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Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike? Received: 5 March t996/Final version: 5 September ...
Psychopharmacology (1997) 129 : 19%205

9 Springer-Verlag 1997

C o n n i e S~inchez 9 Eddi M e i e r

Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression Are they all alike?

Received: 5 March t996/Final version: 5 September 1996

Abstract The behavioral profiles of five clinically used selective serotonin reuptake inhibitors (SSRIs) citalopram, paroxetine, sertraline, fluvoxamine and fluoxetine, have been compared in animal models of antidepressant (mouse forced swim test), anxiolytic (exploration of black and white test box and footshock-induced ultrasonic vocalization in the rat) and antiaggressive (isolation-induced aggressive behavior in the mouse) aftivity. The results are discussed in relation to receptor binding data from the literature. Furthermore, affinities for the aj and a2 binding sites are presented. Citalopram reversed the immobility induced by forced swimming with a potency similar to that of imipramine. Paroxetine, fluvoxamine and fluoxetine reversed swim-induced immobility less potently and with a maximum of 40-50% reversal. Citalopram produced a mixed anxiogenic-/anxiolyticlike response in rats tested in the two-compartment black and white box. Paroxetine induced an anxiogeniclike response at low doses and the other SSRIs were without major effects. Citalopram and paroxetine inhibited footshock-induced ultrasonic vocalization with high potencies. The dose-response curve was biphasic for citalopram with a maximum of 64% inhibition. Sertraline and fluvoxamine inhibited the vocalization less potently, and fluoxetine induced a weak inhibitory effect corresponding to a maximum of 32%. Sertraline, fluvoxamine and fluoxetine inhibited isolation-induced aggressive behavior, whereas citalopram and paroxetine were inactive. Both 5-HTI and 5-HT2 receptors are involved, and there was a functional interaction between 5-HTIA and 5-HT2A or 5-HT2c receptors, as ritanserin potentiated the antiaggressive effect ofl,5-HTP as well as that of 8-OH-DPAT.

C. Sfinchez ( ~ ) . E. Meier Pharmacological Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen - Valby, Denmark FAX (+45)/36 30 52 67

Serotonin reuptake inhibitors 9 Depression 9 Anxiety 9 Aggression - Rodents

Key words

Introduction

The selective serotonin reuptake inhibitors (SSRIs) are generally referred to as a pharmacologically homogeneous group only exhibiting differences in serotonin reuptake inhibitory potency. However, there are differences in their effect on neurotransmitter receptors and pharmacokinetic profiles (for review see Lane et al. 1995). Qualitative and quantitative differences in side effects have been reported (Devane 1995), and it can also be speculated whether there are differences in their clinical effects, but large clinical studies comparing the efficiency of SSRIs remain to be done. Since the introduction of SSRIs as efficient and safe antidepressants, their use has gradually been extended to treatment of other mental disorders. In particular, the SSRIs have proven to be efficient in treatment of panic disorder and obsessive compulsive disorder (e.g. reviewed by Sheehan et al. 1993). There are also studies suggesting a clinical potential of SSRIs for treatment of aggressive behavior (e.g. Cornelius et al. 1990; Castrogiovanni et al. 1992; Fava et al. 1993; Kallioniemi and Suvfilahti 1993). It might be speculated whether the SSRIs have different efficacies on symptoms other than depressive ones. Results derived from animal experiments might suggest differences in pharmacological profiles of the SSRIs, but further comparative studies performed under standardized conditions need to be done. The SSRIs show variable efficiency in the forced swim test (Porsolt et al. 1979), which is the most frequently used screening model for antidepressant effect (Table 1). Unlike the effect of tricyclic antidepressants (TCAs), the efficiency of SSRIs seems to be highly dependent on experimental procedure and animal strain (review

198 Table 1 Effects of SSRIs in the forced swimming test MED (gmol/kg) Mice

Rats

References

Citalopram Paroxetine Sertraline

20; > 25 43 2.9; 9.3

> 160~ 8.0 64; 15

Fluvoxamine

18; 37; > 230

> 92

Fluoxetine

87; 160

23&

Bourin et al. (1991); Mogilnicka et al. (1987); Porsolt et al. (1979) Bourin et al. (1991); Gdrka et al. (1979) Heym and Koe 1988: Doogan and Caillard, 1988; Cervo et al. (1991); Kelly and Leonard 1994 Nixon et al. (1994); Bourin (1991); Doogan and Caillard (1988); Maj et al. (1982) Cesana et al. (1993); Doogan and Caillard (1988); Porsolt et al. (1979)

aTreatment 24 h and 1 h before test

by Borsini and Meli 1988). SSRIs induce anxiolyticlike effects in some animal models o f anxiety, but the efficacies are model dependent (Olivier 1992). C i t a l o p r a m and sertraline facilitated exploratory behavior in the mouse t w o - c o m p a r t m e n t black and white test box, whereas paroxetine, fluvoxamine and fluoxetine were inactive (S/mchez 1995 and unpublished observations). Fluvoxamine inhibited conditioned ultrasonic distress vocalizations in adult male rats and fluvoxamine and ftuoxetine inhibited separationinduced distress call in rat pups (Olivier et al. 1993; Molewijk et al. 1995). Paroxetine increased the time spent in social interaction under bright light conditions, but only after treatment for 3 weeks (Lightowler et al. 1994). Fluoxetine was inactive in the elevated plus maze, but attenuated the anxiolytic-like effect o f alcohol ( D u r c a n et al. 1988). The SSRIs also show to a variable degree antiaggressive effects in animal models, e.g. fluvoxamine, fluoxetine and sertraline, but not citalopram and paroxetine, inhibited aggressive behavior (Olivier and Mos 1992; Sfinchez and Hyttel 1994). The purpose o f the present study was to make parallel comparisons o f the behavioral profiles of five clinically used SSRIs, citalopram, paroxetine, sertraline, ftuvoxamine and fluoxetine in animal models used to assess antidepressant, anxiolytic and antiaggressive activity. The behavioural findings will be discussed in relation to receptor binding profiles, in particular activity at serotonergic receptors and sigma (a) binding sites. Distribution in C N S and effects in behavioral models suggest that the latter also plays a role in mediation o f emotional responses. The a binding sites are a b u n d a n t in limbic brain regions that are involved in modulating emotional responses, e.g. hippocampus, amygdala (for references see review by Debonnel and de M o n t i g n y 1996). Antidepressants have affinity for the G binding site, e.g. sertraline (Schmidt et al. 1989), opipramol (Rao et al. 1990), and long-term treatment with fluoxetine or imipramine decreases the density o f binding sites (Shirayama et al. 1993). A recent study reported that the GI site is involved in mediation o f conditioned fear stress (Kamei et al. 1996), and the a2 ligand Lu 28-179 is reported to have anxiolytic-like

activity in a n u m b e r of animal models (S5.nchez et al. 1994).

Materials and methods General conditions for animaf housing and testing Animals for the two compartment black and white test were housed under a reversed I2-h day/night cycle (lights off 6 p.m.). These animals were adapted to the reversed light/dark cycle for at least 3 weeks prior to, the testing. Other rats were housed in groups of four in macrolon cages type III. The aggressive mice were singlehoused in Macrolon type II cages, and intruder mice as well as mice used in the forced swimming test were housed in plastic cages (35 x 30 x 12 cm), ten in each. The room temperature (21 + 2~ relative humidity (55 + 5%), and air exchange (16 times per hour) were automatically controlled. The animals had free access to commercial food pellets and tap water before test session. All experiments were carried out in conformity with the ethical rules of the Danish Committee on Care and Use of Laboratory Animals.

In vitro binding studies Tissue preparation For [3H](+)-pentazocinebinding, rats (150-250 g) were decapitated and brains (minus cerebellum) quickly removed, placed on ice and homogenized in 200 vol ice-cold (0~ buffer (5 mM TRIS-HC1, pH 7.7) in an ethanol-rinsed glass/teflon homogenizer and kept on ice until use. The binding activity remained stable for up to 3 h at 0~ Tissue was prepared in the same way for [3H]DTG binding except that rat brain was homogenized in 100 vol 50 mM TRIS-HCI (pH 7.7).

[3H] ( +)-pentazocine radioreceptor assay The binding reaction was performed by first mixing 0.25 ml displacer [test compound, (+)-pentazocine, or buffer] and 0.25 ml 18 nM [3H](+)-pentazocine in 5 ml plastic tubes. The binding reaction was initiated by mixing 1.0 ml rat brain homogenate in the solution. The assay mixture was incubated at 37~ for 90 min. Glass fibre filters (Whatman GF/C) were washed with 0.1% polyethyleneimine solution followed by one wash with buffer just before filtration of homogenate. The binding reaction was stopped by rapid filtration (350 mbar) of the assay mixture followed by further four washes with 5 ml ice-coldbuffer. The filters were placed

199 in counting vials and 4 ml scintillation solution added. Specific binding was calculated by subtracting non-specific binding estimated in the presence of 100 gM (+)-pentazocine or (+)-pentazoeine from the total binding. No difference was observed between using the racemate or the (+)-isomer for estimating non-specific binding.

[3H]DTG radioreceptor assay By this method, the inhibition of the binding of 2 nM [3H]DTG to sigma receptors in rat brain homogenates was determined as modified from Weber et al. (1986). The binding reaction was performed by first mixing 0.25 ml displacer (test compound, D T G or buffer), and 0.25 ml 12 n M [3H]DTG into 0.50 ml buffer in 5 ml plastic test tubes and then initiating the binding reaction by mixing 0.50 ml homogenate into the solution. The assay mixture was incubated at 25~ for 20 min. Glass fibre filters ( W h a t m a n G F / B ) were washed with 0.1% polyethyleneimine solution followed by one wash with buffer just before filtration of the homogenate. The binding reaction was stopped by filtration of the assay mixture at reduced vacuum (740 mbar) followed by a further three washes with 5 ml ice-cold buffer. Bound radioactivity was measured as above. Specific binding was estimated by subtracting non-specific binding in the presence of 100 btM DTG from the total binding.

Immobility induced by forced swimming Male mice ( N M R I / B O M , SPF, Molleggtrd, Denmark) weighing 18-20 g were used. The present model was a modified version of the test described by Porsolt et al. (1977). A fully automated test system with six glass jars (2000 ml filled with 1200 ml waterj being assessed in parallel was used. The assessment of immobility was performed by means of image analysis (GIPS: Image House, Copenhagen). A black and white video camera was used and up to six different areas could be defined on the image. The video signals from the camera were digitized by means of a frame grabber (corresponding to 5 1 2 x 5 1 2 pixel resolution). The sampling time between images was 240 ms. The activity measure was expressed as the change in area between two succeeding images and the mouse was defined as immobile if the change in area was < 700 pixels. This criterion had been determined by comparisons between manually and automated assessments of doses response studies of imipramine. After pretreatment with saline or drug the mouse was put into the glass jar containing soiled water (i.e. water in which a mouse had been placed previously) at 23-25~ The mouse was left in the water for 6 min, and the total duration of immobility was measured during the last 3 min. Each treatment group consisted of nine mice. One saline and two or three drug-treated groups were included in each experiment, and each drug was tested in at least two separate experiments with overlapping doses.

Black and white test box, rats Male rats (Wistar WU, Charles River, Germany), weighing 200-250 g were used. The test box consisted of a white open-topped compartment (80 c r u x 6 5 c m x 33 cm) connected to a closed black box (39 cm x 25 cm x 21 cm) as described by S~inchez (I996). The white compartment was illuminated by bright light from two Schott KL 1500 electronic lamps emitting cold light by means of ellipsoid halogen reflector bulbs 15 V/150 W. The test-system was fully automated by two rows of photocells in the transverse direction and one row in the longitudinal direction (lower row). The lower row of photocells (5.5 cm above cage floor) detected horizontal locomotor activity and the upper row of photocells detected rearing activity.

Rats were treated with test drug using a minimum intensity of red light. The rats were tested 30 min after dosing by being placed in the center of the brightly lit while compartment. The test parameters were number of exploratory rearings and line crossings in the two compartments, number of entries into the black compartment and time spent in the white compartment. The test period was 7 min. Each treatment group consisted of eight rats. One saline and two or three drug-treated groups were included in each experiment, and each drug was tested in at least two separate experiments with overlapping doses.

Inhibition of footshock-induced ultrasonic vocalization in adult rats Mate rats (Wistar WU, Charles River, Germany), weighing 150-175 g at the beginning of the study were used. The test procedure is described in details by Sfinchez (1993). Briefly, footshocks were delivered from a metal grid floor in the test cages. The ultrasounds were detected by a microphone sensitive to ultrasounds in the range of 20-30 kHz placed in the center of the lid of the test cage, preamplified and converted from AC signals to DC signals in a signal rectifier, The accumulated time in which the voltage of the rectified signal was larger than the voltage of a previously determined threshold level was recorded. The animals experienced a test session 24 h before the first drug trial. On test days drug or saline was given 30 min before test. The rats were subjected to a test session (four 1.0-mA inescapable footshocks each of a duration of 10 s and intershock intervals of 5 s). The accumulated time spent emitting ultrasound was recorded 1-6 rain after the last shock. After a wash-out period of I week the rats were used in a new test session. The rats were used for a total of 7-8 weeks. At each test session the animal groups were randomly allocated to treatment with saline or test drug. Each treatment group consisted of eight animals, and one saline and two to four drug treated groups were included at each experiment. Each drug was tested at least in two separate experiments with overlapping doses.

Inhibition of isolation-induced aggressive behavior in male mice I

Mate mice ( N M R I / B O M , SPF, Molleg'ard, Denmark) weighing 18 20 g at the beginning of the experiment were used for assessment of antiaggressive effects as described by S'anchez et al. (1993). The aggressive mice were kept isolated for about 21 days and then trained to attack a non-aggressive intruder mouse of the same strain. An attack was defined as biting or as an attempt to bite the intruder mouse. Only mice with attack latencies of less than 10 s were included in the studies, In test sessions mice were pretested immediately before drug treatment and 30 min later. The attack latency was measured with a maximum observation time of 180 s. The mice were tested twice weekly for a total of 7-8 weeks. At each test session the animal groups were randomly allocated to treatment with saline or test drug. Each group consisted of eight aggressive and 16 non-aggressive (for pre- and post- drug testing) mice. A total of two or three separate experiments, each including a control group and three or four doses, were conducted.

Drugs The following drugs were dissolved in saline: citalopram HBr, molecular weight (MW) 405: 8-hydroxy-2-(di-n-propylamino)tetraline HBr (8-OH-DPAT) M W 328; ( - ) - p e n b u t o l o t , M W 292 (all synthesized in the Department of Medicinal Chemistry, H. Lundbeck AtS): fluoxetine HCI, M W 346 (Lilly, USA). The following drugs were dissolved in water: paroxetine acetate, M W 373 (SmithKline Beecham, UK): fluvoxamine maleate, M W 434 (Duphar; Holland): sertraline HCI, M W 343 (Pfizer, USA);

200 imipramine HCI M W 317 (Nomeco, Denmark). Ritanserin, M W 478 (Janssen, Belgium) was dissolved in minimal amounts of tartaric acid and diluted with saline. Pretreatment times were 30 rain, and all drugs were administered SC. The injection volumes were 5 m l / k g for rats and 10 m l / k g for mice.

Statistics IC5o values were estimated on the basis of two full concentrationresponse curves, each containing five concentrations of drug covering 3-5 log units (each data point in triplicate). Estimation of ICso values was performed by means of the receptor program Ligand a n d / o r Multicalc from Wallac. If the log ratio (logR) between the two determinations was greater than corresponding to 3 x SD (99% confidence interval) extra determinations were performed and outliers discarded. The SDs were calculated from a series of n determinations of logR between double determinations. Antilog (SD) applied for the individual binding assays were: G2:2.3 (n = 100), el: 1.8 (n = 74). In vivo results were expressed as treatment group means (+_ SEM). EDs0-values with 95% confidence limits (log-probit analysis) were calculated for results of the forced swim test and the test of inhibition of footshock-induced ultrasonic vocalization. In the two-compartment black and white box, drug effects were evaluated by means of the Kruskal-Wallis test followed by pairwise comparisons of treatment groups when relevant (t-test on rank values). Tests in isolated aggressive mice were evaluated by means of oneway analysis of variance (ANOVA) and post hoc pairwise comparisons of means.

Table 2 In vitro binding affinity to the al (3H-DTG) and ere (SH-pentazocine) binding sites. For details on (5 binding, see Materials and methods In vitro receptor binding

Imipramine Citalopram Paroxetine Sertraline Fluvoxamine Fluoxetine

a] ICso (nM)

a2 IC5o (nM)

200 200 530 8.6 13 75

270 1000 1500 170 710 230

8O

60

8

T

E

k~

~- 40

D

20

Results 0

[3H](+)-pentazocine and [3H]DTG binding

,

i

i

,

i

I

i

,

i

,

~

,

10

,

I

100 pmol/kg (s.c., 30 min)

Sertraline and fluvoxamine had high affinities for the r binding site (labelled by [3HI Pentazocine), whereas the 1Cs0 values of fluoxetine, citalopram and paroxetine were markedly lower (Table 2). There were only weak affinities for the (Y2 binding site as shown in Table 2 (labelled by [3H] DTG).

Fig. 1 Effect of imipramine (O) and citalopram ( e ) in the forced swimming test in male mice. Mean immobility time expressed as percent of control values +_SEM versus dose. Pretreatment time was 30 rain and route of administration was SC. * P < 0.05 (one-way A N O V A followed by post hoc comparison to a control group). n = 9-27

Forced swimming

Table 3 Effect of SSRIs and imipramine in the forced swimming test in mice. The compounds were given SC 30 rain prior to test (17 = 9 -27). For further details, see Materials and methods

Citalopram reversed the immobility induced by forced swimming dose-dependently, with a potency similar to that of imipramine (Fig. 1). Paroxetine, fluvoxamine and fluoxetine also reversed swim-induced immobility, but the effect was partial and of a lower potency (maximum 40-50% reversal; Table 3).

Inhibition of immobility induced by forced swimming, mice EDso (gmol/kg)

Exploration of two-compartment black and white box

Imipramine Citalopram Paroxetine Sertraline Fluvoxamine Fluoxetine

Citalopram, induced a biphasic response. At very low doses (0.000025-0.00025 gmol/kg, SC 30 min before test) citalopram induced an anxiogenic-like response, reducing the number of rearing and line crossings and the time spent in the white compartment while increasing the number of rearing and line crossings in the

black compartment (Table 4). Citalopram doses of 0.025-0.25 gmol/kg, SC 30 min before test, induced an anxiolytic-like response, increasing the exploratory activity in the white compartment and reducing the activity in the black compartment. A further increase

> > > >

19 15 210 230 180 460

Max inh. (%) 90 78 40 48 49 46

201 Table 4 Effect of SSRIs on the exploratory behavior of rats in a two-compartment black and white test box (mean -+ SEM). The compounds were given SC, 30 min before test. * and # indicate statistical significant increase or decrease, respectively, relative to Compound

parallel control responses (P < 0.05 Kruskal Wallis test, followed by pairwise comparisons of groups,) n = 8-24. For further details see Materials and methods Crossing

Entries

Time (sec)

Black

Into black

White

15 (3.3) 18 (7.7) 3.1# (0.97) 18 (3.6) 25* (3.5) 19 (3.4) 11 (2.9)

31 (5.7) 42* (7.1) 43 (12) 42* (7.8) 26 (2.2) 23 (3,2) 16# (3.3)

4.1 (0.99) 2.3 (0.86) 1.1# (0.13) 4.8 (0.95) 6.5* (1.1) 4.8 (0.90) 2.0 (0.71)

150 (26) 95 (49) 24# (7.9) 120 (27) 160 (16) 180 (25) 140 (43)

9.2 (1.9) 11 (1.9) 18" (2.7) 5.6 (2.5) 7.9 (2.9) 6.1 (2.2)

13 (2.1) 29 (5.6) 20 (4.2) 20 (6.1) 11 (4.6) 24 (7.7)

21 (3.2) 24 (3.6) 32* (1.7) 15 (5.2) 14 (4.0) 17 (4.8)

2.3 (0.51) 4.4* (0.89) 5.1" (1.2) 2.8 (l.0) 1.6 (0.60) 1.8 (0.53)

220 (31) 210 (27) 99# (14) 260 (49) 200 (58) 240 (54)

8.9 (2.4) 12 (3.5) 12 (3.2) 11 (5.3) 12 (2.7) 8.9 (3.5)

10 (2.7) 14 (4.2) 12 (4.2) 7.3 (2.0) I4 (4.8) I2 (3.t)

II (3.2) 21 (5.8) 12 (3.5) 18 (7.5) 15 (1.8) i4 (5.7)

20 29 2l 22 29 30

(4.2) (2.7) (4.5) (5.4) (5.I) (5.9)

1.9 (0,66) 4.6* (0.78) 1.5 (0.33) 2.6 (0.80) 2.8* (0.56) 1,6 (0.46)

220 170 210 230 210 t90

(38) (26) (43) (50) (71) (44)

0 0.0023 0.023 0.23 2.3

9.4 (l.8) 13 (4.0) I 1 (1.6) 17 (5.0) 6.8 (2.5)

i2 (2.5) 9.5 (3,4) I3 (2.6) 6.3 (1,9) 8.4 (1.6)

i3 20 t8 20 11

(2.3) (6.9) (5.3) (4.0) (4.4)

20 21 26 22 20

(2.9) (5.0) (4.0) (6.3) (4.9)

1.9 (0.42) 3.3 (1.t) 4.0* (0.50) 2.8 (0.84) 2.0 (0,46)

220 210 190 240 220

(26) (51) (21) (52) . (34)

0 0.029 0.29 2.9

7.3 (3.6) 17 (4.5) 9.8 (4.3) 7.8 (4.3)

11 (2.0) 11 (1.9) 4.9 (1.6) 15 (3.7)

14 30 21 19

(3.8) (9.4) (5.9) (6.7)

2.1 5.5 2,9 3.7

200 200 290 140

(46) (42) (33) (41)

Dose gmol/kg

Rearing White

Black

White

Citalopram

0 0.000025 0.00025 0.0025 0,025 0.25 2.5

10 (1.9) 6.0 (2.7) 1,1# (0.13) 15 (4.2) 28* (5.0) 19" (3.6) 6.9 (1.5)

21 (3.5) 31" (5.6) 29 (7.0) 26 (3.6) 16 (3.0) 12 (1.7) 6.5# (2.3)

Paroxetine

0 0.00027 0.0027 0.027 0.27 2.7

8.4 (1.7) 14 (2.6) 7.7 (1.5) 14 (4.9) 6.3 (2.1) II (3.4)

Sertraline

0 0.00029 0.0029 0.029 0.29 2,9

Fluvoxamine

Fluoxetine

in the dose to 2.5 gmol/kg abolished the effect. The total activity scores (i.e. rearing in white plus rearing in black and crossing in white plus crossing in black) were not significantly different from controls at any dose level (Kruskal-Wallis test followed by pairwise comparisons of treatment groups). Paroxetine, 0.0027 gmol/kg, increased the exploratory behavior in the black compartment and the number of entries into the black compartment significantly, but did not show any significant differences from the controls at any other dose tested. The total activity scores after 0.0027 p.mol/kg were not significantly different from controls. Sertraline and fluvoxamine increased the number of entries into the black compartment significantly, but did not affect any of the other behavioral test parameters. Fluoxetine was inactive at the doses tested (0.29-2.9 gmol/kg). Inhibition of footshock-induced ultrasonic vocalization in rats Citalopram inhibited footshock-induced ultrasonic vocalization potently, but the inhibitory effect ofcitalopram was only partial, with a maximum inhibition of 64% (Table 5). Paroxetine abolished ultrasonic vocal-

20 (5.1) 25 (4.9) 16 (5.1) 2 7 (6.5)

(0.74) (1.8) (1.I) (0.98)

ization with a high potency. Sertraline and fluvoxamine abolished the ultrasonic vocalization at 20-30 times higher doses than paroxetine, and fluoxetine induced a partial inhibition of 32% at 58 gmol/kg.

Inhibition of isolation-induced aggressive behavior of male mice The 5-HT precursor, 1-5-HTR inhibited the isolationinduced aggressive behavior dose-dependently. This effect was reversed by the mixed 5 - H T I A / 5 - H T 1 B receptor antagonist (-)-penbutolol, whereas the 5-HT2A/ 5-HT2c receptor antagonist ritanserin potentiated the effect of I-5-HTP (Fig. 2). Similarly, the 5 - H T I A receptor agonist 8-OH-DPAT inhibited the isolationinduced aggressive behavior dose-dependently; (--)-penbutolol reversed and ritanserin potentiated the effect (Fig. 3).

Discussion

The present study compares antidepressive, anxiolytic, and antiaggressive potentials of the SSRIs citalopram,

202 Table 5 Inhibitory potencies of SSRIs against footshockinduced ultrasonic vocalization in adult rats. Compounds were given SC 30 min prior to test (n = 8-24). For further details, see Materials and methods

Inhibition of foot-shock-induced ultrasonic vocalization, rat

Citalopram Paroxetine Sertraline Fluvoxamine Fluoxetine

EDso (btmol/kg)

Max inh. (%)

1.0 0.86 22 25 > 58

6& 100 70 96 32

"Biphasic response with maximum response at 1.6 gmol/kg

200

200

,!."""

180 160

160

140

140

~" 120

120

t,. ++..t......

g

loo -~

180

v

100

80

--~ 8O

80


99 and > 54 ~tmol/kg) (S6,nchez and Hyttel 1994). This rank order o f potency did not correlate with the 5 - H T reuptake inhibitory potencies. The in-vivo 5 - H T reuptake inhibitory potencies, measured as potentiation o f 1-5-HTP-induced 5 - H T syndrome in mice, are 1.8, 0.62, 5.4, 18 and 88 g m o l / k g for citalopram, paroxetine, sertraline and ftuvoxamine and fluoxetine, respectively (S/mchez and Hyttel 1994). The same study demonstrated that the antiaggressive effects o f the SSRIs depended to variable degrees on the level o f serotonergic activity, as citalopram and paroxetine were potent inhibitors o f aggressive behaviour (EDs0 0.088 and 0.033 g m o l / k g ) if they were administered concomitantly with a low dose o f 1,5-HTP (110 g m o l / k g = 25 m g / k g ) (S/mchez and Hyttel 1994). The responses o f the other SSRIs were also potentiated, but to a minor extent (ED5o = 7.5, 1.9 and 9.8 g m o l / k g ) . 5-HT1A receptor agonists abolish isolation-induced aggressive behavior, and the antiaggressive potencies correlate with the invitro affinity for 5-HTIA receptors (S/mchez et al. 1993), but the SSRIs all have nonsignificant affinity for 5HT1A receptors (Hyttel 1994). 5-HT2A or 5-HT2c receptor stimulation inhibits isolation-induced aggressive behavior (S~nchez et al. 1993). The results o f the present study suggest a functional interaction between 5-HTIA and 5-HT2A or 5 - H T z c receptors, as ritanserin potentiated the antiaggressive behavior o f the 5 - H T precursor, 1,5-HTP, as well as the 5-HTIA receptor agonist, 8-OH-DPAT). This interaction might be involved in the antiaggressive potency o f fluoxetine, as the relative potency o f fluoxetine is high in this test model c o m p a r e d to the potencies o f fluoxetine in other behavioral models. However, the mechanisms involved in mediation o f antiaggressive effects o f the other SSRIs are not readily explained. There is no evidence o f a binding sites being involved in mediation o f the effects. A study o f the (72 ligand, Lu 28-179, failed to demonstrate antiaggressive potency (Sfinchez et al. 1994). It might be speculated whether some o f the differences between SSRIs can be ascribed to different pharmacokinetic properties, resulting in different absorption rates and distributions o f drug. However, results achieved within the same animal strain ( N M R I mice, Wistar W U rats) differ according to test model. It c a n n o t be excluded that active metabolites interact with the effect o f SSRIs, although the behavioural effects are recorded 30 min after drug administration,

a time point where formation o f metabolites is still incomplete In conclusion, the behavioral profiles o f the five SSRIs citalopram, paroxetine, sertraline, fluvoxamine and fluoxetine differ in animal models o f depression, anxiety and aggression in rats and mice. The rank o f potencies is model dependent, and does not merely reflect a difference between animal species. A l t h o u g h the affinities for other binding sites than the 5 - H T transporter site are low, it c a n n o t be excluded t h a t they can influence the net effect. Model d e p e n d e n t differences in functional interaction between 5 - H T receptor subtypes might account for some o f the observed differences. In particular, 5-HT2c receptors might be involved in the effects o f fluoxetine. T h e significance of the affinity o f some o f the SSRIs for the a binding site is uncertain. Whether the differences are o f any clinical relevance remains to be elucidated.

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