Involvement of presynaptic 5-HT(1A) and benzodiazepine receptors in the anticonflict activity of 5-HT(1A) receptor antagonists.
In the present paper, we examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 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-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635) and trans-1-(2-methoxy-phenyl)-4-[4-succinimidocyclohexyl]piperazine (MP 349), pre- and postsynaptic 5-HT(1A) receptor antagonists, and 1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine (MM 77), a postsynaptic 5-HT(1A) 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-HT(1A) receptor antagonists, WAY 100635 and MP 349, but not MM 77, is linked to the presynaptically located 5-HT(1A) 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.
Wesołowska
Anna
A
Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland.
Paluchowska
Maria
M
Chojnacka-Wójcik
Ewa
E
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001362:Avoidance Learning; D003220:Conflict, Psychological; D003975:Diazepam / Q000008:administration & dosage / Q000493:pharmacokinetics; D004327:Drinking Behavior; D004338:Drug Combinations; D005442:Flumazenil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011678:Punishment; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D013388:Succinimides / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D010133:p-Chloroamphetamine / Q000008:administration & dosage / Q000009:adverse effects
D014151:Anti-Anxiety Agents; D004338:Drug Combinations; C413583:MM 77; C479465:MP349; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D017661:Receptors, Presynaptic; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D013388:Succinimides; D044282:Receptor, Serotonin, 5-HT1A; D005442:Flumazenil; D010133:p-Chloroamphetamine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D003975:Diazepam