THE ROLE OF 5-HT1A AUTORECEPTORS AND ALPHA(1)-ADRENOCEPTORS IN THE MODULATION OF 5-HT RELEASE - III - CLOZAPINE AND THE NOVEL PUTATIVE ANTIPSYCHOTIC S-16924

Clozapine and the novel putative, antipsychotic S 16924 )-3-[3-(4-fluo rophenacyl)pyrrolidine]-1-oxapropane HCl) share significant affinity f or alpha(1)-adrenoceptors and 5-HT1A autoreceptors in vitro and displa y an 'atypical' behavioural profile in in vivo models used for detecti ng potential neuroleptic effects. In the present study, in vivo microd ialysis was used to examine the effect of clozapine and S 16924 on 5-H T overflow in the rat ventral hippocampus, and to assess the relative role of putative alpha(1)-adrenoceptor antagonist and 5-HT1A autorecep tor 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 approximate to 70% from baseline 40-60 min after injecti on. Clozapine (0.1-10 mg/kg, s.c.) reduced 5-HT overflow in the same m anner, with a maximum effect of approximate to 60% from baseline, obta ined 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 pretr eatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg, s.c.). The selective alpha(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 bo th WAY 100635 and cirazoline, however, totally reversed the 5-HT-suppr essing 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 m g/kg, i.p.) antagonized the clozapine (0.3 mg/kg, s.c.)-induced decrea se 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 W AY 100635/cirazoline combination failed to antagonise the 5-HT decreas e resulting from a higher dose (3.0 mg/kg, s.c.) of clozapine. We conc lude that both alpha(1)-adrenoceptor antagonist and 5-HT1A receptor ag onist properties of clozapine and S 16924 contribute to the 5-HT relea se-reducing action of these drugs. Whereas these factors apparently ex plain the effect of S 16924 fully, additional mechanism(s) appear to b e involved in the case of clozapine. With regard to the interplay betw een alpha(1)-adrenoceptor and 5-HT1A (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 simult aneous activation of the latter-inhibitory-receptors. (C) 1998 Elsevie r Science Ltd. All rights reserved.