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Objective To assess whether acute 5-hydroqnryptamine-1A (5HT1A)-receptor-mediated corticotropin, cortisol, and temperature responses are maintained after 3 weeks of treatment with controlled-release (CR) ipsapirone and fluoxetine compared with placebo and whether changes are reversible after cessation of treatment. Methods This was a randomized parallel-group study. Ten healthy subjects received ipsapirone CR or fluoxetine, and eight received placebo in a double-blind manner. An ipsapirone challenge test with 20 mg ipsapirone immediate-release formulation (IR) was performed before treatment (day 0) and after 20 days of treatment with placebo, 80 mg/day ipsapirone CR, or 20 mg/day fluoxetine (day 21). From day 22 to day 34 all subjects received placebo in a simple-blind manner. A third ipsapirone challenge test was performed on day 35. Results Before treatment, resting plasma corticotropin and cortisol concentrations and increases in plasma corticotropin and cortisol concentrations after challenge with 20 mg ipsapirone IR were similar for the three groups. After 20 days of treatment, plasma corticotropin and cortisol concentrations were similar before challenge, but ipsapirone IR-induced increases in plasma corticotropin and cortisol concentrations were significantly lower in both the ipsapirone CR group (corticotropin, 6.5 + 2 pg/ml; cortisol, 1.5 rt 0.7 pg/dl) and the fluoxetine group (corticotropin, 4.4 I 2 pg/ml; cortisol, 1.5 -r 0.7 pg/dl) compared with placebo (corticotropin, 34 + 14 pg/ml; cortisol, 5.8 z 2 pg/dl, mean + SEM). After 2 weeks of placebo administration, plasma corticotropin and cortisol responses to ipsapirone IR again became identical in all three groups. Plasma ipsapirone concentrations were similar in all groups during each challenge. The hypothermic response to ipsapirone IR showed no difference before treatment, at the end of the treatment period, or 2 weeks after cessation of treatment. Long-term administration of antidepressants to the healthy subjects did not lead to any serious adverse effects. Conclusions Long-term administration of fluoxetine and ipsapirone did not influence resting plasma corticotropin and cortisol concentrations in the morning. Stimulation of corticotropin and cortisol release by a selective 5-HT1A-agonist is reduced with long-term administration of these serotoninergic antidepressants. This subsensitivity of postsynaptic 5-HT1A-receptors is reversible. Clinical Pharmacology & Therapeutics (1998) 63, 428–436

In a recent study it has been shown that benzodiazepine receptor agonists attenuate novelty-induced suppression of feeding and increase the percentage of animals feeding in the open field. Food-deprived rats were placed in one corner of the open field containing food in the center. The number of rats beginning to eat in the first 5 min was recorded. In the present study this test was validated pharmacologically using known "anxiolytic" or "nonanxiolytic" drugs. The following substances (effective doses, given IP) increased the number of rats feeding within 5 min in the center of the open field: meprobamate (30.0-300 mg/kg), 8-OH-DPAT (10 and 30 microg/kg), ipsapirone (1.0 and 2.0 mg/kg), ritanserin (0.125-0.5 mg/kg), tropisetron (0.1-10.0 microg/kg), ondansetron (0.3-3.0 microg/kg), lisuride (0.28-0.55 mg/kg), morphine (0.3 and 1.0 mg/kg), propranolol (0.3 and 1.0 mg/kg), clozapine (1.0 mg/kg). Drugs without "anxiolytic" effects in other animal models or in humans, including amphetamine, apomorphine, haloperidol, sulpiride, and mCPP did not increase the incidence of food intake in this test. Ethanol and hexobarbital, in nonsedative doses, had no effect in this paradigm. Drugs and doses effective in the modified open-field test caused no increase in food intake in an independent food consumption test using food-deprived rats staying in the familiar cages. The results suggest that the modified open-field test can detect "anxiolytic" drug properties and is valid for the assessment of "anxiolytic" effects from different classes of drugs.

1. 1. We have investigated the ability of several compounds to diminish both infarct area and volume induced by middle cerebral artery occlusion in the mouse. 2. 2. Lifarizine, ipsapirone and N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HC1 (DPPE) all reduced both infarct area and volume. Ifenprodil diminished the infarct area, but the effect on total infarct volume was much less pronounced. 3. 3. In addition, we tested the protective effects of some other drugs on infarct area only. Nimodipine, verapamil, diltiazem, N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazolamine (R56865) and sabeluzole had no effect on infarct area. (S)-Emopamil significantly diminished infarct area. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) also diminished infarct area significantly. 4. 4. In some brain ischemia models hypothermia protects against ischemic damage. Mild hypothermia had no effect on infarct area in the present mouse model of focal ischemia.

To examine if 5-HT1A receptor function is involved in the pathophysiology of bipolar depression, we measured the cortisol, hypothermic and behavioral responses to ipsapirone, a 5-HT1A receptor agonist, in 8 patients with bipolar depression and 26 normal controls. After obtaining blood samples for baseline cortisol levels and measuring baseline body temperature, a single dose of 0.3 mg/kg of ipsapirone was administered orally to all the subjects, and further blood and temperature readings were obtained every 30 min for 3 h. The results showed that the administration of ipsapirone led to a significant increase in cortisol release and a significant decrease in body temperature both in bipolar depressed patients and normal controls. There was no significant difference in the cortisol or hypothermic responses to ipsapirone between groups. However, there was a significant positive correlation between the Hamilton Depression Rating (HAMD) scores and the hypothermic response in the depressed patients, while the HAMD scores were not significantly correlated with the cortisol response. Comparing our findings with those of previous studies, we suggest that the alterations in 5-HT1A receptor sensitivity in depressed patients may be related to the severity of depression, and they may only occur in more severely depressed patients.

Previous in vitro studies showed that glucocorticoid receptor activation (notably by corticosterone) could induce a functional desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus [Laaris et al. (1995) Neuropharmacology 34:1201-1210], similar to that due to in vivo subchronic treatment with a 5-HT reuptake inhibitor, such as fluoxetine, in rats. In the present study, we investigated whether a link might exist between these effects, i.e., whether glucocorticoid receptor activation could be responsible for the fluoxetine-induced desensitization of 5-HT1A autoreceptors. In vitro recording in the dorsal raphe nucleus of brain-stem slices showed that subchronic treatment with fluoxetine (5 mg/kg intraperitoneally (i.p.), daily for 3-7 days) significantly reduced the potency of the 5-HT1A receptor agonist ipsapirone to inhibit the firing rate of serotoninergic neurons. Parallel experiments in adrenalectomized and sham-operated rats indicated that subchronic fluoxetine treatment produced a similar shift to the right of the ipsapirone inhibition curve in both groups of animals. Furthermore, the subchronic blockade of glucocorticoid receptors by RU 38486 (25 mg/kg subcutaneously (s.c.), daily) in intact rats treated with fluoxetine (5 mg/kg i.p., daily for 3 days) did not affect the ability of the latter treatment to reduce the potency of ipsapirone to inhibit the firing of serotoninergic neurons. These data suggest that glucocorticoid receptors (and their possible activation by corticosterone) are not involved in the functional desensitization of somatodendritic 5-HT1A autoreceptors, which occurs during long-term treatment with a serotonin reuptake inhibitor such as fluoxetine.

Hypothermic and hormonal responses to a challenge with a selective 5-HT1A receptor agonist ipsapirone are considered to provide an index of 5-HT1A receptor function in humans. To examine the effects of divalproex sodium (DVP) on 5-HT1A receptor function in humans, we measured the hypothermic, adrenocorticotropic hormone (ACTH) cortisol, and behavioral responses to ipsapirone in 10 healthy male volunteers. After obtaining a blood sample for baseline hormone levels and measuring body temperature, a single dose of 0.3 mg/kg of ipsapirone was given orally to all the subjects and further bloods and temperature reading were obtained at regular intervals for three hours. The ipsapirone challenge tests were repeated after the subjects had been treated with DVP (1000 mg/day) for one week. The results showed that the hypothermia induced by ipsapirone was significantly attenuated by the DVP treatment, whereas the ACTH/cortisol release and the behavioral responses following ipsapirone challenges were not altered. Our findings suggest that DVP may enhance 5-HT neurotransmission in humans via a subsensitization of 5-HT1A autoreceptors but does not appear to affect postsynaptic 5-HT1A receptors.

1. The effects of ipsapirone, nefazodone, tiaspirone, BMS-20661, buspirone and gepirone on the hypothalamic-pituitary-adrenal (HPA) axis were studied. These drugs were selected because they have serontonin 1A (5-HT1A) receptor-binding capability and have the potential for therapeutic activity in the treatment of major affective or anxiety disorders or both. 2. Plasma corticosterone level was used as the end point for determining the effect of each drug on the HPA axis. Each drug increased the plasma corticosterone levels in a dose-dependent manner. The ED50 values were 0.8 mg/kg for BMS-20661, 3.5 mg/kg for gepirone, 3.9 mg/kg for buspirone, 5.3 mg/ kg for tiaspirone, 10.5 mg/kg for ipsapirone and 73.5 mg/kg for nefazodone. Ipsapirone and buspirone were more efficacious than the other four drugs. 3. The effect of a 10-mg/kg (35 mg/kg for nefazodone) test dose of each drug reached a peak between 30 min and 1 hr, and plasma corticosterone levels generally returned to control levels after 2 hr. 4. When the drugs were given 30 min before decapitation, in conjunction with a rotatory stress, BMS-20661 significantly inhibited the stress-induced rise, whereas ipsapirone and gepirone caused a significant increase in plasma corticosterone levels. However, when the drugs were given 2 hr before decapitation, nefazodone caused a significant decrease, whereas ipsapirone, BMS-20661 and gepirone produced significant increases in HPA axis activity. An 0800 hr dose of 0.1 mg/kg of dexamethasone suppressed the 1500 hr HPA activity by 73.1%. The 0.1-mg/kg dose of dexamethasone significantly reduced the drug-activated HPA axis activity of all of the drugs from their saline-control levels. The rank order, from least to greatest inhibitory effect, produced by this dexamethasone treatment on the drug-control levels was gepirone (-42.6%), tiaspirone (-48.9%), buspirone (-56.1%), nefazodone (-68.5%), insapirone (-70.0%), and BMS-20661 (-74.3%).

This study was designed to determine whether psychological stress alters the function of the GABAergic synapse, examined as biochemical changes of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding, in unwashed membranes of rat cerebral cortex. Psychological stress increased the number of [35S]TBPS binding sites by 22%. This enhancement was very similar to that after acute foot shock (24%). Psychological stress was induced very rapidly, because only 1 day after previous foot shock exposure, [35S]TBPS binding was increased by 23%. Diazepam [3 mg/kg intraperitoneally (subcutaneously)] and ipsapirone (5 mg/kg subcutaneously), injected 30 min before psychological stress, antagonized the enhancement of [35S]TBPS binding. This result suggests that psychological stress is a good animal model for investigating the various biochemical changes related to stress, avoiding the physical components associated with most of the normally used stressors and mimicking only emotional state alterations.

The present study was conducted to investigate whether +/- pindolol antagonizes ipsapirone induced biobehavioral changes in a personality dependent way. Our previous work demonstrated that high impulsives show higher immune cell responses than low impulsive subjects upon treatment with ipsapirone. A total number of 80 healthy male volunteers received placebo (N = 20) or 10 mg ipsapirone (N = 20), 30 mg +/- pindolol (N = 20), or a combination of 30 mg +/- pindolol and 10 mg ipsapirone (N = 20). Each group consisted of 10 low and 10 high impulsive subjects. Since 5-HT related drugs induce thermoregulatory responses, the study took place in a climate chamber with a constant ambient temperature. Blood samples (for measurement of CD4+ cell counts) were drawn from an indwelling catheter invisibly for the subjects. The results clearly demonstrate that the ipsapirone induced decreases in body temperature and number of peripheral CD4+ cells are more pronounced in high impulsives. +/- Pindolol antagonizes thermoregulatory and CD4+ cell responses. The results are discussed with respect to mechanisms of alteration in 5-HT function related to impulsivity.

The present study compared the effects of a wide range of 5-hydroxytryptamine (5-HT)-modulating and potential anxiolytic agents in the rat elevated plus-maze using spatiotemporal (i.e., open arm time and entries) and ethologically derived measures (i.e., risk assessment activities and directed exploration). The drugs used were 5-HT1A receptor partial (buspirone and ipsapirone) and full (8-OH-DPAT and flesinoxan) agonists, mixed 5-HT2A/2C receptor antagonists (ritanserin, ketanserin, mianserin, and pirenperone), selective 5-HT3 receptor antagonists (ICS 205-930, MDL 72222, ondansetron, and (RS)-zacopride), and selective (fluoxetine, fluvoxamine, and zimelidine) and nonselective (imipramine) 5-HT reuptake inhibitors. Only buspirone and mianserin produced effects indicative of an anxiolytic-like action on the spatiotemporal measures. However, all 5-HT1A receptor ligands, as well as mianserin, ketanserin, ondansetron, and zacopride, decreased the number of aborted attempts at entry into open arms (risk assessment). In addition, buspirone, mianserin, and zacopride increased head-dipping (directed exploration). Among the 5-HT reuptake inhibitors, zimelidine reduced head-dipping and total entries. The present findings demonstrate that risk assessment responses are sensitive to the action of 5-HT1A receptor ligands, but their modulation by drugs targetting 5-HT2A, 5-HT2C, and 5-HT3 receptors was not convincingly established.

The sleep electroencephalogram (EEG) was used to assay central effects of pindolol (10 and 30 mg p.o.), a mixed beta(1/2)-adrenoceptor/5-hydroxytryptamine (5-HT)(1A/1B) receptor blocker, in humans. Compared to placebo, pindolol produced a dose-related suppression of rapid-eye-movement (REM) sleep, including a prolongation of REM latency, and a decrease of REM time and REM density. At the higher dose, it also reduced EEG spectral power during non-REM sleep in portions of the delta, theta, and alpha frequencies (1.125-5.125 Hz, 7.125-9.625 Hz). By contrast, betaxolol (20 mg p.o.), a selective beta1-antagonist devoid of serotonergic affinity, affected neither REM sleep nor EEG power. REM sleep is, in part, under the inhibitory control of serotonergic neurons projecting from the dorsal raphe nucleus to pontine cholinergic/cholinoceptive cells. The EEG power spectrum induced by pindolol tended to be opposite to what has previously been reported for ipsapirone, a 5-HT1A agonist. Therefore, the present data, tentatively, are consistent with the contention that pindolol inhibits, possibly selectively, somatodendritic 5-HT1A autoreceptors in humans and may antagonize self-inhibition of midbrain raphe nuclei 5-HT neurons.

The azapirones, which are partial agonists of the serotonin (5-HT)1A receptor, possess anxiolytic activity. These agents may act at the pre- or postsynaptic 5-HT1A receptors, and involve the noradrenergic system. To determine whether these drugs activate noradrenergic neurons via 5-HT1A receptors, we have evaluated the expression of the immediate early gene c-fos in the locus coeruleus. Tandospirone and ipsapirone each induced expression of Fos protein in the noradrenergic neurons of the locus coeruleus of conscious rats. This effect was reversed by pretreatment with (+)-WAY100135, a specific 5-HT1A antagonist. These results clearly demonstrate that azapirones activate noradrenergic neurons via 5-HT1A receptors.

Twelve homing pigeons were trained to discriminate the 5-HT 1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT 1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di- n -propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT 1A/1B receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1 H -indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT 1B/2C receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT 1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 (( N -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N -(2-pyridinyl)cyclo-hexane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3(2 H )-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 ( N -tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide), (±)-pindolol and ( S )-UH-301 (( S )-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (±)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, ( S )-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT 1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT 1A receptor and that DU125530 acts as a full antagonist on the 5-HT 1A receptor.

We examined 5HT1a-mediated ACTH release in patients with chronic fatigue syndrome (CFS) using a between-subjects design. Patients attending a specialist outpatient clinic for CFS, who fulfilled CDC criteria, together with age- and sex-matched healthy comparison subjects, were recruited. Subjects had a cannula inserted in a forearm vein at 0830 h and were allowed to relax until 0900 h, when baseline bloods for ACTH and cortisol were drawn. They were then given ipsapirone 20 mg PO and further blood for hormone estimation was taken at +30, +60, +90, +120 and +180 min. Baseline ACTH and cortisol levels did not differ between the two groups. Release of ACTH (but not cortisol) in response to ipsapirone challenge was significantly blunted in patients with CFS. We conclude that serotonergic activation of the hypothalamic-pituitary-adrenal axis is defective in CFS. This defect may be of pathophysiological significance.

The kava-pyrones kavain and dihydromethysticin are constituents of Piper methysticum which possess muscle relaxant, anticonvulsant, analgesic and anxiolytic properties. In the present study the effect of both kava-pyrones were tested on field potential changes induced by the serotonin-1A agonist ipsapirone in the area CA1 and CA3 of the hippocampal slice preparation of guinea pigs. Ipsapirone induced positive field potential changes which were decreased in amplitude by the serotonin-1A antagonist NAN. The ipsapirone response was reduced by extracellular administration of kavain and dihydromethysticin in a dose-dependent manner down to 22·2 and 33·6%, respectively. It is suggested that kavain and dihydromethysticin modulate serotonin-1A receptor activity which may be of importance in the anti-anxiety action of kava-pyrones. © 1997 John Wiley & Sons, Ltd.

Adrenal steroids are important for maintaining neuronal maturation in the adult rats. Two weeks after bilateral adrenalectomy (ADX), hippocampal MAP-2 (microtubule associated protein-2) and calbindin immunoreactivity (IR) decreased in the molecular layer of the superior blade of the dentate gyrus. The molecular and granular cell layer at the lateral tip of the superior blade decreased in width by 32% and 50%, respectively. The granule neurons showed reduced staining with Nissl and an anti-calbindin antibody. These changes suggested a loss of the mature neuronal morphology. In this same localized regions, two glial proteins, glial fibrillary acidic protein (GFAP) and S-100 beta showed dramatically reduced immunoreactivity. These effects induced by ADX were reduced within 72 hrs by ipsapirone (1 mg/kg), a 5HT1A receptor agonist. Loss of adult neuronal morphology by ADX, and reversal by the 5HT1A agonist, may be evidence of the trophic importance of the 5HT1A receptor in granule neurons of hippocampus.

Contents: Section I: A.R. Cools, Introduction. A.R. Green, Behavioural Pharmacology of 5-HT: An Introduction. T.P. Blackburn, D.A. Martin, P. Slater, Is Rotational Behaviour in the Rat a 5-HT1A or 5-HT1B Mediated Response? A.J. Stoessl, C.T. Dourish, S.D. Iversen, Serotonic Mediated Behaviour Following Central or Peripheral Administration of the Selective NK-3 Tachykinin Agonist Senktide. Section II: P. Bevan, 5-HT and Sexual Behavior. S. Ahlenius, K. Larsson, New Aspects on the Serotonergic Modulation of Male Rat Sexual Behaviour. S.D. Mendelson, B.B. Gorzalka, Differential Roles of 5-HT Receptor Subtypes in Female Sexual Behaviour. M.D. James, S.M. Lane, D.R. Hole, C.A. Wilson, Hypothalamic Sites of Action of the Dual Effect of 5-HT on Female Sexual Behaviour in the Rat. L. R nyi, T. Lewander, 5-HT1A and 5-HT1B Agonists Produce Opposite Effects on the Ejaculatory Response Induced by Amphetamine in Rats. H.H.G. Berendsen, R.J.M. Smets, C.L.E. Broekkamp, Functional Interplay of Serotonin(5-HT)-Receptor Subtypes. Section III: P. Bevan, 5-HT and Aggression. B. Olivier, J. Mos, M. Tulp, J. Schipper, P. Bevan, Modulatory Action of Serotonin in Aggressive Behaviour. K.A. Miczek, P. Donat, Brain 5-HT System and Inhibition of Aggressive Behaviour. D.C. Blanchard, K. Hori, R.J. Rodgers, C.A. Hendrie, R.J. Blanchard, Differential Effects of Benzodiazepines and 5-HT1A Agonists on Defensive Patterns in Wild Rattus. C. Gentsch, M. Lichtsteiner, H. Feer, Competition for Sucrose-Pellets in Triads of Male, Wistar Rats, the Effects of Eight 5-HT- Agonists. Section IV: A.R. Cools, Depression and Psychosis. P. Willner, Towards a Theory of Serotonergic Dysfunction in Depression. J.F.W. Deakin, 5-HT Receptor Subtypes in Depression. J.A.M. van der Heyden, Modulation of the 5-HT System and Antipsychotic Activity. G.A. Kennet, G. Curzon, Mechanism of Action of 8-OH-DPAT on a Rat Model for Human Depression. P. Martin, A.M. Laporte, P. Soubrie, E. El Mestikawy, M. Hamon, Reversal of Helpless Behaviour in Rats by Serotonin Uptake Inhibitors. T.F. Meert, C.J.E. Niemegeers, Y.G. Gelders, P.A.J. Janssen, Ritanserin (R 55 667), an Original Thymosthenic. N.M. Barnes, B. Costall, A.M. Domeney, M.E. Kelly, R.J. Naylor, M.B. Tyers, The Abilities of 5-HT3 Antagonists to Inhibit the Hyperreactivity Caused by Dopamine Infusion into the Nucleus Accumbens of the Rat. M.A. Geyer, 5-HT2 Antagonists Increase Tactile Startle Habituation in an Animal Model of a Habituation Deficit in Schizophrenia. Section V: A.R. Cools, Feeding Behaviour. E. Goodall, T. Silverstone, Pharmacological Evidence for the Involvement of Serotonergic Mechanisms in Human Feeding. R. Samanin, Serotonin and Feeding. P.H. Hutson, G.A. Kennett, T.P. Donohoe, C.T. Dourish, G. Curzon, Opposite Effects of 5-HT1A and 5-HT1B/1C agonists on Food Intake. J.D. Leander, Effects of Selective Serotonergic Agonists on Palatability-Induced Ingestion. A.M.J. Montgomery, P. Willner, R. Muscat, 8-OH-DPAT Reliably Increases Ingestion of Solid but not Liquid Diets. C.L. Lawton, J.E. Blundell, Pharmacological Manipulation of 5-HT: Effect on Intake of Diets Supplemented with Either Sweet or Bland Carbohydrates. Section VI: T. Archer, 5-HT, Pain and Anxiety. O-G. Berge, C. Post, T. Archer, The Behavioural Pharmacology of Serotonin in Pain Processes. C.L. Broekkamp, F. Jenck, The Relationship Between Various Animal Models of Anxiety, Fear-Related Psychiatric Symptoms and Response to Serotonergic Drugs. P. Soubrie, 5-HT1A Receptors: A Bridge Between Anxiety and Depression? M.B. Tyers, A Review of the Evidence Supporting the Anxiolytic Potential of 5-HT3 Receptor Antagonists. J. Mos, B. Olivier, Ultrasonic Vocalizations by Rat Pups as an Animal Model for Anxiolytic Activity: Effects of Serotonergic Drugs. S.A. Lorens, H. Mitsushio, L.D. Van der Kar, Effects of the 5-HT1A Agonist Ipsapirone on the Behavioural, Endocrine and Neurochemical Responses to Conditioned Fear. P. Moser, Buspirone, Ipsapirone and 5-HT1A-Receptor Agonists Show an Anxiogenic-Like Profile in the Elevated Plus-Maze. A. Fernandez-Guasti, E. Hong, Antianxiety Effect of Various Putative 5-HT1 Receptor Agonists on the Conditioned Defensive Burying Paradigm. B.Costall, A.M. Domeney, P.A. Gerrard, B.J. Jones, M.E. Kelly, N.R. Oakley, M.B. Tyers, The Anxiolytic Activities of the 5-HT3 Receptor Antagonists GR38032F, ICS 205-930 and BRL 43694. J. Mos, J.A.M. van der Heyden, B. Olivier, Behavioural Effects of 5-HT3 Antagonists in Animal Models for Aggression, Anxiety and Psychosis. Section VII: T.U.C. Jarbe, T.Archer, 5-HT: Drug Discrimination and Aversion. W. Koek, F.C. Colpaert, Receptor Mechanisms of the Discriminative Stimulus Properties of Putative Serotonin Agonists. F.G. Graeff, Serotonin and Aversion. R.A. Glennon, R. Young, M.E. Pierson, Stimulus Properties of Arylpiperazine Second Generation Anxiolytics. J.E. Barrett, S.N. Olmstead, Z. Lei, C. Harrod, S.M. Hoffmann, K. Glover, M.A. Nader, B.A. Weissman, Behavioural, Neurochemical and Discriminative Stimulus Effects of Spiroxatrine, a Putative 5-HT1A Receptor Antagonist. I. Lucki, J.A. South, Rapid Training of the Stimulus Properties of Selective 5-Hydroxtryptamine1A Agonists. Section VIII: P. Bevan, S. Lorens, T. Archer, Behavioural Pharmacology of 5-HT: Possible Progress in the Laterality of Concepts.

The 5-hydroxytryptamine (5-HT)1A receptor has been the focus of considerable research effort over a decade. However, the definitive classification of this receptor and the full characterization of its pharmacology is still in progress. On the one hand, the selective serotonin-1A receptor partial agonist anxiolytics were developed first and represented a new class of pharmacological agents that have demonstrated efficacy in the treatment of generalized anxiety disorder (GAD). These compounds (e.g. buspirone, gepirone, tandospirone or ipsapirone) offered a completely different pharmacologic approach to this disorder from previous medications as benzodiazepines or alcohol. On the other hand, beta-adrenoceptor blockers (e.g. [-]-pindolol, [-]-propranolol) have been shown to have antagonistic properties on the 5-HT1A receptor side. Preliminary results suggest that beta-adrenoceptor blockers may be useful as adjunctive medication in the treatment of depression by augmenting the antidepressant efficacy of selective serotonin reuptake inhibitors. As the beta-adrenoceptor blockers show also affinities to other 5-HT receptors than the 5-HT1A receptor the recently discovered more selective 5-HT1A antagonists became of interest. The pharmacological properties and potential therapeutic utility of these novel compounds will also be discussed.

We evaluated the impact of conditioned stress on outflow of dopamine in the rat prefrontal cortex. Exposure of rats to an environment associated with aversive stimuli-foot shock enhanced outflow of dopamine in a similar way as seen during the conditioning session when foot shocks were applied. Diazepam (2.5 and 10 mg/kg) dose-dependently decreased outflow of dopamine and, when given in a dose of 10 mg/kg, but not 2.5 mg/kg, decreased enhanced dopamine outflow evoked by conditioned stress. On the other hand, ipsapirone (10 mg/kg, but not 2.5 mg/kg) and buspirone (2.5 mg/kg) enhanced basal outflow of dopamine. When ipsapirone (10 mg/kg) and buspirone (2.5 mg/kg) were given to rats exposed to conditioned stress, the stress-evoked elevation in dopamine outflow was abolished. Ipsapirone in a dose of 2.5 mg/kg was ineffective in the stress paradigm tested. It is concluded that conditioned stress in vivo enhances dopaminergic neurotransmission in the rat prefrontal cortex, this effect being attenuated by diazepam, a classic anxiolytic drug, and by such novel anxiolytics as ipsapirone and buspirone, which operate via serotonergic 5-HT1A receptors. Although ipsapirone and buspirone blocked stress-induced enhancement of dopamine outflow, this effect seems to result from their influence on the basal outflow of dopamine. Differential effects of diazepam and 5-HT1A agonists on basal and stress-induced alterations in dopamine outflow are discussed in terms of their possible effectiveness in various types of general anxiety disorders.

The effect on nocturnal melatonin secretion of acute administration of the indirectly acting serotonin (5-HT) receptor agonists d-fenfluramine (30 mg) and paroxetine (20 mg) and a partial 5-HT1A receptor agonist ipsapirone (20 mg) was investigated in healthy male volunteers and compared to a placebo condition. Each subject (n = 8) received each drug on one occasion over a 4 week study period, with drug administration separated by 1 week. A randomized, counter-balanced design was used. Drugs or placebo were administered at 2,000 hours in the light, and all blood samples were collected throughout the night in the dark at regular intervals until 0600 hours. Neither d-fenfluramine, paroxetine, or ipsapirone following acute dosage had a statistically significant effect on nocturnal melatonin synthesis. The lack of effect seen with d-fenfluramine, paroxetine, and ipsapirone may be due to limitations imposed by the dose requirements.

This experiment was conducted to determine whether drugs acting on brain serotonin modulate the effects of the mu opioid, morphine, as measured by the squirrel monkey shock titration procedure and, if so, whether serotonergic modulation is mediated via specific 5HT receptor subtypes. Under this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 s from 0.01 to 2.0 mA in 30 steps. Five responses on a lever during the 15-s shock period terminated the shock for 15 s, after which the shock resumed at the next lower intensity. The intensity below which monkeys maintained shock 50% of the time (median shock level or MSL) and rate of responding (RR) in the presence of shock were determined under control conditions and after administration of morphine alone and in combination with various serotonergic compounds. Morphine increased median shock level and decreased rate of responding in a dose-dependent manner. These effects of morphine was attenuated by the 5HT1A receptor agonists, 8-OH-DPAT [(+)-8-hydroxy-2(di-n-propylamino tetralin HBr] and ipsapirone. The effects of morphine were not altered by the 5HT1A receptor antagonist, NAN-190 [1-(2-methoxyphenyl-4-[4-(2-phthalimido) butyl] piperazine HBr], and 5HT2 receptor antagonist, ketanserin, the 5HT3 receptor antagonist, MDL 72222 [3-tropanyl-3,5-dichlorobenzoate], the alpha 2 adrenergic antagonist, yohimbine, or the alpha2 adrenergic agonist, clonidine. These results suggest that 5HT1A receptors may be involved in the effects of morphine in the shock titration procedure, whereas 5HT2, 5HT3 and alpha 2 adrenergic receptors do not appear to play a role in morphine's effects in this procedure.

There is increasing evidence that the 5-hydroxytryptamine (HT) 1A partial agonist ipsapirone is an effective anxiolytic/antidepressant agent, although its mechanism of action is not clear. In this study, we investigated the effects of chronic ipsapirone treatment (5 or 10 mg/kg; twice daily, 3 weeks) on 5-HT 1A receptor density 8-hydroxy-2-(di-n-propyl amino) tetralin (80H-DPAT) binding and the level of its mRNA (in situ hybridization) in various regions of the rat (male Wistar 250 g) brain. Receptor density was reduced in the frontal cortex, but did not change significantly in the hippocampus and dorsal raphe nucleus. The level of receptor mRNA was unchanged in each of these brain regions. The present results suggest that the clinical anxiolytic effects of ipsapirone may be mediated partly by postsynaptic action on serotonergic transmission in the frontal cortex, but not in the hippocampus or dorsal raphe nuclei.

In the present study, we investigated both the effect of ipsapirone on the dopamine outflow and its selectivity towards 5-HT 1A receptors in the rat prefrontal cortex. Using a brain microdialysis method in freely moving animals, it was found that ipsapirone, 5 and 10 mg/kg dose-dependently enhanced the outflow of dopamine, while 2.5 mg/kg was ineffective. The above effects of ipsapirone were mimicked by buspirone (2.5 and 5 mg/kg), another 5-HT 1A receptor agonist, but not 1-PP (1-pyrimidinylpiperazine, 5 mg/kg) — a centrally active metabolite of ipsapirone. The effect of ipsapirone (10 mg/kg) on the dopamine outflow in the rat prefrontal cortex was antagonized by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190, 1 mg/kg) and ( N -tert-butyl-3-(4-(2-methoxyphenylpiperazin-1-yl)-2-phenylpropionamide (WAY 100135, 10 mg/k.g.), i.e. substances with agonistic/antagonistic and antagonistic properties in relation to 5-HT 1A receptors, respectively. NAN-190 (1 mg/kg) enhanced the outflow of dopamine, while WAY 100135 (10 mg/kg) failed to alter it. It is concluded that 5-HT 1A receptor agonists may be involved in the regulation of dopaminergic neurotransmission in the rat prefrontal cortex and may have therapeutic potential in the treatment of disorders associated with dysfunction of the mesocortical dopaminergic system.

The REM sleep-suppressing effect of postsynaptic 5-HT1A stimulation has been well established. Here we investigate the effects of the 5-HT1A agonist ipsapirone (10 and 20 mg) on sleep EEG power spectra during non-REM sleep in nine healthy humans. At the lower dose, slow wave activity (SWA; EEG power in the delta (1-4.5 Hz) range) was significantly enhanced. At the higher dose, where side-effects occurred, the enhancement in SWA was not significant. The spectral profile was characterized by a bimodal increase of power in the lower delta and in the theta (5-8 Hz) frequencies, and by troughs at 4 Hz and at 11 Hz, a pattern compellingly similar to that reported for a 5-HT2 antagonist (seganserin). We propose that the spectral data following the lower ipsapirone dose reflect a net decrease of neuronal activity at 5-HT2 receptors, mediated through stimulation of somatodendritic autoreceptors in the raphe nuclei (presynaptic) and/or through stimulation of postsynaptic 5-HT1A receptors colocalized with 5-HT2 receptors. The spectral non-REM sleep EEG profile might be used to investigate central 5-HT function in humans.

Genetically selected aggressive and nonaggressive male wild house mice were tested in the shock-probe/defensive burying test. Five distinct behaviors (burying, immobility, rearing, grooming, and exploration) were recorded in two environmental situations: fresh and home cage sawdust. Nonaggressive animals, characterized by a Long Attack Latency (LAL), showed more immobility in both test situations than animals having Short Attack Latencies (SAL), whereas SAL males displayed more defensive burying than LAL ones when tested with fresh sawdust. Testing with home cage sawdust, however, resulted in the same duration of defensive burying in SAL and LAL. These results support earlier findings about the existence of two heritable, fundamentally different strategies to cope with aversive situations. Aggressive (SAL) animals react actively to environmental challenges, whereas nonaggressive animals react actively or passively, depending on the characteristics of the stressful environment. These mouse lines, selected for attack latency, i.e., aggression, may, therefore, be important tools to unravel the genetic architecture underlying the physiological and neuronal mechanisms of behavioral strategies towards stressful events.

That serotonin (5HT) is involved in regulating hypothalamic-pituitary- adrenal axis (HPA) function has long been recognized. A variety of drugs including precursors of 5HT such as 5HTP, drugs which release 5HT such as fenfluramine and drugs which act directly on 5HT receptors such as ipsapirone increase cortisol and ACTH concentrations. There is a general assumption that such stimulation occurs at a hypothalamic level. However, our increasing understanding of the complex interplay between 5HT and the HPA raises questions as to the validity of this simple model. An increasing volume of experimental research indicates that 5HT can act directly on the adrenal gland and possibly on the anterior pituitary as well. These findings have major implications for the interpretation of neuroendocrine studies of 5HT conducted in psychiatric conditions, such as depression.

Our previous study showed that conditioned fear stress (CFS) increased serotonin (5-HT) metabolism in the medial prefrontal cortex and induced freezing behavior. Although these results could support the 5-HT hypothesis of anxiety, the functional significance of the 5-HT response to stress is unclear. In this study, the effects of 5-HT reuptake inhibitors, agonists, antagonists, and diazepam on freezing behavior induced by CFS were examined using a time-sampling procedure. Various doses of test compounds were administered subcutaneously to rats 24 h after the last session of repeated foot-shock for 5 days. Rats were again placed in the shock chamber without shocks 20 min after injections of drugs, and observed. Diazepam (1 mg/kg) and the 5-HT1A agonist ipsapirone (0.5-10 mg/kg) significantly inhibited freezing behavior. L-5-Hydroxytryptophan (with benserazide) and the selective 5-HT reuptake inhibitor citalopram (10 mg/kg) reduced freezing behavior. The 5-HT2 antagonists ICI169,369 and ketanserin failed to change freezing behavior. p-Chlorophenylalanine (200 mg/kg) administered 15 h before the test did not affect freezing. The effect of ipsapirone was not modified in rats with lesions of 5-HT neurons, produced by p-chloroamphetamine (2 x 10 mg/kg). In conclusion, these results suggest the anxiolytic potential of ipsapirone and citalopram, and support the hypothesis that the facilitation of 5-HT neurotransmission decreases anxiety.

The effect of ipsapirone (3 and 10 mg/kg once daily, i.p. for 21 days), was assessed in two animal models of depression, namely the forced swim test and on the hyperactive response of the olfactory bulbectomized (OB) rat in the 'open field' test. The response to 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT; 0.15 mg/ kg, s.c.)-induced hypothermia in rats was examined on day 16 of ipsapirone treatment. In the forced swim test, subacute treatment with ipsapirone (3 and 10 mg/kg) significantly reduced the immobility time in both sham and OB groups. In the OB rat model, chronic treatment with 10 mg/kg ipsapirone antagonized the lesion- induced hyperactivity in the 'open field' apparatus. The hypothermic response to 8-OH-DPAT was attenuated after chronic treatment with 3 mg/kg ipsapirone in both sham and OB groups, while 10 mg/kg ipsapirone attenuated this temperature reduction only in the sham group ( p

Chronic buspirone or ipsapirone (3 mg/kg, twice daily) administration to rats for 10 days decreased the sensitivity of inhibition of single-unit activity of serotonergic dorsal raphe neurons to a challenge by each drug. The ED 50 for buspirone was increased from 0.1 mg/kg to 1.8 mg/kg, and the ED 50 for ipsapirone was increased from 0.7 mg/kg to 1.2 mg/kg. The binding properties ( K d and B max ) of [ 3 H]8-OHDPAT to membranes of cerebral cortex and hippocampus were unaffected by chronic administration of either buspirone or ipsapirone. Chronic buspirone or ipsapirone administration increased the tolerance of the hypothalamic-pituitary-adrenal axis (HPAA) following a challenge by each drug. The ED 50 for elevation of plasma corticosterone levels was increased from 4.0 mg/kg to 7.6 mg/ kg for buspirone and 6.2 mg/kg to 8.0 mg/kg for ipsapirone. Chronic buspirone administration decreased the basal activity of the HPAA by 63%. Chronic buspirone administration did not alter the plasma corticosterone response of the HPAA to a 1-min episode of rotational stress. (Mg 2+ )-ATPase, (Na + + K + )-ATPase, (Ca 2+ +Mg 2+ )-ATPase and calmodulin-stimulated (Ca 2+ +Mg 2+ )-ATPase activities of erythrocyte plasma membrane were unaffected by either chronic or acute buspirone treatment, or by the addition of the drug to the in vitro assay systems.

Fifteen patients with insulin-dependent diabetes mellitus who were stabilised on insulin, participated in an open study to assess the short- and long-term effects of ipsapirone on plasma glucose profiles, and to collect pharmacokinetic data on ipsapirone in this patient population. Plasma glucose concentrations were determined on day 1 (baseline), day 2 (after a single dose of ipsapirone HCl 5mg) and day 7 (after multiple doses of ipsapirone HCl 5mg three times daily) of the study. Plasma ipsapirone concentrations were determined on days 2 and 7. For ethical reasons, a crossover design could not be used, and the treatment order was the same for all the patients. Consequently, the effect of treatment (ipsapirone) on plasma glucose concentrations and possible period effects were confounded. Analysis of covariance and correlation analysis were used to assess the effect of ipsapirone on plasma glucose concentrations. The geometric means (SD) of the plasma glucose AUC0–5h on days 1, 2 and 7 were 56.9 (1.44), 48.1 (1.60) and 44.7 (1.48) mmol/L·h, respectively. The corresponding geometric mean (SD) trough (Oh) plasma glucose concentrations were 10.0 (1.58), 7.21 (1.96) and 6.69 (1.79) mmol/L. Correction for differences in trough glucose concentrations by an analysis of covariance indicated that a single dose of ipsapirone HC1 does not influence plasma glucose concentrations. Lack of correlation between the individual ipsapirone AUCss0–8h on day 7, and the difference between days 1 and 7 in glucose AUC0–5h, indicated that this also applies to multiple doses of ipsapirone. These results suggest that the addition of ipsapirone to insulin regimens does not affect plasma glucose levels to such an extent that an adjustment of insulin dosage is required. Plasma ipsapirone concentrations decline biphasically, with median half-lives of 0.24 hours and 1.71 hours after a single dose, and median half-lives of 0.25 hours and 2.03 hours after multiple doses. The maximum concentrations after a single dose are similar to those after multiple doses, but the AUCss0–8h is somewhat higher than the AUC0–∞ (after a single dose), indicating slight accumulation of the drug.

Pindolol has been shown to be a partial agonist at 5-HT1a receptors in preclinical studies. It has also been reported to inhibit the effects of other 5-HT1a partial agonists such as ipsapirone and buspirone on hormone secretion and body temperature in man, indicating its antagonist action at 5-HT1a receptors in man. To determine if pindolol has 5-HT1a agonist as well as antagonist effects in man, pindolol, 30 mg, p.o. and placebo, were given single blind in random order to 23 normal men with indwelling venous catheters and its effects on hormone secretion and body temperature noted. Pindolol significantly increased basal plasma cortisol concentrations, whereas it decreased plasma prolactin (PRL) concentrations and body temperature. The increase in plasma cortisol due to pindolol suggests a 5-HT1a agonist action and is consistent with a 5-HT1a partial agonist mechanism in man whereas the PRL effects are consistent with an antagonist action at 5-HT1a receptors. The effects of pindolol on plasma cortisol concentration and body temperature were significantly negatively correlated. Furthermore, these results indicate significant differences in the 5-HT1a-dependent regulation of PRL and the hypothalamo-pituitary-adrenal (HPA) axis and body temperature, and suggest that human basal PRL secretion is tonically stimulated by a 5-HT1a mechanism whereas the HPA axis and body temperature are not. Since rodent studies suggest differences in 5-HT1a receptor sensitivity between males and females, the results reported here need to be replicated in females. These differences in the effect of pindolol are discussed in terms of receptor reserve theory.

To test the hypothesis that the mechanisms of 5-HT1 and 5-HT2 receptor-mediated hormonal responses are different, we compared the effects of hypothalamic paraventricular nucleus (PVN) lesions on the ACTH/corticosterone, prolactin and oxytocin responses to the 5-HT1A agonist ipsapirone (1 and 2 mg/kg), the 5-HT2C agonist m-chlorophenylpiperazine (m-CPP, 0.6 mg/kg), which also binds to other 5-HT receptors with lower affinity, and the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg) in chronically cannulated, freely moving male rats. Pharmacological characterization using antagonists with different affinity for 5-HT2A and 5-HT2C receptors revealed that DOI's responses were mediated mainly by 5-HT2A receptors and m-CPP's responses were almost exclusively mediated by 5-HT2C receptors. ACTH/corticosterone responses to ipsapirone, DOI and m-CPP were almost completely blocked after PVN lesions. Prolactin responses were significantly different in lesioned rats only after DOI and m-CPP challenges. Oxytocin responses to ipsapirone and DOI, but not m-CPP were markedly attenuated after PVN lesions. The present findings suggest that the PVN, or neural pathways close to it, mediate corticosterone and in some cases prolactin and oxytocin responses to selective stimulation of 5-HT1A, 5-HT2A, or 5-HT2C receptors.

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The rate-decreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.

Drugs with different intrinsic activity at 5-HT1A receptors and antagonists at 5-HT2A/2C and 5-HT3 receptors were studied for their ability to increase the rates of punished operant responding in rats. Like chlordiazepoxide (5 and 10 mg/kg) and diazepam (1.25 and 2.5 mg/kg), 0.125 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, and 5 and 10 mg/kg ipsapirone, a partial agonist at these receptors, increased the rates of punished responding, whereas (S)-WAY 100135, a 5-HT1A receptor antagonist, had no effect at doses from 1 to 10 mg/kg. 8-OH-DPAT and ipsapirone, like benzodiazepines, significantly reduced unpunished responding. The 5-HT2A/2C receptor antagonists ritanserin (2 mg/kg), mianserin (8 mg/kg), and mesulergine (0.1 mg/kg) significantly increased the rates of punished responding, whereas 0.5-2 mg/kg ketanserin, that has higher affinity for 5-HT2A than 5-HT2C receptors, had no effect. Antagonists, at 5-HT3 receptors such as ondansetron (0.001-0.1 mg/kg) and tropisetron (0.001-0.1 mg/kg), had no effect on punished or unpunished responding. The results show that agents acting as full or partial agonists at 5-HT1A receptors and blockers of postsynaptic 5-HT2C receptors have anxiolytic-like effects in a model of punished operant responding, whereas antagonists at 5-HT1A and 5-HT3 receptors have no such effect.

The present study was conducted to investigate the relationship between the serotonergic neurotransmitter system and migration patterns of peripheral lymphocytes. Altogether 40 healthy male volunteers were given either a single dosage of the 5-HT 1 a -receptor agonist ipsapirone (10 mg) or a placebo ( n = 20 each) in a double-blind randomized trial. Blood samples were drawn 55, 90 and 110 min after drug intake (baseline) and were analyzed for the number of peripheral lymphocytes. Furthermore, saliva samples were obtained at 13 defined time points which were analyzed for cortisol concentrations. Personality traits impulsivity, psychoticism and boredom susceptibility) were measured by questionnaires to investigate personality related differences in levels of serotonergic responsiveness. Analyses of covariance indicated that ipsapirone leads to highly significant reductions of peripheral CD4+ cells (T-helper/inducer-cells). This was significantly correlated to the ipsapirone-induced release of cortisol in a time-dependent manner. Furthermore, subjects scoring high on impulsivity, psychoticism and boredom susceptibility could be identified as being more responsive to the 5-HT agonist, indicated by their larger reduction in T-helper cells and greater cortisol release. This was hypothesized to be either due to their subsensitivity of presynaptic or supersensitivity of postsynaptic 5-HT 1 a -receptors.

Various models of rodent agonistic behavior are described, which differentiate between offensive and defensive/flight models. Particular attention is given to one male and one female paradigm for offensive aggression, i.e. resident/intruder or territorial aggression (RI) and maternal aggression (MA). After an overview of the serotonin (5-HT) system in the CNS, a description is given of the ligands available. Subsequently, the effects of various drugs affecting serotonergic transmission in the RI- and MA-paradigms are described. The 5-HT1A receptor agonists busipirone, ipsapirone, and 8-OH-DPAT decreased aggression in RI and MA, but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific antiaggressive profile. Nonselective 5-HT1 receptor agonists, such as RU24969, eltoprazine, and TFMPP reduced aggression quite specifically, did not decrease social interest or exploration, and sometimes even increased these behaviors. In RI and MA, the behavioral effects of these drugs were roughly similar. In contrast, MA was more sensitive to treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression nonspecifically at the highest dose only. DOI, a 5-HT2A/2C# receptor agonist, decreased aggressive behavior and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by "wet dog shaking" characteristic of 5-HT2 receptor stimulation. The nonspecific 5-HT receptor agonist (and 5-HT2 receptor antagonist) quipazine also induced "wet dog shaking" at doses which suppressed aggression, social interest, and exploration but increased inactive behaviors (sitting and lying). The discussion delineates a specific role for 5-HT1B receptor-subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs, and this fact underlines the consistent role of 5-HT in different forms of aggression.

Antidepressant properties of 5-HT 1A receptor ligands (the full agonist 8-OH-DPAT, the partial agonists ipsapirone and buspirone, and the selective antagonist WAY 100135) were studied in a chronic mild stress model of depression. In this model, rats subjected to a variety of mild Stressors for a prolonged period of time show a substantial decrease in the consumption of a 1 % sucrose solution (anhedonia), an effect being sensitive to repeated treatment with antidepressant drugs. In the present study we found that the stress-induced deficit in the sucrose intake was gradually reversed by chronic (3–5 weeks) administration of buspirone (2.5 and 5 mg/kg, i.p., b.i.d.) or WAY 100135 (10 mg/kg, s.c., b.i.d.), but not 8-OH-DPAT (0.5 mg/kg, s.c., b.i.d.) or ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude of the effect of buspirone and WAY 100135 was comparable to that observed following similar administration of the antidepressant drugs imipramine (10 mg/kg i.p.) or citalopram (10 mg/kg i.p.). Increases in the sucrose intake following chronic treatment with buspirone, WAY 100135, imipramine and citalopram were specific to the stressed animals; the behaviour of control non-stressed animals was unchanged by any drug. These results suggest that buspirone and WAY 100135 may have antidepressant properties. Possible links between the anti-anhedonic effect of these drugs and their interaction with 5-HT 1A receptors and/or the dopamine system are discussed.

Major depressed patients have been reported to exhibit significantly attenuated cortisol and hypothermic responses to ipsapirone, a serotonin (5-HT)- 1A partial agonist, compared to normal controls. This study further investigated the cortisol and temperature responses to ipsapirone (0.5 mg/kg orally) and placebo in 20 normal volunteers and 12 major depressed patients. Both plasma cortisol and temperature were measured every 30 min before ipsapirone or placebo administration until 180 min post administration. Ipsapirone administration produced a significant increase in plasma cortisol levels as well as hypothermia. Major depressed patients showed significantly blunted ipsapirone-induced cortisol responses compared to normal controls. No significant differences in ipsapirone-induced hypothermic responses were found between major depressed patients and normal controls.

The effect of ipsapirone, a partial agonist at 5-HT1A receptors, and of diazepam on punished operant responding was studied in rats injected intracerebroventricularly with 150 microg 5,7-dihydroxytryptamine to deplete brain serotonin or pretreated with (S)-WAY 100135 (N-tert-butyl) 3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpropanamide dihydrochloride), an antagonist at 5-HT1A receptors. 5,7-Dihydroxytryptamine markedly depleted brain serotonin and caused a sustained increase in punished responding with no effect on rates of unpunished responding in sham-operated rats but had no effect in animals which had received 5,7-dihydroxytryptamine. At 5 and 10 mg/kg ipsapirone reduced unpunished responding similarly in sham-operated and 5,7-dihydroxytryptamine-treated rats. Diazepam 2.5 mg/kg i.p.significantly increased punished responding and reduced rates of unpunished responding similarly in sham-operated and in 5,7-dihydroxytryptamine-treated animals. At 3 and 10 mg/kg (S)-WAY 100135 did not modify punished or unpunished responding but at 10 mg/kg it completely antagonized the effect of 5 mg/kg/s.c. ipsapirone on unpunished and punished responding. The results suggest that ipsapirone releases behaviour that is suppressed by punishment by stimulating presynaptic 5-HT1A receptors.

The effect of various psychotropic drugs on the ambivalent behaviour "stretched approach posture" (SAP) in the rat was assessed. SAP was elicited after a mild startle reaction due to physical contact with an electrified prod at one end of a straight runway. Using ethological observation methods, SAP as well as intention movements, prod contact, crossings, rearing, exploration, grooming and immobility were recorded. The benzodiazepine receptor agonists chlordiazepoxide, diazepam and alprazolam, the 5-HT1A receptor agonists flesinoxan and ipsapirone and the 5-HT uptake inhibitor clomipramine selectively (no effect on crossings) reduced SAP. Except for alprazolam, these drugs also reduced intention movements. In addition, chlordiazepoxide and diazepam enhanced prod contact. Reductions of SAP and intentions with concomitant reductions of crossings (nonspecific antiambivalent effects) were established for the alpha 2-adrenoceptor agonist clonidine and the MAO inhibitor clorgyline. The 5-HT uptake inhibitor fluvoxamine suppressed intention movements, but not SAP. The mixed 5-HT/NA uptake inhibitor imipramine did not significantly affect SAP or intentions, but reduced crossings. The 5-HT2C/1B receptor agonist m-CPP, the inverse BZD receptor agonists FG 7142 and DMCM, and the alpha 2-adrenoceptor antagonist yohimbine, to all of which putative anxiogenic effects have been ascribed, had no effect on SAP directed towards the prod. m-CPP, however, produced an increase in the stretched posture directed away from the prod (SAwayP). FG 7142 reduced intentions while strongly enhancing immobility (freezing). SAwayP and/or freezing may possibly reflect anxiogenic properties of drugs. The putative anxiogenic drug pentylenetetrazol false positively reduced SAP while increasing exploration. The dopamine-D2 receptor antagonist haloperidol and the catecholamine releaser dl-amphetamine had no effect on ambivalent behaviour. The muscarine receptor antagonist scopolamine reduced SAP and intentions while stimulating crossings. Finally, the 5-HT2C receptor antagonist ritanserine, the CCKA receptor antagonist devazepide, the CCKB receptor antagonist L-365.260 and the strychnine-insensitive glycine site antagonist 7-Cl-kynurenic acid were without effect on the behaviours in this paradigm using single doses. In conclusion, SAP and intention movements were reduced selectively by anxiolytic agents from different classes, including benzodiazepine receptor agonists, 5-HT1A receptor agonists and a 5-HT uptake inhibitor, whereas an alpha 2-adrenoceptor agonist and a MAO inhibitor reduced SAP non-selectively. SAP in relation to other behaviours may therefore serve as a valuable paradigm to characterize anxiolytic drugs.

A fully automated version of the black and white two-compartment box for mice is presented. The anxiolytic-like effects of the benzodiazepines, diazepam and chlordiazepoxide, were confirmed, and the involvement of serotonergic mechanisms was studied in this animal model of anxiety. The partial 5-HT 1A receptor agonists, buspirone and ipsapirone showed anxiolytic-like effects in a limited dose interval. The full agonist hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) was inactive. The non-selective 5-HT 1 receptor agonist, eltoprazine, induced marked increases of exploratory behaviour in the white compartment over a broad range of doses. Also pindolol a mixed 5-HT 1A/1B and β-adrenergic receptor antagonist showed anxiolytic-like effects, whereas another compound with a similar profile (-)-, penbutolol and the β-adrenoceptor antagonist ICI 118,551, was inactive. The 5-HT 2A/2C receptor antagonist, ritanserin, showed anxiogenic-like, and the 5-HT 3 receptor antagonists, zacopride and ondansetron, showed anixiolytic-like effects. An overall increase of serotonergic activity by means of 5-HT uptake inhibition (citalopram), 5-HT release (fenfluramine) or administration of a 5-HT precursor (1-5-HTP) facilitated exploratory activity in the white compartment. Reduction of serotonergic activity by treatment with the 5-HT depletor p-chloro-phenylalanine methyl ester (PCPA) did not change the exploratory behaviour, but attenuated the response to fenfluramine significantly.

Behavioral and neurochemical measures of brain 5-hydroxytryptamine (5-HT) function in the Fawn-Hooded rat are abnormal relative to outbred strains of rats. Fawn-Hooded rats freely drink large amounts of 10% ethanol in the presence of water and have been proposed to be an animal model for studies related to alcoholism. In this study, Fawn-Hooded rats were given solutions of ethanol increasing in concentration from 3% to 30% (w/v in tap water) over 10 days with tap water in a second drinking tube and a third tube left empty. The solutions of ethanol that produced maximal drinking with a preference (ml ethanol/ml total fluid) near 50% ranged from 5% to 13%, which became the fixed individual concentrations for each rat. After a 5-day baseline period the rats were offered a solution in the third drinking tube of either 0.5% aspartame or chocolate Ultra SlimFast (diluted with water 2:1). The chocolate drink, but not aspartame, significantly reduced the consumption of alcohol by 73%. For the drug experiments, the rats were given successive 4-day periods of: baseline drinking; drug or saline injections b.i.d.; and a posttreatment period. Neither ipsapirone, a 5-HT1a partial agonist, nor naltrexone injected inhibited the intakes of ethanol solutions. Treatment with 2.5 mg/kg of amperozide, a 5-HT2 antagonist, decreased the consumption of ethanol by 38%, but also caused a decrease in consumption of food. These results show a pattern of drinking of increasing concentrations of ethanol different than other strains of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventeen women who met the criteria for bulimia nervosa (DSM-III-R) were treated for 4 weeks in an open trial with ipsapirone, a partial 5-HT1A agonist. Bulimic symptoms diminished in 66.6% of the patients after only 1 week of treatment, 93.3% showed a reduction of more than 50% of weekly binge eating attacks after 4 weeks. The mean frequency of binges was reduced by 81% at endpoint. Ipsapirone was well tolerated. © 1995 by John Wiley & Sons, Inc.

A simple capillary electrophoretic method was developed for the analysis of a new generation of serotonergic anxiolytics and their related substances: zalospirone, gepirone, ipsapirone and buspirone. All compounds run in a Tris/phosphate buffer at pH 3 as cations and the experimental conditions allowed good resolution of four drugs and their principal impurities. The analyses were made using two different kinds of capillary. The suitability of CZE and HPLC methods for the analysis of these non-benzodiazepinic anxiolytic agents and their impurities was compared.

1. Because the 5-HT1A agonist anxiolytic azapirones have a common alpha 2-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (1PP), we measured central and peripheral alpha 2-adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day-1 for 4 days and 10 mg on day 5), ipsapirone (15 mg day-1 for 4 days and 5 mg on day 5) or placebo. 2. Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4-dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C-peptide concentrations. Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3. The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4. Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma 1PP concentration which was higher on buspirone than on ipsapirone (2.76 micrograms l-1, 95% CI:1.3-4.22 vs 0.65 microgram l-1, 95% CI: 0.32-0.98, P = 0.006). 5. Mean AUC of the 1PP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC 1PP ratio was 6.45 and the AUC buspirone/AUC 1PP ratio was 0.076.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.

The present studies were designed to determine the effects of 5-HT1A receptor agonists and 5-HT2A/2C and 5-HT3 antagonists on adrenocortical responses to a variety of stress paradigms in conscious male rats. The following stressors were examined: acoustic stress (105 dB for 2 min); foot shock (0.2 mA, five shocks over 5 min); conditioned fear (animals placed in the foot shock chamber for 5 min, 24 h after foot shock); restraint (Plexiglas restrainer for 5 min); injection of recombinant human interleukin-1 alpha (IL-1, 20 micrograms/kg, IP); injection of cocaine hydrochloride (20 mg/kg, IP). Drug treatments consisted of intracerebroventricular (ICV) or intraperitoneal (IP) injections of the 5-HT1A agonists, 8-OH-DPAT and ipsapirone (0.1 pmol, ICV), the 5-HT2A/2C antagonist, ketanserin (2 mumol/kg, IP), and the 5-HT3 antagonist, MDL-72222 (20 nmol, ICV). The plasma corticosterone (CS) responses to foot shock and restraint stress were not affected by any of the serotonergic drugs tested. The 5-HT1A agonist, 8-OH-DPAT, was able to attenuate the adrenocortical responses to acoustic stimulation, conditioned fear, IL-1 alpha, and cocaine administration, with ipsapirone also being effective in reducing the responses to acoustic stimulation and cocaine injection. The 5-HT2 antagonist, ketanserin was able to reduce the adrenocortical response in the conditioned fear paradigm and the response to IL-1 alpha injection. The 5-HT3 antagonist, MDL-72222 was only effective in reducing the response to acoustic stimulation. Thus, adrenocortical responses to each of the applied stressors were differentially affected by the 5-HT receptor ligands tested. The results of this study indicate that 5-HT1A agonists may be efficient stress response-reducing agents. However, their efficacy depends on the lack of a somatosensory component to the applied stressor and their agonist properties suggest that their action may not involve direct effects on serotonergic pathways mediating the observed responses. In contrast, the specificity of the 5-HT2 and 5-HT3 antagonists in blocking adrenocortical responses to certain stressors suggests that these drugs exert their effects by blocking serotonergic neurotransmission in pathways mediating the adrenocortical responses to specific stimuli.

Ipsapirone is a new pyrimidinylpiperazine ligand specific for 5-HT1A receptors, with potential therapeutic use in affective disorders. Because 5-HT is involved in the regulation of sleep, we investigated the effect of ipsapirone hydrochloride on sleep patterns in 18 normal, healthy subjects of both sexes. Compared to placebo, ipsapirone 5 mg administered by mouth three times daily for 14 days decreased rapid eye movement (REM) sleep duration and, by the tenth day of treatment, began to reduce slow wave sleep (SWS) duration. The decrease in REM sleep occurred in the first 3 h of sleep. The latency to REM sleep was increased from the first night following ipsapirone administration, remained increased throughout the 14 days of administration, and fell to equal latency on placebo immediately administration ended. Subjective assessments of sleep revealed no differences between ipsapirone and placebo. Our experiments confirm a role of 5-HT1A receptors in sleep. The effects of ipsapirone on the sleep patterns of patients with affective disorders still need to be determined.

SummarySerotonin 1A receptor selective agents have been developed throughout the world, but have different degrees of acceptance in different countries. Although buspirone has been marketed in the United States and Europe, positive results were not obtained for trials of buspirone in anxiety in Japan. Positive results were also not obtained for a related agent, ipsapirone, in Japan, although another related agent, tandospirone, has been demonstrated to show clinical efficacy in anxiety in Japanese studies. This may lead to the ultimate marketing of tandospirone for anxiety disorders in Japan.