies and from animal models point out to an ongoing oxidative stress process in the substantia nigra, which could induce degeneration of nigrostriatal DA neurons (Johnsson, 1983; Cohen, 1987). Although the electrolytic and 6-OHDA PD models have in common the experimentally induced destruction of nigrostriatal neurons, the neurotoxic process shows no progression, in contrast with the chronic progressive course of PD. Moreover, electrolytic and 6-OHDA-induced


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lesions have been shown to neurochemically differ (Iwamoto et al., 1976) probably because the former is also able to destroy additional neuronal pathways in addition to DA nigrostriatal tract (Costall and Naylor, 1975; Costall et al., 1976). Also, the electrolytic lesion of Substantia Nigra Compacta causes a similar depletion of striatal DA but no loss of limbic DA (Costall and Naylor, 1975; Costall et al., 1976). We recently published a study showing that the number of NADPH-d and NOS positive neurons increase in ipsilateral CaudatePutamen (Fig. 6) and decrease in the substantia nigra after either 6-OHDA or electrolytic lesions of the medial forebrain bundle (Gomes and Del Bel, 2003). Only in animals that received 6-OHDA the number of cells decreased in contralateral nucleus accumbens. This evidence may raise questions regarding which brain NO containing structure is mainly affected on Parkinson’s disease. Our findings are in agreement with previous studies of our group

Fig. 6. Effect of L-NOARG chronic treatment (40 mg/kg i.p. twice a day for 4 days) in the number of NADPH-d positive neurons in the CaudatePutamen (Striatum). A = CaudatePutamen from animals treated chronically with saline; B = CaudatePutamen from animals treated chronically with L-NOARG. Further specifications as in Figs. 1 and 5.

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(Ponzoni et al., 2000), showing an increase in CaudatePutamen NADPH-d neurons after lesion of Substantia Nigra compacta caused by manganese chloride. In this study, a protective role of NO was suggested since systemic L-NOARG treatment increased apomorphine-induced rotations. Subchronic inhibition of NO synthesis increased the number of NADPH-d positive neurons in CaudatePutamen and decreased it in the Substantia Nigra Compacta (Del Bel and Guimaraes, 2000). In contrast, Castagnoli et al. (1999), Hantraye et al. (1996), described a neuroprotective role of 7NIO in animal model of Parkinsonism. Results obtained using postmortem brains suggest that NO systems in the basal ganglia can be altered in Parkinson Disease patients (Mufson and Brandabur, 1994). In these patients a significant increase in NOS mRNA expression was observed in the medial medullar lamina of the globus pallidus whereas it was significantly reduced in the putamen (Eve et al., 1998). Hunot et al. (1996) found a significant increase in NADPH-d-positive cell density in DA cell groups characterized by neuronal loss in Parkinson Disease. Further studies are needed to elucidate NO role in Parkinsonism. CONCLUSIONS Our results show that NO modulates motor behavior, probably by interfering with dopaminergic, serotonergic, cholinergic and glutamate neurotransmission in the striatum. They also show that chronic NO synthesis inhibition induces plastic changes in NO-producing neurons in areas related to motor control and caused cross-tolerance to the cataleptic effect of haloperidol. This raises the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, our experimental Parkinson disease studies suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system. ACKNOWLEDGMENTS We acknowledge the helpful technical support provided by C. A da Silva, J. C. de Aguiar, E. T. Gomes; S. Saltareli, E. C. Zieri, P. Marchi, and R. Ferreira-da-Silva. The authors were recipients of CNPq, FAPESP and CAPES fellowships. EADB wish to dedicate this paper to Hugo Arechiga. REFERENCES Abekawa, T., Ohmori, T., and Koyama, T. (1994). Effect of NO synthase inhibition on behavioral changes induced by a single administration of methamphetamine. Brain Res. 666:147–150. Agid, Y., Javoy-Agid, F., and Ruberg, M. (1987). Biochemistry of neurotransmitters in Parkinson’s disease. In Marsden, C. D., and Fahn, S. (eds.), Movement Disorders, Butterworths, London, pp. 166–230. Allikmets, L. H., Zarkovsky, A. M., and Nurk, A. M. (1981). Changes in catalepsy and receptor sensitivity following chronic neuroleptic treatment. Eur. J. Pharmacol. 75:145–147.


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Amalric, M., Moukhles, H., Nieoullon, A., and Daszuta, A. (1995). Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat. Eur. J. Neurosci. 7:972–980. Araki, T., Mizutani, H., Matsubara, M., Imai, Y., Mizugaki, M., and Itoyama, Y. (2001). Nitric oxide synthase inhibitors cause motor deficits in mice. Eur. Neuropsychopharmacol. 11:125–133. Ariano, M. A. (1983). Distribution of components of the guanosine 3 ,5 -phosphate system in rat caudateputamen. Neuroscience 10:707–723. Ariano, M. A., Lewicki, J. A., Brandwein, H. J., and Murad, F. (1982). Immunohistochemical localization of guanylate cyclase within neurons of rat brain. Proc. Natl. Acad. Sci. U.S.A 79:1316–1320. Ariano, M. A., and Matus, A. I. (1981). Ultrastructural localization of cyclic GMP and cyclic AMP in rat striatum. J. Cell Biol. 91:287–292. Babbedge, R. C., Hart, S. L., and Moore, P. K. (1993a). Anti-nociceptive activity of nitric oxide synthase inhibitors in the mouse: Dissociation between the effect of L-NAME and L-NMMA. J. Pharm. Pharmacol. 45:77–79. Babbedge, R. C., Wallace, P., Gaffen, Z. A., Hart, S. L., and Moore, P. K. (1993b). L-NG-nitro arginine p-nitroanilide (L-NAPNA) is anti-nociceptive in the mouse. Neuroreport 4:307–310. Barjavel, M. J., and Bhargava, H. N. (1995). Nitric oxide synthase activity in brain regions and spinal cord of mice and rats: Kinetic analysis. Pharmacology 50:168–174. Barneoud, P., Parmentier, S., Mazadier, M., Miquet, J. M., Boireau, A., Dubedat, P., and Blanchard, J. C. (1995). Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat. Neuroscience 67:837–848. Black, M. D., Matthews, E. K., and Humphrey, P. P. (1994). The effects of a photosensitive nitric oxide donor on basal and electrically-stimulated dopamine efflux from the rat striatum in vitro. Neuropharmacology 33:1357–1365. Bohme, G. A., Bon, C., Stutzmann, J. M., Doble, A., and Blanchard, J. C. (1991). Possible involvement of nitric oxide in long-term potentiation. Eur. J. Pharmacol. 199:379–381. Bredt, D. S. (1999). Endogenous nitric oxide synthesis: Biological functions and pathophysiology. Free Radic. Res. 31:577–596. Bredt, D. S., Hwang, P. M., and Snyder, S. H. (1990). Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347:768–770. Bredt, D. S., and Snyder, S. H. (1990). Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. U.S.A 87:682–685. Bredt, D. S., and Snyder, S. H. (1992). Nitric oxide, a novel neuronal messenger. Neuron 8:3–11. Buisson, A., Margaill, I., Callebert, J., Plotkine, M., and Boulu, R. G. (1993). Mechanisms involved in the neuroprotective activity of a nitric oxide synthase inhibitor during focal cerebral ischemia. J. Neurochem. 61:690–696. Calabresi, P., Pisani, A., Centonze, D., and Bernardi, G. (1997). Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum. Neurosci. Biobehav. Rev. 21:519– 523. Carreau, A., Duval, D., Poignet, H., Scatton, B., Vige, X., and Nowicki, J. P. (1994). Neuroprotective efficacy of N omega-nitro-L-arginine after focal cerebral ischemia in the mouse and inhibition of cortical nitric oxide synthase. Eur. J. Pharmacol. 256:241–249. Castagnoli, K., Palmer, S., and Castagnoli, N., Jr. (1999). Neuroprotection by (R)-deprenyl and 7nitroindazole in the MPTP C57BL/6 mouse model of neurotoxicity. Neurobiology (Bp) 7:135–149. Caton, P. W., Tousman, S. A., and Quock, R. M. (1994). Involvement of nitric oxide in nitrous oxide anxiolysis in the elevated plus-maze. Pharmacol. Biochem. Behav. 48:689–692. Cavas, M., and Navarro, J. F. (2002). Coadministration of L-NOARG and tiapride: Effects on catalepsy in male mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 26:69–73. Cheramy, A., Leviel, V., and Glowinski, J. (1981). Dendritic release of dopamine in the substantia nigra. Nature 289:537–542. Choi, D. W. (1993). Nitric oxide: Foe or friend to the injured brain? Proc. Natl. Acad. Sci. U.S.A. 90:9741– 9743. Clarke, K. A., and Still, J. (1999). Gait analysis in the mouse. Physiol. Behav. 66:723–729. Coderre, T. J. (1993). The role of excitatory amino acid receptors and intracellular messengers in persistent nociception after tissue injury in rats. Mol. Neurobiol. 7:229–246. Cohen, G. (1987). Monoamine oxidase, hydrogen peroxide, and Parkinson’s disease. Adv. Neurol. 45:119– 125. Contestabile, A. (2000). Roles of NMDA receptor activity and nitric oxide production in brain development. Brain Res. Brain Res. Rev. 32:476–509. Costall, B., Marsden, C. D., Naylor, R. J., and Pycock, C. J. (1976). The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain. Brain Res. 118:87–113.

388

Del Bel et al.

Costall, B., and Naylor, R. J. (1975). A comparison of circling models for the detection of antiparkinson activity. Psychopharmacologia 41:57–64. Dall’Igna, O. P., Dietrich, M. O., Hoffmann, A., Neto, W., Vendite, D., Souza, D. O., and Lara, D. R. (2001). Catalepsy and hypolocomotion induced by a nitric oxide donor: Attenuation by theophylline. Eur. J. Pharmacol. 432:29–33. Danysz, W., Gossel, M., Zajaczkowski, W., Dill, D., and Quack, G. (1994). Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?—Case of amantadine and memantine. J. Neural Transm. Park Dis. Dement. Sect. 7:155–166. Dawson, T. M., Bredt, D. S., Fotuhi, M., Hwang, P. M., and Snyder, S. H. (1991). Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Natl. Acad. Sci. U.S.A. 88:7797–7801. de Medinaceli, L., Freed, W. J., and Wyatt, R. J. (1982). An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp. Neurol. 77:634–643. De Oliveira, C. L., Del Bel, E. A., and Guimaraes, F. S. (1997a). Effects of L-NOARG on plus-maze performance in rats. Pharmacol. Biochem. Behav. 56:55–59. De Oliveira, C. L., Del Bel, E. A., and Guimaraes, F. S. (1997b). Effects of L-NOARG on plus-maze performance in rats. Pharmacol. Biochem. Behav. 56:55–59. De Oliveira, R. M., Del Bel, E. A., and Guimaraes, F. S. (2001). Effects of excitatory amino acids and nitric oxide on flight behavior elicited from the dorsolateral periaqueductal gray. Neurosci. Biobehav. Rev. 25:679–685. Del Bel, E. A., da Silva, C. A., and Guimaraes, F. S. (1998). Catalepsy induced by nitric oxide synthase inhibitors. Gen. Pharmacol. 30:245–248. Del Bel, E. A., da Silva, C. A., Guimaraes, F. S., and Bermudez-Echeverry, M. (2004). Catalepsy induced by intra-striatal administration of nitric oxide synthase inhibitors in rats. Eur. J. Pharmacol. 485:175– 181. Del Bel, E. A., and Guimaraes, F. S. (2000). Sub-chronic inhibition of nitric-oxide synthesis modifies haloperidol-induced catalepsy and the number of NADPH-diaphorase neurons in mice. Psychopharmacology (Berl) 147:356–361. Del Bel, E. A., Oliveira, P. R., Oliveira, J. A., Mishra, P. K., Jobe, P. C., and Garcia-Cairasco, N. (1997). Anticonvulsant and proconvulsant roles of nitric oxide in experimental epilepsy models. Braz. J. Med. Biol. Res. 30:971–979. Del Bel, E. A., Souza, A. S., Guimaraes, F. S., da Silva, C. A., and Nucci-da-Silva, L. P. (2002). Motor effects of acute and chronic inhibition of nitric oxide synthesis in mice. Psychopharmacology (Berl) 161:32–37. Deumens, R., Blokland, A., and Prickaerts, J. (2002). Modeling Parkinson’s disease in rats: An evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp. Neurol. 175:303–317. Dwyer, M. A., Bredt, D. S., and Snyder, S. H. (1991). Nitric oxide synthase: Irreversible inhibition by L-NG-nitroarginine in brain in vitro and in vivo. Biochem. Biophys. Res. Commun. 176:1136–1141. Dzoljic, E., De Vries, R., and Dzoljic, M. R. (1997). New and potent inhibitors of nitric oxide synthase reduce motor activity in mice. Behav. Brain Res. 87:209–212. Elliott, P. J., Close, S. P., Walsh, D. M., Hayes, A. G., and Marriott, A. S. (1990). Neuroleptic-induced catalepsy as a model of Parkinson’s disease. I. Effect of dopaminergic agents. J. Neural Transm. Park Dis. Dement. Sect. 2:79–89. Esplugues, J. V. (2002). NO as a signalling molecule in the nervous system. Br. J. Pharmacol. 135:1079– 1095. Eve, D. J., Nisbet, A. P., Kingsbury, A. E., Hewson, E. L., Daniel, S. E., Lees, A. J., Marsden, C. D., and Foster, O. J. (1998). Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson’s disease. Brain Res. Mol. Brain Res. 63:62–71. Ezrin-Waters, C., and Seeman, P. (1977). Tolerance of haloperidol catalepsy. Eur. J. Pharmacol. 41:321– 327. Fahn, S. (1988). Parkinsonism. In Wyngaarden, J. B., and Smith, L. H., Jr. (eds.), Cecil’s Textbook of medicine, Saunders, Philadelphia, pp. 2143–2147. Faria, M. S., Muscara, M. N., Moreno, J. H., Teixeira, S. A., Dias, H. B., De Oliveira, B., Graeff, F. G., and De Nucci, G. (1997). Acute inhibition of nitric oxide synthesis induces anxiolysis in the plus maze test. Eur. J. Pharmacol. 323:37–43. Forstermann, U., Schmidt, H. H., Pollock, J. S., Sheng, H., Mitchell, J. A., Warner, T. D., Nakane, M., and Murad, F. (1991). Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem. Pharmacol. 42:1849–1857. Garthwaite, J. (1991). Glutamate, nitric oxide and cell–cell signalling in the nervous system. Trends Neurosci. 14:60–67.


389

Gerlach, M., and Riederer, P. (1996). Animal models of Parkinson’s disease: An empirical comparison with the phenomenology of the disease in man. J. Neural Trans. 103:987–1041. Goldberger, M. E., Bregman, B. S., Vierck, C. J., Jr., and Brown, M. (1990). Criteria for assessing recovery of function after spinal cord injury: Behavioral methods. Exp. Neurol. 107:113–117. Gomes, M. Z., and Del Bel, E. A. (2003). Effects of electrolytic and 6-hydroxydopamine lesions of rat nigrostriatal pathway on nitric oxide synthase and nicotinamide adenine dinucleotide phosphate diaphorase. Brain Res. Bull. 62:107–115. Graeff, F. G. (1990). Brain defense system and anxiety. In Burrows, G. D., Roth, M., and Noyes, R. (eds.), Handbook of Anxiety, Elsevier Science, Amsterdam, pp. 307–354. Graveland, G. A., Williams, R. S., and DiFiglia, M. (1985). Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227:770–773. Graybiel, A. M. (1990). Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. 13:244–254. Graybiel, A. M., Besson, M. J., and Weber, E. (1989). Neuroleptic-sensitive binding sites in the nigrostriatal system: Evidence for differential distribution of sigma sites in the substantia nigra, pars compacta of the cat. J. Neurosci. 9:326–338. Greenberg, J. H., Hamada, J., and Rysman, K. (1997). Distribution of N(omega)-nitro-L-arginine following topical and intracerebroventricular administration in the rat. Neurosci. Lett. 229:1–4. Guevara-Guzman, R., Emson, P. C., and Kendrick, K. M. (1994). Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J. Neurochem. 62:807–810. Guimaraes, F. S., de Aguiar, J. C., Del Bel, E. A., and Ballejo, G. (1994). Anxiolytic effect of nitric oxide synthase inhibitors microinjected into the dorsal central grey. Neuroreport 5:1929–1932. Hantraye, P., Brouillet, E., Ferrante, R., Palfi, S., Dolan, R., Matthews, R. T., and Beal, M. F. (1996). Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat. Med. 2:1017–1021. Hauber, W. (1998). Involvement of basal ganglia transmitter systems in movement initiation. Prog. Neurobiol. 56:507–540. Hecker, M., Mitchell, J. A., Harris, H. J., Katsura, M., Thiemermann, C., and Vane, J. R. (1990). Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine. Biochem. Biophys. Res. Commun. 167:1037–1043. Hirsch, E. C., Graybiel, A. M., Duyckaerts, C., and Javoy-Agid, F. (1987). Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc. Natl. Acad. Sci. U.S.A. 84:5976–5980. Hope, B. T., Michael, G. J., Knigge, K. M., and Vincent, S. R. (1991). Neuronal NADPH diaphorase is a nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A 88:2811–2814. Hoyt, K. R., Tang, L. H., Aizenman, E., and Reynolds, I. J. (1992). Nitric oxide modulates NMDA-induced increases in intracellular Ca2+ in cultured rat forebrain neurons. Brain Res. 592:310–316. Hughes, R. N. (1993). Effects on open-field behavior of diazepam and buspirone alone and in combination with chronic caffeine. Life Sci. 53:1217–1225. Hunot, S., Boissiere, F., Faucheux, B., Brugg, B., Mouatt-Prigent, A., Agid, Y., and Hirsch, E. C. (1996). Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 72:355– 363. Iadecola, C., Xu, X., Zhang, F., Hu, J., and el Fakahany, E. E. (1994). Prolonged inhibition of brain nitric oxide synthase by short-term systemic administration of nitro-L-arginine methyl ester. Neurochem. Res. 19:501–505. Inglis, W. L., and Winn, P. (1995). The pedunculopontine tegmental nucleus: Where the striatum meets the reticular formation. Prog. Neurobiol. 47:1–29. Iravani, M. M., Millar, J., and Kruk, Z. L. (1998). Differential release of dopamine by nitric oxide in subregions of rat caudate putamen slices. J. Neurochem. 71:1969–1977. Iversen, S. D., Howells, R. B., and Hughes, R. P. (1980). Behavioral consequences of long-term treatment with neuroleptic drugs. Adv. Biochem. Psychopharmacol. 24:305–313. Iwamoto, E. T., Loh, H. H., and Way, E. L. (1976). Circling behavior in rats with 6-hydroxydopamine or electrolytic nigral lesions. Eur. J. Pharmacol. 37:339–356. Johnsson, G. (1983). Chemical lesioning techniques:monoamine neurotoxins. In Bjorklund, A., and Hokfelt, T. (eds.), Handbook of Chemical Neuroanatomy, Sciences Publishers, Amsterdam, pp. 463–507. Johnston, H. M., and Morris, B. J. (1994). NMDA and nitric oxide increase microtubule-associated protein 2 gene expression in hippocampal granule cells. J. Neurochem. 63:379–382. Kawaguchi, Y. (1993). Physiological, morphological, and histochemical characterization of three classes of interneurons in rat neostriatum. J. Neurosci. 13:4908–4923.

390

Del Bel et al.

Keifer, J., and Kalil, K. (1991). Effects of infant versus adult pyramidal tract lesions on locomotor behavior in hamsters. Exp. Neurol. 111:98–105. Kiss, J. P., and Vizi, E. S. (2001). Nitric oxide: A novel link between synaptic and nonsynaptic transmission. Trends Neurosci. 24:211–215. Klatt, P., Heinzel, B., John, M., Kastner, M., Bohme, E., and Mayer, B. (1992). Ca2+ /calmodulindependent cytochrome c reductase activity of brain nitric oxide synthase. J. Biol. Chem. 267:11374– 11378. Klemm, W. R. (1983). Cholinergic-dopaminergic interactions in experimental catalepsy. Psychopharmacology (Berl) 81:24–27. Klemm, W. R. (1985). Evidence for a cholinergic role in haloperidol-induced catalepsy. Psychopharmacology (Berl) 85:139–142. Koffer, K. B., Berney, S., and Hornykiewicz, O. (1978). The role of the corpus striatum in neurolepticand narcotic-induced catalepsy. Eur. J. Pharmacol. 47:81–86. Kolesnikov, Y. A., Pick, C. G., and Pasternak, G. W. (1992). NG-nitro-L-arginine prevents morphine tolerance. Eur. J. Pharmacol. 221:399–400. Koob, G. F., Simon, H., Herman, J. P., and Le Moal, M. (1984). Neuroleptic-like disruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems. Brain Res. 303:319–329. Korf, J., and Sebens, J. B. (1987). Relationship between dopamine receptor occupation by spiperone and acetylcholine levels in the rat striatum after long-term haloperidol treatment depends on dopamine innervation. J. Neurochem. 48:516–521. Kriegsfeld, L. J., Eliasson, M. J., Demas, G. E., Blackshaw, S., Dawson, T. M., Nelson, R. J., and Snyder, S. H. (1999). Nocturnal motor coordination deficits in neuronal nitric oxide synthase knock-out mice. Neuroscience 89:311–315. Kulig, B. M., Vanwersch, R. A., and Wolthuis, O. L. (1985). The automated analysis of coordinated hindlimb movement in rats during acute and prolonged exposure to toxic agents. Toxicol. Appl. Pharmacol. 80:1–10. Kunkel-Bagden, E., Dai, H. N., and Bregman, B. S. (1993). Methods to assess the development and recovery of locomotor function after spinal cord injury in rats. Exp. Neurol. 119:153–164. Lavoie, B., and Parent, A. (1994). Pedunculopontine nucleus in the squirrel monkey: Projections to the basal ganglia as revealed by anterograde tract-tracing methods. J. Comp Neurol. 344:210–231. Linden, D. J., and Connor, J. A. (1992). Long-term depression of glutamate currents in cultured cerebellar Purkinje neurons does not require nitric oxide signalling. Eur. J. Neurosci. 4:10–15. Lipton, S. A., Choi, Y. B., Pan, Z. H., Lei, S. Z., Chen, H. S., Sucher, N. J., Loscalzo, J., Singel, D. J., and Stamler, J. S. (1993). A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626–632. Manzoni, O., Prezeau, L., Marin, P., Deshager, S., Bockaert, J., and Fagni, L. (1992). Nitric oxide-induced blockade of NMDA receptors. Neuron 8:653–662. Marras, R. A., Martins, A. P., Del Bel, E. A., and Guimaraes, F. S. (1995). L-NOARG, an inhibitor of nitric oxide synthase, induces catalepsy in mice. Neuroreport 7:158–160. Meffert, M. K., Premack, B. A., and Schulman, H. (1994). Nitric oxide stimulates Ca(2+)-independent synaptic vesicle release. Neuron 12:1235–1244. Mitchell, I. J., Clarke, C. E., Boyce, S., Robertson, R. G., Peggs, D., Sambrook, M. A., and Crossman, A. R. (1989). Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 32:213–226. Mollace, V., Bagetta, G., and Nistico, G. (1991). Evidence that L-arginine possesses proconvulsant effects mediated through nitric oxide. Neuroreport 2:269–272. Moore, N. A., Blackman, A., Awere, S., and Leander, J. D. (1993). NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists. Eur. J. Pharmacol. 237:1–7. Morris, B. J., Hollt, V., and Herz, A. (1988). Dopaminergic regulation of striatal proenkephalin mRNA and prodynorphin mRNA: Contrasting effects of D1 and D2 antagonists. Neuroscience 25:525– 532. Morris, B. J., Simpson, C. S., Mundell, S., Maceachern, K., Johnston, H. M., and Nolan, A. M. (1997). Dynamic changes in NADPH-diaphorase staining reflect activity of nitric oxide synthase: Evidence for a dopaminergic regulation of striatal nitric oxide release. Neuropharmacology 36:1589–1599. Mufson, E. J., and Brandabur, M. M. (1994). Sparing of NADPH-diaphorase striatal neurons in Parkinson’s and Alzheimer’s diseases. Neuroreport 5:705–708. ´ Navarro, J. F., Vera, F., Manzaneque, J. M., Mart´ın-Lopez, M., Santi´ın, L. J., and Pedraza, C. (1997). Tolerance to the cataleptic effect of L-NOARG after subchronic administration in female mice. Med. Sci. Res. 25:625–626.


391

Ninan, I., and Kulkarni, S. K. (1999). Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics. Methods Find. Exp. Clin. Pharmacol. 21:603–608. Noda, Y., Yamada, K., Furukawa, H., and Nabeshima, T. (1995). Involvement of nitric oxide in phencyclidine-induced hyperlocomotion in mice. Eur. J. Pharmacol. 286:291–297. Nucci-da-Silva, L. P., Guimaraes, F. S., and Del Bel, E. A. (1999). Serotonin modulation of catalepsy induced by N(G)-nitro-L-arginine in mice. Eur. J. Pharmacol. 379:47–52. O’Dell, T. J., Hawkins, R. D., Kandel, E. R., and Arancio, O. (1991). Tests of the roles of two diffusible substances in long-term potentiation: Evidence for nitric oxide as a possible early retrograde messenger. Proc. Natl. Acad. Sci. U.S.A. 88:11285–11289. Oka, M., Yamada, K., Kamei, C., Yoshida, K., and Shimizu, M. (1979). Differential antagonism of antiavoidance, cataleptic and ptotic effects of neuroleptics by biperiden. Jpn. J. Pharmacol. 29:435– 445. Onstott, D., Mayer, B., and Beitz, A. J. (1993). Nitric oxide synthase immunoreactive neurons anatomically define a longitudinal dorsolateral column within the midbrain periaqueductal gray of the rat: Analysis using laser confocal microscopy. Brain Res. 610:317–324. Osborne, P. G., O’Connor, W. T., Beck, O., and Ungerstedt, U. (1994). Acute versus chronic haloperidol: Relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release. Brain Res. 634:20–30. Papa, S. M., Engber, T. M., Boldry, R. C., and Chase, T. N. (1993). Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists. Eur. J. Pharmacol. 232:247–253. Ponzoni, S., Guimaraes, F. S., Del Bel, E. A., and Garcia-Cairasco, N. (2000). Behavioral effects of intra-nigral microinjections of manganese chloride: Interaction with nitric oxide. Prog .Neuropsychopharmacol. Biol. Psychiatry 24:307–325. Prinssen, E. P., Colpaert, F. C., and Koek, W. (2002). 5-HT1A receptor activation and anti-cataleptic effects: High-efficacy agonists maximally inhibit haloperidol-induced catalepsy. Eur. J. Pharmacol. 453:217–221. Pycock, C., Dawbarn, D., and O’Shaughnessy, C. (1982). Behavioural and biochemical changes following chronic administration of L-dopa to rats. Eur. J. Pharmacol. 79:201–215. Pycock, C. J. (1980). Turning behaviour in animals. Neuroscience 5:461–514. Quock, R. M., and Nguyen, E. (1992). Possible involvement of nitric oxide in chlordiazepoxide-induced anxiolysis in mice. Life Sci. 51:L255–L260. Rosa, W. C., Oliveira, G. M., and Nakamura-Palacios, E. M. (1994). Effects of the antihypertensive drugs alpha-methyldopa and hydralazine on the performance of spontaneously hypertensive rats in the elevated plus-maze. Braz. J. Med. Biol. Res. 27:55–59. Royland, J. E., Delfani, K., Langston, J. W., Janson, A. M., and Di Monte, D. A. (1999). 7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced ATP loss in the mouse striatum. Brain Res. 839:41–48. Salter, M., Duffy, C., and Hazelwood, R. (1995). Determination of brain nitric oxide synthase inhibition in vivo: Ex vivo assays of nitric oxide synthase can give incorrect results. Neuropharmacology 34:327– 334. Sanberg, P. R., Bunsey, M. D., Giordano, M., and Norman, A. B. (1988). The catalepsy test: Its ups and downs. Behav. Neurosci. 102:748–759. Sanberg, P. R., Pevsner, J., and Coyle, J. T. (1984). Parametric influences on catalepsy. Psychopharmacology (Berl) 82:406–408. Sanberg, P. R., Pisa, M., Faulks, I. J., and Fibiger, H. C. (1980). Experimental influences on catalepsy. Psychopharmacology (Berl) 69:225–226. Sandi, C., Venero, C., and Guaza, C. (1995). Decreased spontaneous motor activity and startle response in nitric oxide synthase inhibitor-treated rats. Eur. J. Pharmacol. 277:89–97. Sandor, N. T., Brassai, A., Puskas, A., and Lendvai, B. (1995). Role of nitric oxide in modulating neurotransmitter release from rat striatum. Brain Res. Bull. 36:483–486. Saner, A., and Thoenen, H. (1971). Model experiments on the molecular mechanism of action of 6hydroxydopamine. Mol. Pharmacol. 7:147–154. Sardo, P., Ferraro, G., Di Giovanni, G., Galati, S., and La, G. V. (2002). Inhibition of nitric oxide synthase influences the activity of striatal neurons in the rat. Neurosci. Lett. 325:179–182. Schmidt, H. H., Gagne, G. D., Nakane, M., Pollock, J. S., Miller, M. F., and Murad, F. (1992). Mapping of neural nitric oxide synthase in the rat suggests frequent co-localization with NADPH diaphorase but not with soluble guanylyl cyclase, and novel paraneural functions for nitrinergic signal transduction. J. Histochem. Cytochem. 40:1439–1456. Shibuki, K., and Okada, D. (1991). Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 349:326–328.

392

Del Bel et al.

Silva, M. T., Rose, S., Hindmarsh, J. G., Aislaitner, G., Gorrod, J. W., Moore, P. K., Jenner, P., and Marsden, C. D. (1995). Increased striatal dopamine efflux in vivo following inhibition of cerebral nitric oxide synthase by the novel monosodium salt of 7-nitro indazole. Br. J. Pharmacol. 114:257–258. Silva, M. T., Rose, S., Hindmarsh, J. G., and Jenner, P. (2003). Inhibition of neuronal nitric oxide synthase increases dopamine efflux from rat striatum. J. Neural Transm. 110:353–362. Sistiaga, A., Miras-Portugal, M. T., and Sanchez-Prieto, J. (1997). Modulation of glutamate release by a nitric oxide/cyclic GMP-dependent pathway. Eur. J. Pharmacol. 321:247–257. Starr, M. S., and Starr, B. S. (1995). Do NMDA receptor-mediated changes in motor behaviour involve nitric oxide? Eur. J. Pharmacol. 272:211–217. Stewart, T. L., Michel, A. D., Black, M. D., and Humphrey, P. P. (1996). Evidence that nitric oxide causes calcium-independent release of [3H] dopamine from rat striatum in vitro. J. Neurochem. 66:131–137. Sugaya, K., and McKinney, M. (1994). Nitric oxide synthase gene expression in cholinergic neurons in the rat brain examined by combined immunocytochemistry and in situ hybridization histochemistry. Brain Res. Mol. Brain Res. 23:111–125. Traystman, R. J., Moore, L. E., Helfaer, M. A., Davis, S., Banasiak, K., Williams, M., and Hurn, P. D. (1995). Nitro-L-arginine analogues. Dose- and time-related nitric oxide synthase inhibition in brain. Stroke 26:864–869. Ungerstedt, U. (1968). 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur. J. Pharmacol. 5:107–110. Ungerstedt, U. (1971a). Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand. Suppl 367:69–93. Ungerstedt, U. (1971b). Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. Acta Physiol Scand. Suppl 367:49–68. Ushijima, I., Kawano, M., Kaneyuki, H., Suetsugi, M., Usami, K., Hirano, H., Mizuki, Y., and Yamada, M. (1997). Dopaminergic and cholinergic interaction in cataleptic responses in mice. Pharmacol. Biochem. Behav. 58:103–108. Uzbay, I. T. (2001). L-NAME precipitates catatonia during ethanol withdrawal in rats. Behav. Brain Res. 119:71–76. Vale, A. L., Green, S., Montgomery, A. M., and Shafi, S. (1998). The nitric oxide synthesis inhibitor L-NAME produces anxiogenic-like effects in the rat elevated plus-maze test, but not in the social interaction test. J. Psychopharmacol. 12:268–272. Vincent, S. R., and Kimura, H. (1992). Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46:755–784. Volke, V., Koks, S., Vasar, E., Bourin, M., Bradwejn, J., and Mannisto, P. T. (1995). Inhibition of nitric oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze. Neuroreport 6:1413–1416. West, A. R., and Galloway, M. P. (1998). Nitric oxide and potassium chloride-facilitated striatal dopamine efflux in vivo: Role of calcium-dependent release mechanisms. Neurochem. Int. 33:493–501. West, A. R., Galloway, M. P., and Grace, A. A. (2002). Regulation of striatal dopamine neurotransmission by nitric oxide: Effector pathways and Signaling mechanisms. Synapse 44:227–245. Wichmann, T., and DeLong, M. R. (1996). Functional and pathophysiological models of the basal ganglia. Curr. Opin. Neurobiol. 6:751–758. Yildiz, F., Ulak, G., Erden, B. F., and Gacar, N. (2000). Anxiolytic-like effects of 7-nitroindazole in the rat plus-maze test. Pharmacol. Biochem. Behav. 65:199–202. Yoshida, Y., Ono, T., Kawano, K., and Miyagishi, T. (1994). Distinct sites of dopaminergic and glutamatergic regulation of haloperidol-induced catalepsy within the rat caudate-putamen. Brain Res. 639:139–148. Zarrindast, M. R., Modabber, M., and Sabetkasai, M. (1993). Influences of different adenosine receptor subtypes on catalepsy in mice. Psychopharmacology (Berl) 113:257–261.