The role of 5-HT 1A autoreceptors and α1-adrenoceptors in the modulation of 5-HT release—III. Clozapine and the novel putative antipsychotic S 16924

Abstract

Clozapine and the novel putative, antipsychotic S 16924 ((1-(benzodioxane-5-yl)-3-[3-(4-fluorophenacyl)pyrrolidine]-1-oxapropane HCl) share significant affinity for α 1-adrenoceptors and 5-HT 1A autoreceptors in vitro and display an ‘atypical’ behavioural profile in in vivo models used for detecting potential neuroleptic effects. In the present study, in vivo microdialysis was used to examine the effect of clozapine and S 16924 on 5-HT overflow in the rat ventral hippocampus, and to assess the relative role of putative α 1-adrenoceptor antagonist and 5-HT 1A autoreceptor agonist properties of the drugs in this regard. S 16924 (0.1–3 mg/kg, s.c.) reduced dialysate 5-HT in a dose- and time-dependent fashion by maximally ≈70% from baseline 40–60 min after injection. Clozapine (0.1–10 mg/kg, s.c.) reduced 5-HT overflow in the same manner, with a maximum effect of ≈60% from baseline, obtained after 60–80 min. The 5-HT decrease elicited by S 16924 (1.0 mg/kg, s.c.) was significantly, though only partially, antagonized by pretreatment with the selective 5-HT 1A receptor antagonist WAY 100635 (0.3 mg/kg, s.c.). The selective α 1-adrenoceptor agonist cirazoline (0.02 mg/kg, i.p.) alone did not significantly attenuate the effect of S 16924 (1.0 mg/kg, s.c.) on 5-HT overflow. Combined treatment with both WAY 100635 and cirazoline, however, totally reversed the 5-HT-suppressing effect of S 16924 (1.0 mg/kg, s.c.). By comparison, when given separately, neither WAY 100635 (0.3 mg/kg, s.c.) nor cirazoline (0.02 mg/kg, i.p.) antagonized the clozapine (0.3 mg/kg, s.c.)-induced decrease of 5-HT in ventral hippocampus dialysates. In the presence of both WAY 100635 and cirazoline, the response to this dose of clozapine was however significantly, though modestly, attenuated. In contrast, the WAY 100635/cirazoline combination failed to antagonise the 5-HT decrease resulting from a higher dose (3.0 mg/kg, s.c.) of clozapine. We conclude that both α 1-adrenoceptor antagonist and 5-HT 1A receptor agonist properties of clozapine and S 16924 contribute to the 5-HT release-reducing action of these drugs. Whereas these factors apparently explain the effect of S 16924 fully, additional mechanism(s) appear to be involved in the case of clozapine. With regard to the interplay between α 1-adrenoceptor and 5-HT 1A (auto)receptor mechanisms in the control of 5-HT release in the rat forebrain, the present data suggest that an excitation mediated by the former is outweighed by the simultaneous activation of the latter-inhibitory-receptors.