Involvement of presynaptic 5-HT1A and benzodiazepine receptors in the anticonflict activity of 5-HT1A receptor antagonists

In the present paper, we examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2X10 mg/kg), and the influence of flumazenil (Ro 15-1788, 10 mg/kg), a benzodiazepine receptor antagonist, on the anticonflict activity of N-{2-[4-(2-methoxy,phenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclobexanecarboxamide (WAY 100635) and trans-1-(2-methoxyphenyl)-4-[4-succinimidocyclohexyl]piperazine (MP 349), pre- and postsynaptic 5-HT1A receptor antagonists, and 1-(2-methoxyphenyl)4-(4-succinimidobutyl)-piperazine (MM 77), a postsynaptic 5-HT1A receptor antagonist, in the Vogel conflict drinking test in rats. Diazepam was used as a reference compound. WAY 100635 (0.5-1 mg/kg), MP 349 (0.25-0.5 mg/kg), MM 77 (0.03-0.25 mg/kg) and diazepam (2.5-5 mg/kg) significantly increased the number of shocks accepted during experimental sessions in the conflict drinking test. In p-chloroamphetamine-pretreated rats, neither WAY 100635 (1 mg/kg) nor MP 349 (0.25 mg/kg) induced an anticonflict effect, whereas MM 77 (0.06 mg/kg) did produce it. Flumazenil fully blocked the anticonflict effects of WAY 100635 (1 mg/kg) and diazepam (5 mg/kg), and it partly but significantly reduced the anticonflict effects of MP 349 (0.25 mg/kg) and MM 77 (0.06 mg/kg). p-Chloroamphetamine and flumazenil alone were inactive in the conflict drinking test. The present results suggest that, first, the anticonflict effect of the 5-HT1A receptor antagonists, WAY 100635 and MP 349, but not MM 77, is linked to the presynaptically located 5-HT1A receptors, and second, benzodiazepine receptors are indirectly involved in such effects of WAY 100635, MP 349 and MM 77, due maybe to a possible interaction between the 5-HT and the gamma-aminobutyric acid (GABA)/benzodiazepine systems. (C) 2003 Elsevier Science B.V. All rights reserved.