Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission

Abstract

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 caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.

Vasopressin/Serotonin Interactions in the Anterior Hypothalamus Control Aggressive Behavior in Golden Hamsters

“…Corroborating the human and monkey studies are neurobiological data from rodents linking 5-HT to the inhibition of aggression responding (Ellison, 1976;McMillen et al, 1987;Vergnes et al, 1988). As mentioned earlier, in a resident /intruder model, eltoprazine, the 5-HT 1 agonist, produces a dose-dependent decrease in offensive aggression in a rat resident /intruder model without altering other behaviors, including defensive aggression (Sijbesma et al, 1990).…”

Serotonergic modulation of social interactions in isolated male mice

“…For the detection of specific effects on aggressive behavior one cannot rely on only one model; different animal aggression paradigms, preferably in various animal species, must be considered (e.g., Olivier and Mos 1988). McMillen et al (1987) also describe the anti-aggressive effects of 5-HT1A agonists (8-OH-DPAT, buspirone and gepirone) and 5-HT~B agonists (mCPP and TFMPP) but do not provide detailed behavioral recordings, making comparison with the present study difficult. Their suggestion to use the isolation-induced aggression paradigm as an antianxiety model seems premature, as much more work is needed to implicate 5-HT receptor subsites in anxiety processes.…”

Quantitative autoradiographic distribution and pharmacological characterization of (3H)buspirone binding to sections from rat, bovine and marmoset brain

“…Using calf hippocampus, Glaser and Traber (1983) were the first to detect the high affinity of buspirone towards 5-HT1 a receptors (K I = 20nM). Thereafter, ICs0 values of 95nM (Riblet etal., 1984), 411 nM (Skolnick etal., 1985) and 10nM (McMillan et al, 1987) were published for rat and 24 nM (Peroutka, 1985) for bovine hippocampus. The inhibitory potency (ICs0) of buspirone against (3H)8-OH-DPAT binding was determined as 24 nM (Gozlan et al, 1983).…”