Behav Brain Res. 1997 Feb;83(1-2):217-20.
Role of hippocampal serotonergic neurons in ischemic neuronal death.

Nakata N, Suda H, Izumi J, Tanaka Y, Ikeda Y, Kato H, Itoyama Y, Kogure K.

Pharmacological Research Department, Zeria Pharmaceutical Co. Ltd., Saitama, Japan.

To clarify the serotonergic mechanisms involved in the protection against ischemic neuronal damage, ZD-211 (citalopram HBr), a serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitor, or buspirone, a 5-HT1A agonist, was locally administered into the hippocampus of gerbils. Additionally, to clarify the role of the 5-HT nervous system in the hippocampus during ischemic neuronal damage, animals were subjected to the local administration of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neurotoxin, before ischemia challenge. Gerbils received intrahippocampal administration of ZD-211 (200 nmol/animal) or buspirone (20 nmol/animal) before 5-min ischemia. 5,7-DHT was intrahippocampally administered 7 days before a 2-min non-lethal ischemia challenge. In vehicle-treated animals subjected to 5 min of ischemia, almost all hippocampal CA1 pyramidal neurons were lost. The treatment with ZD-211 or buspirone showed a significant protective effect, and the number of neurons was significantly increased compared to vehicle-treated animals. Pretreatment with NAN-190, a 5-HT1A antagonist, completely abolished the protective effect of ZD-211 or buspirone. In the 5,7-DHT-treated animals, the number of neurons was significantly reduced following 2 min of ischemia compared to vehicle-treated animals in which this period of ischemia is non-lethal. Thus, intrahippocampal treatment with ZD-211 or buspirone can protect neuronal damage following transient ischemia in gerbils. These effects of ZD-211 and buspirone were mediated through the 5-HT1A receptor in the hippocampus. Furthermore, the destruction of the 5-HT nervous system in the hippocampus aggravated ischemic neuronal damage. Therefore, this study showed that the enhanced activity of the 5-HT nervous




Br J Pharmacol. 1995 May;115(1):203-9.
Drug-induced defaecation in rats: role of central 5-HT1A receptors.

Croci T, Landi M, Bianchetti A, Manara L.

SANOFI-MIDY S.p.A. Research Center, Milan, Italy.

1. We investigated the acute effects of 5-hydroxytryptamine (5-HT), and of the 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and SR 57746A, on rat faecal pellet output and water content. 2. 5-HT, 8-OH-DPAT, buspirone and SR 57746A, a new selective 5-HT1A receptor agonist, displaced [3H]-8-OH-DPAT from specific binding sites in rat hippocampus membranes (Ki, nM; 1.8, 1.2, 15, 3.1 respectively) and stimulated rat defaecation dose-dependently. SR 57746A and buspirone induced 1 g dry weight of faeces at 1.3 and 6.1 mg kg-1, p.o. (AD1) respectively. 8-OH-DPAT and 5-HT stimulated defaecation after s.c. injection (AD1, 0.07 and 7.5 mg kg-1, respectively). All these agents increased faecal water content. 3. The putative 5-HT1A receptor antagonist, pindolol, injected s.c. or i.c.v., significantly reduced the defaecation induced by systemically administered 8-OH-DPAT, buspirone or SR 57746A, but not 5-HT. 4. Pretreatment with p-chlorophenylalanine (i.p.) or 5,7-dihydroxytryptamine (i.c.v.), according to protocols designed to cause either generalized or CNS-limited 5-HT depletion respectively, also reduced the defaecation induced by buspirone or SR 57746A. 5. No specific 5-HT1A binding sites could be labelled by incubating rat colon membranes with [3H]-8-OH-DPAT, and in vitro preparations of rat colon segments showed no response to 8-OH-DPAT or SR 57746A up to 5 microM. 6. After eight days' repeated daily treatment, complete tolerance developed to the stimulant effects of SR 57746A and buspirone on faecal water content, but not on faecal pellet output.(ABSTRACT TRUNCATED AT 250 WORDS)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7647978&dopt=Abstract buspirone Buspar




J Chromatogr A. 1997 Feb 21;762(1-2):269-73.
Measurement and pharmacokinetic analysis of buspirone by means of brain microdialysis coupled to high-performance liquid chromatography with electrochemical detection.

Tsai TH, Chen CF.

Department of Pharmacology, National Research Institute of Chinese Medicine, Taipei, Taiwan.

The feasibility of an electrochemical detection system with on-line microdialysis coupled with sensitive microbore high-performance liquid chromatography for the measurement and brain pharmacokinetic analysis of buspirone was investigated. A microdialysis probe was inserted into the right striatum of male Sprague-Dawley rats, which had been administered buspirone 10 mg/kg. i.v.). Dialysates were automatically injected through an on-line injector into a cyano microbore column coupled to an electrochemical detector. Samples were eluted with a mobile phase containing 0.1 M monosodium dihydrogenphosphate acetonitrile-diethylamine (85:15:0.1, v/v/v). pH 3.0, adjusted with orthophosphoric acids at a flow-rate of 0.06 ml/min. A biphasic phenomenon with a rapid distribution phase followed by a slower elimination phase was observed from the brain buspirone concentration-time curve. The results indicate that the brain pharmacokinetics of buspirone appear to conform to a two-compartment model.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9098985&dopt=Abstract buspirone Buspar




Brain Res. 1996 Dec 2;742(1-2):141-8.
Differential effects of haloperidol and two anxiolytic drugs, buspirone and lesopitron, on c-Fos expression in the rat striatum and nucleus accumbens.

Palacios G, Muro MA, Paz Marin A.

Departamento de Patologia, Laboratorios del Dr. Esteve, Barcelona, Spain.

We have studied the effects of the neuroleptic haloperidol and the non-benzodiazepine anxiolytics buspirone and lesopitron on the expression of c-Fos immunoreactivity in the rat forebrain. Haloperidol and buspirone administration resulted in a significant quantitative increase in the number of Fos-immunoreactive neurons in the lateral striatum and a presumable qualitative increase in the nucleus accumbens. In contrast, lesopitron did not lead to a significant increase in the c-Fos expression in the striatum. The induction of c-Fos immunoreactivity by buspirone is compatible with an interaction of this compound with D2 dopamine receptors, as documented for haloperidol. The lack of effects after lesopitron administration suggests that, in contrast with buspirone, this compound has no dopaminergic blocking activity.

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Alcohol Clin Exp Res. 1997 May;21(3):452-9.
Effects of maternal ethanol consumption and buspirone treatment on dopamine and norepinephrine reuptake sites and D1 receptors in offspring.

Gillespie RA, Eriksen J, Hao HL, Druse MJ.

Department of Molecular and Cellular Biochemistry, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.

Previously, it was shown that in utero ethanol exposure results in decreased serotonin (5-HT) and altered concentrations of 5-HT reuptake sites and 5-HT1A receptors in fetal and/or postnatal rats. Because fetal 5-HT is an essential trophic factor, this laboratory previously investigated the hypotheses that the early ethanol-associated 5-HT deficit contributed to subsequent development abnormalities in the serotonergic system and that the effects of the fetal 5-HT deficit could be prevented by maternal treatment with buspirone, a 5-HT1A receptor agonist. The present report determined the effects of maternal treatment with buspirone on two other neurotransmitter systems in the developing offspring of ethanol-fed dams: dopamine (DA) and norepinephrine reuptake sites and D1 receptors in postnatal day 19 offspring of control and ethanol-fed dams, that received daily injections of saline or 4.5 mg/kg buspirone. These investigations found that in utero ethanol exposure significantly decreased norepinephrine reuptake sites in the dorsomedial hypothalamic nucleus and anteroventral thalamic nucleus. There was also an ethanol effect in the dorsal raphe. D1 receptors were moderately increased (5-10% increase) in the striatum, and DA reuptake sites were unchanged in PN19 ethanol-exposed offspring. No other significant ethanol-related effects were noted. Maternal buspirone treatment did not adversely affect the concentration of DA reuptake sites or D1 receptors in control rats. Thus, whereas buspirone exerts protective effects on the developing 5-HT system of ethanol-exposed rats, it does not appear to damage the development of the DA system. Maternal buspi




Neuropharmacology. 1997 Mar;36(3):373-81.
Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor agonists.

Callahan PM, Cunningham KA.

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555, U.S.A.

The present investigation examined the ability of serotonin (5-HT) agonists to substitute for, or alter (i.e. enhance or antagonize), the discriminative stimulus properties of a moderately low dose of cocaine (5 mg/kg) utilizing a two-lever, water-reinforced FR 20 drug discrimination procedure in rats. In substitution tests, the 5-HT1A receptor partial agonists buspirone and gepirone, the 5-HT1A/B receptor agonist RU 24969 and the 5-HT1B/2C receptor agonist m-trifluoromethyl-phenylpiperazine (TFMPP) failed to substitute for the cocaine stimulus, although RU 24969 did engender a maximum of 72% cocaine-lever responding. Fluoxetine (4 mg/kg) engendered primarily saline-appropriate responding. In combination tests, a fixed dose of either fluoxetine (4 mg/kg), RU 24969 (0.5 mg/kg) or TFMPP (0.5 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.313-5 mg/kg). In contrast, buspirone (2.5-20 mg/kg) resulted in a dose-dependent attenuation (approximately 60% reduction) of the cocaine stimulus. Moreover, a dose of 10 mg/kg of buspirone co-administered with various doses of cocaine (1.25-10 mg/kg) engendered a rightward shift in the cocaine dose-response curve. Gepirone in combination with cocaine neither enhanced nor antagonized the cocaine discriminative stimulus. Whereas 5-HT agonists do not fully substitute for cocaine, the present results demonstrate that 5-HT1B, but not 5-HT1A, receptor agonists can modulate the discriminative stimulus properties of cocaine in a manner similar to that observed following administration of the 5-HT reuptake inhibitor fluoxetine. The ability of buspirone, but not gepirone, to attenuate the cocaine stimulus probably reflects its dopam




J Pharmacol Exp Ther. 1997 Jul;282(1):148-61.
S 15535, a novel benzodioxopiperazine ligand of serotonin (5-HT)1A receptors: II. Modulation of hippocampal serotonin release in relation to potential anxiolytic properties.

Millan MJ, Hjorth S, Samanin R, Schreiber R, Jaffard R, De Ladonchamps B, Veiga S, Goument B, Peglion JL, Spedding M, Brocco M.

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, France.

In these studies, we characterized the influence of the novel benzodioxopiperazine serotonin (5-HT)1A ligand, S 15535, on the release of 5-HT in rat hippocampus and compared its potential anxiolytic properties with those of the 5-HT1A receptor partial agonist, buspirone, the 5-HT1A antagonist, WAY 100,635 and the benzodiazepine, diazepam (DZM). (Doses are in milligrams per kilogram s.c., unless otherwise specified.) S 15535 dose-dependently (0.3-3.0) reduced dialysate concentrations of 5-HT in the hippocampus of anesthetized rats. This action of S 15535 (3.0) was blocked by WAY 100,635 (0.3), (-)-penbutolol (2.0) and (-)-tertatolol (8.0), antagonists at 5-HT1A autoreceptors. In rats, fear-induced ultrasonic vocalizations (USVs) were dose-dependently abolished by S 15535 (0.16-2.5 s.c. and 0.63-10.0 p.o.), an action mimicked by buspirone (0.02-2.5) and DZM (0.16-10.0). Further, the action of S 15535 (0.63) was abolished by WAY 100,635 (0.16) and (-)-penbutolol (10.0), which were inactive alone. S 15535 dose-dependently (0.63-10.0 s.c. and 2.5-40.0 p.o.) blocked aggressive encounters in isolated mice; buspirone (0.16-10.0) and, at high doses, DZM (2.5-40.0) were also effective. WAY 100,635 (0.16), which was inactive alone, fully antagonized the antiaggressive actions of S 15535 (2.5). In an elevated plus-maze, neither S 15535 (0.0025-10.0), buspirone (0.0025-10.0) nor WAY 100,635 (0.00063-0.63) significantly increased open-arm entries, whereas they were increased by DZM (0.16-0.63). In the pigeon conflict test, S 15535 (0.04-0.16 i.m.)




Life Sci. 1997;61(4):371-82.
Effects of buspirone on dopaminergic supersensitivity.

Queiroz CM, Frussa-Filho R.

Department of Pharmacology, Universidade Federal de Sao Paulo, Escola Paulista de Medicina, Brasil.

The effects of buspirone treatment on dopaminergic supersensitivity induced by long-term haloperidol administration were studied; both spontaneous activity (locomotion and rearing frequencies) of rats observed in an open-field and apomorphine-induced stereotypy were used as experimental parameters. Buspirone per se (3.0 mg/kg, twice daily, for 30 days) did not produce dopaminergic supersensitivity. When buspirone was given in combination to haloperidol (2.0 mg/kg, once daily, for 30 days), it decreased the neuroleptic withdrawal symptoms as detected in open-field behavior but not in apomorphine-induced stereotypy. Although single administration of buspirone per se decreased both open-field and apomorphine-induced stereotypy behavior, buspirone single administration did not modify the acute effects of haloperidol on these two behavioral models. Taken together with previous behavioral results showing that buspirone reverses haloperidol-induced catalepsy, the present data suggest that buspirone co-administration may lead to important clinical advantages concerning different extrapyramidal side effects of neuroleptic treatment.

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