1. The purpose of the present study was to relate the effects of the novel
drug,
anpirtoline, on
5-hydroxytryptamine (5-HT) receptor subtypes to its antinociceptive and
antidepressant-like actions in rodents. 2. Binding assays with rat brain membranes have shown that
anpirtoline bound with a much higher affinity to
5-HT1B receptor (Ki = 28 nM) than to 5-HT1A (Ki = 150 nM) and 5-HT2 (Ki = 1.49 microM) receptors. 3. Like
5-HT,
anpirtoline concentration-dependently inhibited
forskolin-stimulated
adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by
5-HT1B receptor antagonists such as
propranolol and
penbutolol. 4. In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked
tritium overflow was inhibited by
anpirtoline and
5-HT. Whereas
5-HT was equipotent in both tissues (EC50 = 69 nM),
anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for
anpirtoline was shifted to the right by
metitepine in both preparations. 5. In the social behaviour deficit test,
anpirtoline and trifluoromethylphenyl-
piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the
5-HT1B receptor. 6. In the electrostimulated
pain test using mice,
anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52 mg kg-1, i.p. The antinociceptive activity of
anpirtoline was abolished by pretreatment with
cyproheptadine or
propranolol.7. In the forced swimming test in rats,
anpirtoline induced a dose-related increase in swimming activity. With an ED50 value of 4.6mgkg-1, i.p.,
anpirtoline was 4 times more potent than the two standard compounds
imipramine and
desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of
antidepressant drugs.8.
Anpirtoline exhibits both antinociceptive and
antidepressant-like activities in animals. It is probable that
anpirtoline elicits these pharmacological effects via its agonist effect on 5-HT1B and 5-HT1A receptors.