Sertindole and several antipsychotic drugs differentially inhibit the discriminative stimulus effects of amphetamine, LSD and St 587 in rats

Sertindole, an atypical antipsychotic, blocks the effects of the hallucinogen d-LSD and the alpha-1 agonist St 587 but does not block the effects of d-amphetamine, a dopamine stimulant. Clozapine, another atypical antipsychotic, broadly blocks d-LSD, St 587, and d-amphetamine, though it increases reaction time. The typical antipsychotics haloperidol and Cis(Z)-flupentixol primarily block d-amphetamine, with haloperidol also disrupting behavior in animals trained on St 587 and d-LSD. The selective 5-HT2 antagonist ketanserin blocks only d-LSD, while the alpha-1 antagonist prazosin partially blocks St 587 but not d-LSD or d-amphetamine. Drug discrimination techniques reveal different activity profiles of typical and atypical neuroleptics.

Study at a glance

Abstract

The effects of sertindole, clozapine, Cis(Z)-flupentixol and haloperidol on the discriminative stimulus properties of d-amphetamine (dopamine DA stimulant), d-LSD (5-HT(2) agonist) and St 587 (alpha(1)-adrenoceptor agonist; 2-chloro-5-trifluoromethyl-phenylimino)-imidazolidine) have been studied. Sertindole, a putative antipsychotic compound with limbic selectivity, antagonized the effects of d-LSD and St 587, whereas that of d-amphetamine was unchanged. Clozapine preferentially inhibited St 587, but also antagonized d-LSD and d-amphetamine, together with increases in reaction time. Cis(Z)-flupentixol antagonized d-amphetamine and St 587 effects, whereas haloperidol antagonized d-amphetamine only. Behavioural disruption was induced by haloperidol in St 587 and d-LSD-trained animals. The 5-HT(2) antagonist ketanserin selectively inhibited the effect of d-LSD, and the selective alpha(1)-adrenoceptor antagonist prazosin partially inhibited the effect of St 587, but did not inhibit d-LSD or d-amphetamine. The partial inhibition of St 587 effects by prazosin was not further increased by co-treatment with haloperidol. Prazosin partially substituted for the training dose of St 587. The results indicate that drug discrimination techniques can be used to demonstrate different activity profiles of typical and atypical neuroleptics. The classical neuroleptics have preferential amphetamine antagonistic activity, whereas clozapine has a broad activity profile. Furthermore, the atypical neuroleptic sertindole fails to induce acute DA antagonism in doses much higher than those inhibiting d-LSD and St 587.