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Publisher Summary This chapter focuses on animal models of Obsessive–Compulsive Disorder (OCD). It briefly summarizes the clinical phenomenology and psychobiology of OCD, focusing in particular on the question of whether understanding the heterogeneity of OCD or its underlying endophenotypes may be useful for future research on this disorder. Animal models of OCD can be divided into three classes, behavioral, pharmacological, and genetic, according to the method used to induce compulsive behavior in the model. The chapter focuses only on animal models that seem most relevant to the development of new approaches for the treatment of OCD and discusses only laboratory models whose predictive validity has been assessed and that have some construct validity. It also reviews existing animal models of OCD, discussing recent work in this area in terms of the face, construct, and predictive validity of models, provides a current perspective from the pharmaceutical industry, focusing on selected targets and how the use of neurocognitive testing can perhaps facilitate the development of novel drugs for these targets. The chapter concludes that a better understanding of OCD spectrums and subtypes, their mediating circuitry, and the relevant genes and proteins in these circuits, will help bring about new pharmacotherapies for this disorder. Although there has been considerable progress in understanding the psychobiology of OCD and in developing medications for this disorder, much remains to be done.

Cloned in the human in 1996 and localized to human chromosome 1p35–p36 (1), the 5-hydroxytryptamine6 5-ht6 receptor was initially discovered in the rat central nervous system (CNS) using methods from molecular biology (2,3). A 440-amino-acid polypeptide, the human receptor exhibits 89% homology to that of the resequenced rat receptor (1). The almost exclusive distribution of the receptor in the rat CNS (but see refs. 3 and 4), the high abundance of receptor expression in limbic, cortical, and striatal brain regions (5, 6, 7), as well as the high affinity of tricyclic antidepressants and atypical antipsychotic drugs for this receptor (8) have prompted extensive investigation into the role of this receptor in psychiatric disorders. To date, the receptor has been implicated in affective disorder (8, 9, 10), anxiety (11,12), epilepsy (13), and regulation of food consumption (14,15), with the most compelling evidence suggesting a role in cognitive function. Since the role in cognitive function with respect to Alzheimer’s disease has received the most attention (reviewed in ref. 16), herein we have chosen to focus more specifically on the biological rationale for the treatment of cognitive deficits in schizophrenia and we provide recommendations for the evaluation of the potential of 5-ht6 receptor antagonists in this indication.

Rats trained to discriminate ethanol (EtOH, 1 g/kg IP) from saline in a two-lever procedure completely generalized to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Substitution of fluoxetine was completely blocked by the selective 5-HT2A receptor antagonist MDL 100,907 and not affected by the selective 5-HT1A receptor antagonist WAY-100635. It is suggested that the previously reported effectiveness of SSRIs in reducing EtOH consumption could be based on similarities in discriminative stimulus effects of SSRIs and EtOH. Stimulation of 5-HT2A receptors may underlie these stimulus similarities and contribute to the EtOH intake-reducing effects of SSRIs.

This study investigated the possible behavioral mechanisms underlying the anorectic effect of the cannabinoid CB 1 receptor antagonist/inverse agonist N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide hydrochloride (SR141716A). Male or female rats were food-restricted and trained to emit stable responding in daily 10-min, fixed ratio 10 food-reinforced operant sessions. Under these conditions, as well as under free-feeding conditions, SR141716A inhibited food-maintained responding (ED 50 values ranging from 0.92 to 2.52 mg/kg, i.p.). In the same operant procedure, SR141716A suppressed intracranial self-stimulation with a potency which was slightly lower than the anorectic potency (ED 50 : 4.50 mg/kg). As assessed during a 10-min test period SR141716A (1–10 mg/kg) did not affect activity counts; suggesting that the observed inhibition of operant behavior is not a direct consequence of impairment of locomotor activity. SR141716A, however, attenuated saccharin-preference in a conditioned taste aversion paradigm (ED 50 : 6.45 mg/kg). Although the data support the suggestion that the anorectic effect of SR141716A results from an attenuating effect on the rewarding effect of food, the contribution of drug-induced aversion/malaise cannot be excluded.

Fluoxetine, a selective serotonin reuptake inhibitor, shows moderate efficacy and potency in the rat forced swimming depression test and the shock-induced ultrasonic vocalization anxiety test, whereas the 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is highly efficient and potent in both models. Whereas the 5-HT(1A) receptor antagonist WAY 100,635 abolishes the effect of 8-OH-DPAT in both models, it only attenuates the antidepressant-like effect of fluoxetine. Pretreatment with the 5-HT-depleting agent parachlorophenylalanine attenuates the antidepressant-like effect of fluoxetine, but not that of 8-OH-DPAT. This suggests that the antidepressant-like effect of fluoxetine and 8-OH-DPAT results from indirect (via increased synaptic availability of 5-HT) and direct stimulation of postsynaptic 5-HT(1A) receptors, respectively; whereas the anxiolytic-like effect of fluoxetine is not mediated by 5-HT(1A) receptors. The data support the hypothesis that the antidepressant- and anxiolytic-like effect of 8-OH-DPAT is predominantly mediated by post- and presynaptic 5-HT(1A) receptors, respectively, and that 5-HT(1A) receptors are only partially involved in the antidepressant-like effect of fluoxetine.

Hypophagic effects of serotonergic drugs have mostly been investigated in free-feeding paradigms and are generally ascribed to drug-induced acceleration of satiety, or to behavioral disruption. The present study investigated the hypophagic effects of various 5-HT(1/2) receptor agonists in an operant paradigm. Because of its limited duration (10-min session) the procedure was considered to be relatively insensitive to satiety processes. The behavioral specificity of the hypophagic effect was assessed by additional testing of the compounds in a locomotor activity assay. Male Wistar rats, maintained at about 80% of their free-feeding weights, were trained to acquire stable operant responding in daily fixed ratio:10 food-reinforced sessions; after which they were tested once a week with a 5-HT receptor agonist. Each compound dose-dependently suppressed the number of earned pellets after i.p. administration: DOI (5-HT(2A/2C) receptor agonist; ED(50): 0.36 mg/kg), TFMPP (5-HT(1B/2C/2A); 0.37 mg/kg), m-CPP (5-HT(2C/1B/2A); 0.54 mg/kg), ORG 37684 (5-HT(2C/2A); 0.85 mg/kg), CP-94,253 (5-HT(1B); 2.09 mg/kg), BW 723C86 (5-HT(2B); 6.26 mg/kg) and ipsapirone (5-HT(1A); 10.17 mg/kg). When tested at the dose equivalent to the ED(50) value in the operant paradigm, only ORG 37684 and DOI weakly suppressed activity counts in a locomotor activity assay; suggesting that the inhibition of operant food intake obtained with the other compounds at these doses is not a direct consequence of unconditioned motor effects. It is suggested that the hypophagic effect induced by relatively low doses of CP-94,253, TFMPP and m-CPP, and by moderate doses of ipsapirone and BW 723C86, is partly due to a drug-induced suppression of appetite. Although the exact contribution of the diverse 5-HT(1/2) receptor subtypes to appetite control remains to be studied in more detail, it is hypothesized that activation of 5-HT(1B) and/or 5-HT(2C) receptors attenuates appetite.

Serotonin (5-HT) receptor agonists with high affinity for the different subtypes (i.e. 5-HT(1A-1F), 5-HT(2A-2C)) of the 5-HT(1)- and 5-HT(2) receptor families have been shown to affect ingestive behavior. It has been assumed that: (1) stimulation of hypothalamic 5-HT(2C) or 5-HT(1B) receptors leads to a behaviorally specific hypophagic effect by accelerating satiety processes; (2) stimulation of 5-HT(2A) receptors leads to a disruption of the feeding cascade; and (3) stimulation of 5-HT(1A) and 5-HT(2B) receptors leads to a hyperphagic effect. The present paper reviews studies performed with the relatively selective receptor agonists ipsapirone (5-HT(1A)), CP-94,253 (5-HT(1B)), BW 723C86 (5-HT(2B)) and ORG 37684 (5-HT(2C)), as well as the nonselective receptor agonists TFMPP (5-HT(1B/2C)), m-CPP (5-HT(2C/1B)) and DOI (5-HT(2A/2C)) in a variety of feeding paradigms in rats, both after systemic and local injection. These studies support a role for other neuroanatomical regions (i.e. brain stem) and behavioral mechanisms (i.e. appetitive processes) in the hypophagic effects of these compounds, possibly as a function of the administered dose. Studies with 5-HT receptor antagonists indicate that the proposed role of particular 5-HT(1/2) receptor subtypes in the hypophagic effects of these 5-HT receptor agonists may be more complicated than originally thought. Further characterization of the role of 5-HT(1/2) receptor subtypes in the control of ingestive behavior will require extensive pharmacological and behavioral studies, using more selective receptor agonists and antagonists and different behavioral procedures, as well as verification in transgenic animals.

LY354740 ¿(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylate monohydrate¿, a selective group II metabotropic glutamate (mGlu) receptor agonist, was recently reported to attenuate the behavioral effects of phencyclidine (PCP) in rats. In the present study, LY354740 failed to attenuate the discriminative stimulus properties of PCP and its disruption of prepulse inhibition of the acoustic startle response, at a dose range which decreased startle responding. The suggestion that mGlu group II receptor activation induces antipsychotic effects may be premature.

Although the serotonin (5-HT)1A receptor agonist ipsapirone reduces ethanol intake in a variety of animal models of alcoholism, such effects have only been reported in models based on nonoperant behavior (e.g., two-bottle choice procedures). It was the aim of the present study to characterize the effects of ipsapirone in an operant model of alcohol self-administration. Rats were trained during daily 30-min sessions to respond for oral delivery of an ethanol solution (10% w/v) or water in a two-lever, fixed-ratio:1, saccharin-fading procedure. After establishment of stable responding, ipsapirone (0, 2.5–20 mg/kg, intraperitoneal) was tested in combination with different ethanol unit doses (0, 1.25–20%). Ethanol-reinforced responding was related to the ethanol unit dose in an inverted U-shaped manner. Ipsapirone dose-dependently decreased the number of ethanol- and water-reinforced lever responses, irrespective of the ethanol unit dose, and failed to affect ethanol preference. As there was only a minor difference between the minimal effective dose which reduced operant responding for ethanol and water (i.e., 10 and 20 mg/kg, respectively), and there was no evidence for a drug-induced left- or rightward shift of the ethanol unit dose–response curve, the effects of ipsapirone are considered to be nonselective. It is suggested that the ethanol intake-reducing effects of ipsapirone are not the result of a drug-induced interference (either of an attenuating, or potentiating, nature) with the positive reinforcing stimulus properties of alcohol.

Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

Drugs which possess selective actions on a given voltage operated calcium (Ca2+) channel (VOCC) are reportedly involved in the pharmacological actions of alcohol. Recently it was shown that the 1,4-dihydropyridine (−)-BAY k 8644, an L-type VOCC agonist, reduces alcohol intake relatively selectively in the genetic drinking AA rat. This study determined whether (−)-BAY k 8644 would alter volitional alcohol drinking in two other genetic models of alcoholism, male P rats and a new strain of male and female high ethanol preferring (HEP) rats. By use of a standard 10-day preference test for water versus 3 to 30% alcohol, the maximally preferred concentration of alcohol was first determined for each rat individually, i.e. 9%, 13% or 15%. Then the rats were allowed free access over 24 h or limited access to alcohol for only 2 h, during which time the intakes of water and preferred solution of alcohol were recorded. After the drinking patterns stabilized for 4 days, saline, a solutol vehicle solution or (−)-BAY k 8644 was administered: (1) in a dose of 0.125, 0.25 or 0.5 mg/kg given intraperitoneally twice daily for 4 days during free access to alcohol; and (2) for 3 days in a dose of 0.125 or 0.25 mg/kg given subcutaneously 30 min prior to 2 h of limited access to alcohol. Fluid intakes were recorded for either 4 or 8 days after limited and free access conditions, respectively. Whereas the control solutions were without effect during 24 h access, (−)-BAY k 8644 caused a significant dose-dependent suppression of up to 80% in absolute g/kg and proportion of alcohol to total fluid consumed; this decline persisted in the post drug period. During the limited access paradigm, (−)-BAY k 8644 similarly reduced alcohol drinking maximally within the first 15 min of presentation of alcohol; again, this reduction persisted over the remaining 105 min of alcohol access. Also, individual levels of blood alcohol declined concurrently with the suppression of drinking. These results demonstrate that (−)-BAY k 8644 possesses a short latency of action on alcohol intake and that its salutary effects on drinking persist after the drug is terminated. Finally, the hypothesis that L-type calcium channel agonists may be useful as a therapeutic adjunct in the treatment of alcoholism is extended.

The present study aimed to investigate the role of serotonin 5-HT2A and 5-HT2C receptors in the control of alcohol preference and consummatory behavior in alcohol-preferring cAA rats. Effects of the 5-HT(2A/2C) receptor agonist, DOI, the 5-HT(2C/1B) receptor agonist, mCPP, the 5-HT(2A/2C) receptor antagonist, ritanserin, and the 5-HT2A receptor antagonist, MDL 100,907, on ethanol (EtOH, 10% v/v) preference and intake, as well as total fluid and food intake were evaluated in a 12-h limited-access two-bottle paradigm. DOI (0.3-3 mg/kg, i.p.) reduced EtOH intake and preference, but not total fluid or food intake; whereas mCPP (1-10 mg/kg, s.c.) reduced EtOH, total fluid, and food intake. Therefore, it is concluded that DOI induces a specific and selective antialcohol effect, whereas mCPP rather induces a general suppressive effect on consummatory behavior. Ritanserin (1-10 mg/kg, i.p.) did not affect EtOH intake and preference, nor total fluid and food consumption. MDL 100,907 (0.1-1 mg/kg, i.p.) induced only a small reduction of food intake at the highest dose tested. Pretreatment with ritanserin (3 mg/kg, i.p.) and MDL 100,907 (0.3 mg/kg, i.p.) blocked the effects of DOI (3 mg/kg, i.p.), but not those of mCPP (10 mg/kg, i.p.). It is suggested that activation of 5-HT2C and/or 5-HT1B receptors results in a general decrease of consummatory behavior, whereas activation of 5-HT2A receptors selectively decreases EtOH intake and preference, as assessed in the cAA rat model of alcoholism.

We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (>30), dose dependently reduced shock-induced USV. The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(±)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of the mixed 5-HT2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/ kg, SC), or GR 127935 (30 mg/kg, IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT1A and 5-HT2A receptors produces a decrease of USV, we postulate that only 5-HT2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety.

In the pigeon conflict test of anxiety, the novel, high efficacy 5-HT1A receptor ligand, S 14671, very potently [minimal effective dose (MED): 0.0025 mg/kg, IM] and markedly (maximal percentage increase relative to control: 17232%) increased punished responding. In analogy, its structural analogue, the 5-HT1A receptor agonist, S 14506, equipotently, though less markedly, augmented punished responding (MED: 0.0025 mg/kg; maximal effect: 5557%). In contrast, the arylpiperazine 5-HT1A receptor agonists, LY 165,163 and tandospirone, increased punished responding only at higher doses (MED: 0.16 and 0.63 mg/kg, respectively), and also with a lesser maximal effect (2065% and 3695%, respectively). Although S 14671 and S 14506 showed a 16-fold separation between doses, increasing punished and decreasing unpunished responding, respectively, this separation was only fourfold for LY 165,163 and tandospirone. The anticonflict activity of S 14671 (0.01 mg/kg) was significantly antagonised by the 5-HT1A receptor antagonist, (-)-alprenolol (10 mg/kg), but not by combined treatment with the selective beta 1 receptor antagonist, betaxolol, and the selective beta 2 receptor antagonist, ICI 118,551. Further, a correlation analysis across each of the above agonists, as well as 8-OH-DPAT, buspirone, and (+)-flesinoxan, revealed a significant correlation for their relative potency in augmenting punished responding and their affinity for 5-HT1A receptors in vitro (r = +0.95, p0.001). It is concluded that S 14671 is an exceptionally potent and efficacious ligand in the pigeon conflict test and that its anxiolytic action reflects the activation of 5-HT1A receptors.

In a drug discrimination paradigm, the 5-HT2A/2C receptor antagonists, ritanserin, ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) and mianserin, and the preferential 5-HT2A receptor antagonist, ketanserin, antagonised the discriminative stimulus effects of the 5-HT2A/2C receptor agonist, DOI ((2,5-dimethoxy-4-iodohenyl)-2-aminopropan) (0.63 mg/kg i.p.). Effective dose50 (ED50) values were: 0.32, 0.39, 0.15 and 0.03 mg/kg s.c., respectively. While the novel, selective 5-HT2C receptor antagonist, SB 200,646 (N-(1-methyl-5-iodolyl)-N'-(3-pyridyl) urea hydrochloride) was inactive (10 mg/kg s.c. and 20 mg/kg p.o.), the highly selective 5-HT2A receptor antagonist, MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4- piperidine-methanol) very potently (ED50 = 0.0006) abolished the action of DOI. MDL 100,907 may display antipsychotic properties and the 'atypical' antipsychotics, clozapine, risperidone and sertindole, each of which possesses marked affinity at 5-HT2A receptors, abolished the discriminative stimulus effects of DOI (ED50 values of 0.07, 0.03 and 0.33 mg/kg, respectively). In contrast, haloperidol (0.16) was ineffective. These data demonstrate that 5-HT2A receptors mediate the discriminative stimulus effects of DOI and support the hypothesis that an antagonistic action at 5-HT2A receptors contributes to the in vivo actions of 'atypical' antipsychotics.

A putative animal model of anxiety based on shock-induced ultrasonic vocalization was pharmacologically validated in young adult rats. Suppression of shock-induced ultrasonic vocalization was obtained with diazepam, chlordiazepoxide, meprobamate and pentobarbital; the serotonin (5-HT)1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], buspirone, ipsapirone, gepirone and tandospirone; the nonselective 5-HT receptor agonists TFMPP [1-(3-trifluoromethylphenyl)piperazin], mCPP [1-(3-chlorophenyl)piperazin] and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane); the NMDA antagonists PCP (phencyclidine) and MK-801; the alpha 2-adrenoceptor antagonists idazoxane, yohimbine and 1-PP (1-pyrimidinylpiperazine); and the atypical neuroleptic clozapine. The alpha 2-adrenoceptor agonist clonidine, the 5-HT2/5-HT1C antagonist ritanserin, the 5-HT3 antagonists ondansetron and ICS-205,930, and the 5-HT reuptake inhibitor fluoxetine did not, or only partially, reduce ultrasonic vocalization. Tricyclic and tetracyclic, as well as some atypical antidepressants and a monoamineoxidase (MAO) inhibitor, showed no ultrasonic vocalization reducing effects, or reduced ultrasonic vocalization only at high doses. An opiate, an antimuscarinic, (pro)convulsants and typical neuroleptics did not reduce ultrasonic vocalization. The present findings suggest that the ultrasonic vocalization model specifically measures anxiolytic effects. Because ultrasonic vocalization responding develops within five days, remains stable for at least three months and gives highly reproducible results, the test appears suitable for rapid and repeated testing of new anxiolytics in the same animals.

In rats, the 5-HT1A receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT1A receptor partial agonists ipsapirone and buspirone dose dependently and completely inhibited shock-induced ultrasonic vocalization after systemic injection and after microinjection into the dorsal raphe nucleus, a brain region rich in somatodendritic 5-HT1A receptors. As compared with injection into the dorsal raphe nucleus, ipsapirone and 8-OH-DPAT were significantly less potent after microinjection into the lateral ventricle or the median raphe nucleus. Depletion of brain 5-HT (5-hydroxytryptamine) by means of 5,7-dihydroxytryptamine or parachlorophenylalanine inhibited ultrasonic vocalization. In lesioned rats, however, ipsapirone (i.p. or dorsal raphe nucleus) and 8-OH-DPAT (dorsal raphe nucleus) retained their ability to inhibit ultrasonic vocalization and, in non-lesioned rats, bilateral injection of ipsapirone, buspirone and 8-OH-DPAT into the dorsal hippocampus and the amygdala - two brain regions rich in postsynaptic 5-HT1A receptors - also inhibited ultrasonic vocalization. In a Geller-Seifter conflict test, i.p. and local injection of 8-OH-DPAT in the dorsal raphe nucleus and the hippocampus selectively enhanced punished responding. It is suggested that both presynaptic and (possibly to a lesser extent) postsynaptic 5-HT1A receptors are involved in the anxiolytic effects of ipsapirone, buspirone, and 8-OH-DPAT.

Ipsapirone, a 5-HT1A receptor agonist, is a psychoactive compound with anxiolytic and antidepressive properties. Concerning the mechanism of action of ipsapirone, most studies point towards an interaction with the central serotonergic system. For characterization of the anxiolytic properties of ipsapirone, the ultrasonic vocalization test, a rat model based on conditioned anxiety, was used. In this test ipsapirone time and dose dependently inhibited the shock induced ultrasonic vocalization of rats after systemic application of ipsapirone, indicating its potent anxiolytic properties. To gain further insight into the mechanism underlying the anxiolytic activity of ipsapirone, the effects of this compound on the central serotonergic system of rats were characterized. Extracellular single unit recordings, measuring the firing rate of serotonergic dorsal raphe neurons in anaesthetized rats, showed that ipsapirone dose and time dependently suppressed neuronal firing. In the hippocampus, one of the projection areas of the serotonergic dorsal raphe neurons, systemic application of ipsapirone resulted in a dose- and time-dependent reduction in serotonergic neurotransmission, measured as a reduced serotonin output in microdialysis experiments with freely moving rats. The time- and dose-effect curves reflecting the anxiolytic, electrophysiological, and biochemical effects correlated well with each other for different doses of ipsapirone. It is concluded that ipsapirone exhibits its anxiolytic effects, at least partially, by stimulating presynaptic somatodendritic 5-HT1A receptors in the brain stem raphe nuclei (i.e., the dorsal raphe), resulting in attenuation of presynaptic cell firing and subsequent inhibition of serotonergic neurotransmission in the limbic system (i.e., the hippocampus).

1. Preclinical and clinical studies suggest that 5-HT1A receptor agonists are a new class of mixed anxiolytics/antidepressants with, possibly, impulsivity reducing properties. 2. The anxiolytic effects of 5-HT1A receptor agonists result predominantly from an interaction with presynaptic 5-HT1A receptors (resulting in a decrease of serotonergic transmission), whereas the antidepressive and, possibly, the impulse control enhancing effects, result predominantly from an interaction with postsynaptic 5-HT1A receptors. 3. These proposed mechanism(s) of action fit well with the generally held view that anxiety is the result of a hypersensitive 5-HT system; whereas impulsivity and depression is the result of a hyposensitive 5-HT system. 4. However, it appears very likely that activation of pre- and postsynaptic 5-HT1A receptors is additionally involved in the antidepressive and impulse control enhancing effects, on the one hand, and in the anxiolytic effects of these compounds, on the other hand. 5. These latter, seemingly paradoxical, findings can be explained by assuming that (1) the presynaptic mechanism reflects an anxiolytic component in the animal models of impulsivity and depression, (2) antagonism of postsynaptic 5-HT1A receptors by these compounds contributes to their anxiolytic effects, (3) postsynaptic 5-HT1A and 5-HT2 receptors have functionally opposing effects or, alternatively, that (4) downregulation of postsynaptic 5-HT2 receptors contributes to the therapeutic effects of these compounds.

Brain 5-HT receptors have been classified in at least six subtypes (5-HT1A, 1B, 1C, 1D, 2 AND 3; Peroutka, 1988), among which the 5-HT1A subtype has been the focus of intense research during the last few years. This receptor type is located both presynaptically on the 5-HT cell bodies (somatodendritic receptors), predominantly in the dorsal and median raphe nuclei and postsynaptically, predominantly in the limbic system (Verge et al., 1985; Weissmann-Nanopoulos et al., 1985). Activation of presynaptic 5-HT1A receptors with 5-HT1A ligands inhibits serotonergic neurotransmission (Hamon et al., 1988; Hjorth and Magnusson, 1988; Sharp et al., 1989a, b) and the physiological role of these receptors is probably to provide the brain with an autoinhibitory feedback system controlling 5-HT neurotransmission. At the postsynaptic level, activation of 5-HT1A receptors results in neuronal inhibition, the consequences of which are not well understood (e.g. Sprouse and Aghajanian, 1988; Martin and Mason, 1987).