Catalepsy induced by the 5-HT(1A) receptor antagonist WAY 100635 in rats pretreated with the selective serotonin reuptake inhibitor citalopram

Neither a high dose of the selective serotonin reuptake inhibitor citalopram (100 micromol kg(-1) s.c.), nor the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY 100635) (0.1--0.4 micromol kg(-1) s.c.) produced any evidence of catalepsy in adult male rats. When combined with citalopram, however, WAY 100635 produced a dose-dependent, and statistically significant, catalepsy in the inclined grid test.     

WAY100635 prevents the changes induced by fluoxetine upon the 5-HT1A receptor functionality

5-HT1A receptor-mediated signalling in rat brain was evaluated after chronic administration (14 days; s.c.) of the selective serotonin reuptake inhibitor (SRRI) fluoxetine (10 mg/kg/day) alone, or in combination with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg/day). The density of 5-HT1A binding sites was unchanged following fluoxetine, WAY100635, or the combination of fluoxetine and WAY100635. However, the net stimulation of [35S]GTPgammaS binding induced by the 5-HT1A agonist 8-OH-DPAT was significantly attenuated in dorsal raphe nucleus (DRN), but not in hippocampus, after chronic fluoxetine. Moreover, depending of the area analysed, the basal binding of [35S]GTPgammaS was differentially affected by this treatment: increased in DRN and decreased in hippocampal dentate gyrus. Interestingly, the changes in [35S]GTPgammaS basal binding and on 5-HT1A receptors functionality were prevented by the concomitant administration of WAY100635. The inhibition of dorsal raphe firing by 8-OH-DPAT was also attenuated in fluoxetine-treated rats (ED50 = 2.12 +/- 0.32 microg/kg and 4.34 +/- 0.09 microg/kg, for vehicle and fluoxetine respectively), an effect which was also prevented by the concomitant administration of WAY100635 (ED50 = 2.10 +/- 0.58 microg/kg). Chronic administration of WAY100635 alone did not affect the 5-HT1A receptor-induced stimulation of [35S]GTPgammaS binding, nor the 8-OH-DPAT-induced inhibition of 5-HT neuron firing. These results demonstrate that the concomitant blockade of 5-HT1A receptors when administering fluoxetine prevents those adaptive changes of 5-HT1A receptor function associated with the chronic administration of this antidepressant. These findings could be relevant from the therapeutic point of view, and further support the potential benefit of treatments with a SSRI/5-HT1A receptor antagonist combination.     

Aversive stimulus properties of the 5-HT2C receptor agonist WAY 161503 in rats

Serotonin2C (5-HT2C) receptors may influence motivation and reward through effects on the mesocorticolimbic dopamine (DA) system. Previous work from this laboratory indicated that 5-HT2C receptor stimulation does not induce place conditioning when animals are tested in a drug-free state, but does result in decreased locomotor activity and increased frequency thresholds for electrical self-stimulation of the ventral tegmental area (VTA). The present study was conducted to determine whether the 5-HT2C receptor agonist WAY 161503 may induce place conditioning in a state-dependent manner and also whether this compound will induce gustatory avoidance conditioning in the conditioned taste aversion (CTA) paradigm. The effects of the 5-HT2C receptor agonist WAY 161503 in the place conditioning and CTA (two-bottle choice test) paradigms were assessed in male Sprague-Dawley rats. Administration of WAY 161503 (3.0 mg/kg) induced a state-dependent conditioned place aversion and a CTA to saccharin. The differential state dependency of 5-HT2C receptor agonists' effects in place conditioning (state dependent) and CTA (non-state dependent) is consistent with the activation of different brain systems in these two paradigms. The state-dependent effects in place conditioning underscore the need to include controls for state dependency in studies of 5-HT receptor related compounds.     

Evidence for accelerated desensitisation of 5-HT(2C) receptors following combined treatment with fluoxetine and the 5-HT(1A) receptor antagonist, WAY 100,635, in the rat

Both pre-clinical and clinical studies suggest that additional treatment with 5-HT(1A) receptor antagonists may accelerate the antidepressant efficacy/onset of selective serotonin re-uptake inhibitors (SSRIs). Given that chronic SSRI treatment has been shown to desensitise 5-HT(2C) receptor mediated responses, we have used the rat social interaction test to determine if combined treatment with WAY 100,635, a selective 5-HT(1A) receptor antagonist, will accelerate this effect. In pairs of unfamiliar rats, acute administration of the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP) or fluoxetine decreased the time spent in social interaction, responses which were reversed by the 5-HT(2C/2B) receptor antagonists SB 200646A and SB 221284. Similar reductions in social interaction were observed in rats treated with fluoxetine (10 mg/kg, i.p. daily) for 4, 7 and 14 days but was no longer apparent after 28 days of treatment. In contrast, only 7 days of combined treatment with WAY 100,635 (1 mg/kg/s.c./day) and fluoxetine were needed to reverse this response. The decrease in social interaction induced by an acute challenge of mCPP (1 mg/kg, i. p.) was also reduced after 6 days co-treatment with WAY 100,635 and fluoxetine. Thus, WAY 100,635 accelerates SSRI-induced desensitisation of 5-HT(2C) receptors, suggesting that this response might contribute towards the therapeutic effects of SSRIs in man.     

Functional subsensitivity of 5-HT2A and 5-HT2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT2A/2C receptor antagonists

 In the present study, we investigated the duration of attenuation of the temperature increases produced by (±) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) which followed pretreatment with four serotonin (5-HT) antagonists; metergoline, mesulergine, mianserin and ritanserin. The duration of attenuation of m-CPP-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for the 5 mg/kg doses of both mianserin and metergoline and more than 2 days for the 5 mg/kg dose of mesulergine. The duration of attenuation of DOI-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for mianserin, more than 2 days for the 5 mg/kg dose of metergoline and more than 4 days for mesulergine. Daily administration of a low (1.0 mg/kg per day) dose of ritanserin for 14 days led to an attenuation of the temperature increases produced by m-CPP given 24 h after the last dose of ritanserin, but did not cause a similar desensitization of DOI-induced hyperthermia. On the other hand, daily administration of both low (1.0 mg/kg per day) and high (5.0 mg/kg per day) doses of mianserin for 14 days caused desensitization of DOI-induced hyperthermia but did not cause desensitization of m-CPP-induced hyperthermia when these agonists were administered 48 h after the last dose of mianserin. These findings demonstrate functional subsensitivity of both 5-HT_2A and 5-HT_2C receptors mediating hyperthermia following both acute and chronic administration of 5-HT_2A/5-HT_2C receptor antagonists; some differences in time course and in responses to individual antagonists at 5-HT_2A versus 5-HT_2C sites were also observed. Received: 14 June 1996 / Final version: 28 August 1996     

Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing.

1. The effects of 5-HT1A antagonists on guinea-pig behaviour and dorsal raphe neuronal activity were investigated. 2. WAY100135 (10 mg kg-1, s.c.) and WAY100635 (1 mg kg-1, s.c.) significantly reduced the behaviours induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-1, s.c.) indicative of post-synaptic 5-HT1A receptor antagonism. WAY100635 (10 mg kg-1, s.c.) alone induced ear twitches, which were antagonized by ketanserin (1 mg kg-1, s.c.), but no other overt behaviours. 3. WAY100635 (0.125 mg kg-1, i.v.) produced a right-ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100 micrograms kg-1, i.v.) but did not affect the maximum inhibition induced by 8-OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5-HT1A somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig. WAY100635 also produced a dose-related increase in the basal firing of 5-HT neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe neurones previously inhibited by 8-OHDPAT (10 micrograms kg-1, i.v.). 4. The results indicate that WAY100635 is a competitive 5-HT1A antagonist in the guinea-pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it blocks a 5-HT1A receptor-mediated inhibitory tone acting on guinea-pig 5-HT neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated behaviours.     

Comparative effects of serotonergic agonists with varying efficacy at the 5-HT(1A) receptor on core body temperature: modification by the selective 5-HT(1A) receptor antagonist WAY 100635.

A reduction in core body temperature is one of the characteristic consequences of 5-HT1A receptor activation in rodents. In this study, we characterized the hypothermic effects of four 5-HT1A receptor ligands with varying affinity and selectivity at the 5-HT1A receptor. 8-OH-DPAT and flesinoxan (full agonists); ipsapirone (selective partial agonist) and eltoprazine (non selective partial agonist), all induced a dose-dependent reduction in core body temperature, which was maximal 30 min subsequent to administration. This response differed quantitatively between the agonists, in both the extent and the duration of its effects. The selective 5-HT1A receptor antagonist WAY 100635 (0.15 mg/kg), attenuated the hypothermia induced by the partial agonists, ipsapirone (10 mg/kg) and eltoprazine (10 mg/kg). In contrast, the higher dose of WAY 100635 (1 mg/kg) antagonized the effects of all agonists. This study therefore further confirms the utility of hypothermia as a simple, robust in-vivo probe of 5-HT1A receptor function. This paradigm, which was enhanced by use of specific antagonists such as WAY 100635, may prove useful for the detection and characterization of novel 5-HT1A receptor ligands.     

Latency to paroxetine-induced anxiolysis in the rat is reduced by co-administration of the 5-HT(1A) receptor antagonist WAY100635

We report here the use of rat high-light social interaction to model the temporal anxiolytic/antidepressant effects of SSRIs seen in the clinic. Compared to vehicle controls, 21, but not 14, days of paroxetine treatment (3 mg kg(-1), p.o., daily) produced a marked increase in rat social interaction (Vehicle=71.3+/-7.3 s; Paroxetine=116.7+/-14.7 s; P<0.01) with no concurrent effect on locomotor activity, consistent with anxiolysis. To assess whether concurrent 5-HT(1A) receptor blockade reduces the time to onset of anxiolysis seen with paroxetine alone (21 days), rats were implanted with osmotic minipumps to continuously infuse the 5-HT(1A) receptor antagonist WAY100635 (1 mg kg(-1) day(-1), s.c., 7 days) alone or in combination with paroxetine (3 mg kg(-1), p.o., daily, 7 days), prior to anxiety testing. Paroxetine (Veh/Par=61.9+/-7.9 s) or WAY100635 (WAY/Veh=71.6+/-4.7 s) alone, had no effect on social interaction time compared to vehicle treated controls (Veh/Veh=76.4+/-4.9 s), whilst coadministration of WAY100635 with paroxetine, produced a marked elevation in social interaction (WAY/Par=149.3+/-16.8 s; P<0.01) relative to all other groups with no concurrent change in locomotor activity. In contrast, acute administration of WAY100635 (0.03 mg kg(-1), s.c.) with paroxetine (3 mg kg(-1), p.o.) did not alter any behavioural measure, suggesting that the anxiolysis induced by the combination after 7 days is attributable to a CNS adaptive response. This data demonstrates that coadministration of a 5-HT(1A) receptor antagonist with paroxetine markedly reduces the latency to anxiolysis, in the rat. This study supports the use of the rat social interaction test to further delineate adaptive changes in the CNS responsible for the anxiolytic/antidepressant action of SSRIs seen in humans.     

Regional differences in the effect of the combined treatment of WAY 100635 and fluoxetine: an in vivo microdialysis study

We studied the changes in extracellular serotonin (5-HT) levels in the frontal cortex (FC) and ventral hippocampus (vHi) in conscious rats, induced by the combined administration of a highly selective 5-HT_1A receptor antagonist, WAY 100635 (0.1 mg/kg, i.v.), and fluoxetine (1 mg/kg, i.p.), a selective 5-HT reuptake inhibitor (SSRI). In the two brain areas studied, no change in extracellular 5-HT concentrations was observed following fluoxetine administration over the 210 min post-injection period. However, in animals co-administered with [WAY 100635 + fluoxetine], the maximal increase in 5-HT levels in the FC was to 215% of the respective basal value (100%), while no significant change in 5-HT was observed in dialysates from the vHi. Furthermore, the [norfluoxetine]-to-[fluoxetine] ratio in the FC was significantly higher than in the hippocampus as measured in homogenates of animals treated with either fluoxetine alone or a prior administration of WAY 100635. Thus, WAY 100635 made the fluoxetine short-lasting effect apparent in the FC, but not by interfering with pharmacokinetic parameters of fluoxetine. Taken together, our data suggest the possibility, that either 5HT-_1A autoreceptor sensitivity or uptake carrier density or higher [metabolite]-to-[parent drug] ratios in the FC than in the hippocampus may be involved in regional specific responses to SSRIs.     

Citalopram combined with WAY 100635 inhibits ejaculation and ejaculation-related Fos immunoreactivity

The role of 5-HT (5-hydroxytryptamine, 5-HT)(1A) receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation.     

5-HT 2C receptor sensitivity during treatment with selective serotonin re-uptake inhibitors

We studied the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRIs) on the sensitivity of brain 5-HT(2C) receptors, by measuring the decrease in slow wave sleep (SWS) that follows administration of meta-chlorophenylpiperazine (mCPP) (7.5 mg orally). mCPP significantly lowered SWS both in patients taking SSRIs and in a group of healthy controls. There was, however, no difference in the response between the two groups. The results do not support the suggestion that repeated SSRI treatment alters the sensitivity of 5-HT(2C) receptors in the human brain. The present study, however, cannot exclude the possibility that a decrease in 5-HT(2C) receptor sensitivity was offset by higher plasma levels of mCPP in the SSRI-treated group.     

New 5-HT2C receptor agonists

While there is evidence for the involvement of different serotonin (5hydroxytryptamine; 5-HT) receptors in the regulation of food intake and body weight maintenance, the data supporting the role of the 5-HT_2C receptor are especially strong. This information has elevated 5-HT_2C receptor activation into one of the most competitive research areas for antiobesity therapy, a therapeutic area with few (if any) safe, effective pharmacological agents available. Varying amounts of evidence also exist to support the use of 5-HT_2C agonists for the pharmacological treatment of several other conditions, including anxiety, depression, obsessive–compulsive disorder, sexual dysfunction, epilepsy, urinary incontinence and hot flushes. The therapeutic potential of 5-HT_2C receptor modulation has spawned a successful search for 5-HT_2C receptor agonists. This review will focus on recent patent applications through August 2003 that describe compounds that have agonist activity at the 5-HT_2C receptor, and should be complementary to previous Expert Opinion discussions on the 5-HT_2C receptor [1-7].     

WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by blockade of hippocampal NMDA receptors.

We studied the effect of WAY 100635, a 5-HT1A receptor antagonist, on the impairment of spatial learning caused by intrahippocampal injection of 3-((R)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive NMDA receptor antagonist, in a two-platform spatial discrimination task. CPP, 3 and 10 ng/microl, administered bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, dose-dependently reduced choice accuracy in the two-platform spatial discrimination task with little or no effect on choice latency and errors of omission. A volume of 10 ng/microl intrahippocampal CPP did not affect choice accuracy or latency of a non-spatial visual discrimination task. Subcutaneous doses of 0.3 and 1 mg/kg WAY 100635 did not modify the choice accuracy, but prevented the impairment caused by 10 ng/microl intrahippocampal CPP. A dose of 20 ng/microl WAY 100635 into the dorsal hippocampus prevented the deficit caused by 10 ng/microl CPP administered in the same region. The results suggest that blockade of 5-HT1A receptors can compensate the loss of NMDA-mediated excitatory input to pyramidal cells in the hippocampus. These findings may have clinical relevance for the symptomatic treatment of memory disorders associated with reduced glutamate transmission mediated by NMDA receptors.     

Differential influence of selective 5-HT5A vs 5-HT1A, 5-HT1B,or 5-HT2C receptor blockade upon light-induced phase shifts in circadian activity rhythms: Interaction studies with citalopram

Though serotonergic mechanisms modulate circadian rhythms, roles of individual serotonin (5-HT) receptors remain uncertain since data are lacking for antagonists. Herein, both the 5-HT_5A receptor antagonist, A843277 (10 mg/kg), and the 5-HT_1B antagonist, SB224289 (1 mg/kg), inhibited light-induced phase advances in hamster circadian wheel-running rhythms. Conversely, though 5-HT_1A and 5-HT₇ receptors are likewise implicated in circadian scheduling, their blockade by WAY100635 (0.5 mg/kg) and SB269970 (1 mg/kg), respectively, was ineffective. Since actions of 5-HT reuptake inhibitors are modified by antagonists, we evaluated their influence on suppression of phase advances by citalopram (10 mg/kg). Its action was potentiated by WAY100635 and the 5-HT_2C antagonist, SB242084 (1 mg/kg), but not by A842377, SB224289, SB269970, and antagonists at 5-HT_2A (MDL100907) and 5-HT₆ (SB399885) receptors. In conclusion, this is the first in vivo evidence for an influence of 5-HT_5A receptors upon circadian rhythms, but no single class of 5-HT receptor mediates their control by citalopram.     

Attenuation of 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists,antagonists or antidepressants

The effects of chronic (10 days) treatment with serotonin (5-HT) receptor agonists on 5-HT_1A receptor mediated lower lip retraction (LLR), 5-HT_1C receptor mediated penile erections (PE) or 5-HT₂ receptor mediated head shakes (HS) were studied in rats. It was found that the 5-HT_1A and 5-HT₂ receptor mediated behaviour could be attenuated after chronic treatment, whereas 5-HT_1C receptor mediated behaviour remained unchanged. The ED₅₀ for the 5-HT_1A receptor mediated, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced LLR showed an increase from 0.07 mg/kg in placebo pretreated rats to 0.13 in 8-OH-DPAT (1mg/kg/day) pretreated rats. The number of 5-HT₂ receptor mediated (±)-1-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.46 and 1 mg/kg)-induced HS was significantly reduced (67% and 50%, respectively) after 10 days' pretreatment with DOI (1 mg/kg/day). In the same animals the number of 5-HT_1C receptor mediated PE was increased. Ten days' pretreatment with MK 212 (0.46 mg/kg/day) failed to affect MK 212 (0.22 and 0.46 mg/kg)-induced PE. In addition, the effects of chronic treatment with some antidepressants were studied. The monoamine oxidase (MAO) inhibitor tranylcypromine (4 mg/kg/day) given for 10 days caused an increase in the ED₅₀ for 8-OH-DPAT induced LLR (ED₅₀ values were 0.06 and 0.14 mg/kg, respectively, in placebo — and tranylcypromine — pretreated rats) and attenuated MK 212 (0.22 and 0.46 mg/kg)-induced PE. Chronic treatment with mianserin (10 mg/kg/day), a tetracyclic antidepressant with 5-HT_1C and 5-HT₂ receptor antagonistic properties, did not change PE induced by MK 212, but caused an increase of PE induced by DOI and a decrease of DOI-induced HS. Ten days' pretreatment with the 5-HT re-uptake inhibitor Org 6997 (5 mg/kg/day) had no effect on MK 212-induced PE. The results demonstrate that 5-HT_1A and 5-HT₂ but not 5-HT_1C receptor mediated behaviour can be attenuated by chronic treatment with agonists for these receptors. The 5-HT_1C receptor mediated behaviour remains unchanged in response to chronic agonist treatment. Chronic treatment with antidepressants have differential effect on these behaviours. The possible implication for the mechanism of action of antidepressants is discussed.     

5-HT2C receptor agonists with potential anorectic activity

Substituted 2,3,4,4a-tetrahydropyrazino[2,1-c][1,4]benzoxazin-5-(1H)-ones were synthesized and evaluated as 5-HT(2C) receptor agonists for the possible treatment of obesity. A number of compounds exhibited 5-HT(2C) agonist binding activity with compound 19 showing the most potent in vitro activity.     

5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion

Rationale Global serotonin (5-HT) depletion increases the number of premature responses made on the five-choice serial reaction time task (5CSRT) in rats. In contrast, the 5-HT_2A receptor antagonist M100907 decreases this measure of impulsivity. Mounting evidence suggests that 5-HT_2A and 5-HT_2C receptors have opposing effects on behaviour, and that the 5-HT_2C receptor antagonist SB 242084 produces a pattern of behaviour similar to 5-HT depletion.Objectives To assess the effects of 5-HT_2A and 5-HT_2C receptor antagonists on performance of the 5CSRT, to directly compare the effects of these drugs with those of ICV 5,7-dihydroxytryptamine (5,7-DHT) lesions and to investigate whether 5-HT depletion affects the action of these agents.Methods The effects of M100907 (0, 0.01, 0.03, 0.1 mg/kg IP) and SB 242084 (0, 0.1, 0.25, 0.5 mg/kg IP) were investigated on performance of the 5CSRT in both ICV 5,7-DHT-lesioned and sham-operated rats.Results ICV 5,7-DHT lesions, which significantly decreased forebrain levels of 5-HT by around 90%, increased levels of premature responding, decreased omissions and the latency to respond correctly, yet did not affect performance accuracy. M100907 decreased premature responding in sham-operated controls but not in 5-HT-depleted rats. In contrast, SB 242084 increased premature responding in all animals, and also decreased the latency to make a correct response in sham-operated controls.Conclusions These data support the view that serotonergic regulation of impulsive behaviour through different members of the 5-HT₂ receptor family is functionally heterogeneous. Although both 5-HT_2A and 5-HT_2C receptors participate in controlling this form of impulsive action, their relative contribution may depend on the endogenous state of the 5-HT system.     

Behavioural and biochemical studies of citalopram and WAY 100635 in rat chronic mild stress model

Reversal of chronic mild stress (CMS)-induced decrease of sucrose consumption has been studied in rats after 2, 7, 14, and 35 days treatment with imipramine, citalopram (both 10 mg/kg per day, i.p.), WAY 100635 (0.2 mg/kg sc, b.i.d.), and citalopram plus WAY 100635. Bmax, Kd, and functional status [cyclic AMP (cAMP) generation] of beta1-adrenoceptors were assessed in cortical tissue at the same time points. Citalopram reversed CMS-induced reduction of sucrose intake at an earlier time point than imipramine. WAY 100635 was not effective and did not potentiate the effect of citalopram. CMS produced increase of Bmax. Imipramine decreased Bmax in controls (Days 2, 7, 14, and 35) and normalised Bmax in stressed animals (Day 35). Citalopram, WAY 100635, and the combination increased Bmax in stressed animals and controls (Days 14 and 35). Inconsistent changes of Kd values and of cAMP responses to noradrenaline (NA) stimulation were observed. Thus stress- and drug-induced effects on beta1-adrenoceptors do not appear to be a common biochemical marker of antidepressant-like activity in the CMS model.