Naunyn Schmiedebergs Arch Pharmacol. 1987 Apr;335(4):454-64.
Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission.

McMillen BA, Scott SM, Williams HL, Sanghera MK.

Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT cause




Arch Int Physiol Biochim. 1987 Dec;95(5):439-46.
Electrophysiological and microiontophoretic studies with buspirone: influence on the firing rate of central monoaminergic neurons and their responsiveness to dopamine, clonidine or GABA.

Scuvee-Moreau J, Giesbers I, Dresse A.

Department of Pharmacology, University of Liege, Sart Tilman.

The influence of an i.v. perfusion of buspirone on the firing rate of central monoaminergic neurons was studied in rats anaesthetized with chloral hydrate. Buspirone increased the firing rate of A10 dopaminergic neurons and blocked the inhibitory effect of iontophoretically applied dopamine on these neurons. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Buspirone increased the firing rate of locus coeruleus (LC) noradrenergic neurons and induced an attenuation of the inhibitory effect of iontophoretically applied clonidine. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Furthermore buspirone was a very potent inhibitor of the firing rate of dorsal raphe (DR) serotonergic neurons. It is concluded that activation of A10 neurons by buspirone is due to blockade of dopaminergic autoreceptors and that activation of LC neurons is related to blockade of alpha-2 autoreceptors. The significance of the interaction with gabaergic inhibition is unclear. The mechanisms involved in the inhibition of DR neurons remain to be investigated.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2452617&dopt=Abstract buspirone Buspar




J Neural Transm. 1989;78(2):131-44.
Quantitative autoradiographic distribution and pharmacological characterization of (3H)buspirone binding to sections from rat, bovine and marmoset brain.

Bruning G, Kaulen P, Schneider U, Baumgarten HG.

Department of Anatomy, Freie Universitat Berlin, Federal Republic of Germany.

(3H)Buspirone binds with high affinity (KD = 11 nM) to sections from rat striatum. Spiroperidol, chlorpromazine, (+)-butaclamol and apomorphine are the most potent inhibitors of (3H)buspirone binding. Ketanserin, SCH 23390, serotonin and phentolamine are clearly less active. The regional distribution of (3H)buspirone binding in rat and marmoset brain is characterized by high silver grain densities in the olfactory tubercle, nucleus accumbens and striatum. In the hypophysis, the pars intermedia is strongly labeled. Within the hippocampal formation, slightly higher binding site densities are found in the dentate gyrus. The distribution pattern of binding sites in the dentate gyrus varies according to the species investigated. The data presented in this study permit the conclusion that (3H)buspirone binds with high affinity to dopamine 2 receptors but do not exclude additional binding to other types of receptors, e.g. 5-HT1 receptors. The interaction of buspirone with dopamine 2 receptors may be mainly responsible for its pharmacological profile.

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J Pharmacol Exp Ther. 1989 Jan;248(1):50-6.
Effects of buspirone and its metabolite, 1-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats.

Fuller RW, Perry KW.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.

Buspirone, an anxiolytic drug with selective affinity for the 5-HT-1A subtype of serotonin receptors, caused a dose-related decrease in 5-hydroxyindole acetic acid (5-HIAA) concentration in rat hypothalamus after doses of 1 to 10 mg/kg s.c. The decrease in 5-HIAA concentration after a 3 mg/kg s.c. dose of buspirone persisted at 4 hr but not at 7 hr. The decrease was due apparently to a reduced turnover of serotonin; the accumulation of 5-hydroxytryptophan after decarboxylase inhibition was also suppressed by buspirone, not only in hypothalamus but also in brain stem, hippocampus and striatum. 1-(2-Pyrimidinyl)-piperazine (1-PP), a major metabolite of buspirone, did not affect hypothalamic 5-HIAA concentration at doses up to 10 mg/kg s.c. Both buspirone and 1-PP increased hypothalamic concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) sulfate, the norepinephrine metabolite, the effect being more pronounced with 1-PP but occurring after doses as low as 0.3 mg/kg s.c. with each compound. The increase in MHPG sulfate concentration persisted for at least 4 hr after a 3 mg/kg s.c. dose of each compound. The increase in MHPG sulfate produced by buspirone may have been due partly to 5-HT-1A receptor activation, inasmuch as other serotonin agonists have been found to cause a similar increase. 1-PP is reported to lack affinity for 5-HT-1A receptors so its elevation of MHPG sulfate concentration may have resulted from alpha-2 receptor blockade. The increase in MHPG sulfate concentration after buspirone injection may have been due at least partly to formation of the metabolite, 1-PP.(ABSTRACT TRUNCATED AT 250 WORDS)

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Psychopharmacology (Berl). 1989;97(3):319-25.
Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine.

Barrett JE, Hoffmann SM, Olmstead SN, Foust MJ, Harrod C, Weissman BA.

Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine a




Psychopharmacology (Berl). 1989;99(1):48-53.
An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone.

Moser PC.

Merrell Dow Research Institute, Strasbourg, France.

Previous work suggests that the elevated plus-maze test of anxiety is insensitive to the anxiolytic effects of the novel anxiolytic buspirone, which shows an anxiogenic-like profile in this test. This paper examines some of the possible reasons for this and the role that buspirone's agonist activity at 5-HT1A receptors plays in this effect. A variety of 5-HT1A receptor agonists (p-aminophenylethyl-m-trifluromethylphenyl piperazine, (+)- and (-)-MDL 72832) showed similar activity to buspirone, as did the related compound ipsapirone. (-)-MDL 72832 was more potent than (+)-MDL 72832, in keeping with its stereoselective action at 5-HT1A receptors. The alpha 2-adrenoceptor antagonist properties of 1-pyrimidinyl piperazine, a metabolite of buspirone, did not appear to be relevant to this action of buspirone as neither it nor idazoxan showed an anxiogenic-like profile. Neither chronic treatment with buspirone (1 mg/kg SC twice a day for 16 days) nor depletion of 5-HT with p-chlorophenylalanine changed the anxiogenic-like activity of buspirone in the elevated plus-maze test. These results suggest that an agonist action at postsynaptic 5-HT1A receptors mediates the anxiogenic-like effects of buspirone in the elevated plus-maze test and that this test may either be insensitive to certain classes of anxiolytics or is measuring something unrelated to human anxiety states.

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Eur J Pharmacol. 1989 Aug 11;167(1):21-9.
Serotonergic involvement in the inhibitory effects of repeated buspirone treatment on synaptic transmission in the hippocampus.

O'Connor JJ, Rowan MJ, Anwyl R.

Department of Pharmacology and Therapeutics, Trinity College, Dublin, Ireland.

The effects of acute and long-term treatment with buspirone on synaptic transmission in the hippocampus were compared in alert rats with chronic indwelling electrodes and cannula. Buspirone produced a transient dose-dependent reduction in the amplitude of the excitatory postsynaptic potential (EPSP) when acutely injected either systemically (0.3-3.0 mg/kg i.p.) or directly into the hippocampus (0.1-1.0 microgram i.h.). Whereas acute application of 0.5 mg/kg i.p. produced a 20% reduction which reversed within 2 h, during long-term treatment with this relatively low dose there was a gradual reduction of the baseline EPSP amplitude which reached a maximum (40%) between days 7-14 and which did not reverse completely until 72 h after the last injection. Intrahippocampal injection of either buspirone or 5-hydroxytryptamine did not have any additional effect during the period of baseline reduction. The 5-HT1A receptor antagonist spiroxatrine (1 mg/kg i.p.) produced a transient reversal of the effect of chronic buspirone. It is concluded that the chronic inhibitory effect of buspirone is probably an extension of its acute action on 5-HT1A receptors in the hippocampus.

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J Neural Transm. 1989;76(2):91-8.
A metabolite of buspirone increases locus coeruleus activity via alpha 2-receptor blockade.

Engberg G.

Department of Pharmacology, University of Gothenburg, Sweden.

Extracellular single unit recording techniques was used to pharmacologically analyze the excitatory action of buspirone on locus coeruleus (LC) noradrenergic neurons. Intravenously administered buspirone (0.5-8 mg/kg) dose-dependently increased LC firing rate. Furthermore, pretreatment with buspirone (8 mg/kg, i.p.) caused a parallel shift to the right of the dose-response curve for the inhibitory action of the alpha 2-receptor agonist clonidine on LC neurons. The inhibitory effect of microiontophoretically applied noradrenaline on LC neurons was not altered by the simultaneous application of buspirone, but almost totally blocked by its major metabolite 1-(2-pyrimidinyl-piperazine) (1-PP). The results indicate that buspirone causes activation of LC neurons via an alpha 2-receptor antagonistic action of its metabolite, 1-PP.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2565361&dopt=Abstract buspirone Buspar