Neuropsychopharmacological profile of remoxipride in comparison with clozapine

Central effects of remoxipride /(-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-6-dimethoxybenz amide hydrochloride, RPD/, one of newer antipsychotic drugs with high affinity to sigma sites was studied in comparison with clozapine (CLOZ), another atypical antipsychotic agent, devoid of such an activity. It has been found that RPD decreased the locomotor activity of naive rats, as well as hyperactivity induced by D-amphetamine and apomorphine. The drug antagonized stereotypy induced by both dopamine agonists as well as apomorphine-induced climbing in mice. RPD shortened the time of SKF 38393 (dopamine D1 receptor agonist)-induced grooming in rats. Moreover, it markedly decreased quinpirole (dopamine D2/3 receptor agonist)-induced hyperactivity of rats, and less potently inhibited stimulatory activity induced by cocaine and MK-801 (non-competitive NMDA receptor antagonist). The drug impaired retention of conditioned avoidance responses and induced catalepsy in rats, at relatively high doses though. The effects of CLOZ differed to some extent from those of RPD. The former did not antagonize the apomorphine-induced stereotypy and decreased that caused by D-amphetamine less potently than RPD did. Besides, it did not induce catalepsy, even at relatively high doses while its inhibitory activity towards apomorphine- and quinpirole-induced hyperactivity, as well as locomotor activity of naive rats were much less potent. The effects of RPD and CLOZ in other experimental models were comparable. The obtained results indicating many similarities between psychopharmacological profiles of RPD and CLOZ with some essential differences as well as an equivalence of RPD central effects and the activity of EMD 57445 (selective sigma ligand devoid of any effects at other receptors) permit a supposition that, beside dopamine receptors, the sigma receptors may also be of importance to the mechanism of action of RPD.