Effects of typical and atypical antipsychotic drugs on two-way active avoidance. Relationship to DA receptor blocking profile.
The dose-dependent and time-dependent effects of the novel antipsychotic compound remoxipride, as well as the reference compounds chlorpromazine, clozapine, haloperidol, pimozide and sulpiride upon the retention of two-way active avoidance (conditioned avoidance responses, CARs) were studied in male rats. The dose-dependent effects of remoxipride as well as haloperidol and chlorpromazine on the acquisition of CARs were also studied. The acquisition and retention of CARs were tested in shuttleboxes using a 1.0-mA shock intensity and a 10-stone signal (1000 Hz). All the compounds studied, including remoxipride, caused a dose-dependent impairment of acquisition and retention of CARs. The effect of remoxipride on CAR acquisition correlated with remoxipride's effectiveness to block the hyperactivity induced by the dopamine (DA) agonist apomorphine. Unlike chlorpromazine and haloperidol, the potency of remoxipride and clozapine for antagonising CAR retention was found at dose levels much lower than those producing cataleptic effects or blocking apomorphine-induced stereotypies. Based on the DA receptor blocking profile and the relative effectiveness to block CAR it is concluded that the mechanism(s) by which clozapine and remoxipride affect CAR differ from typical neuroleptic drugs. This difference may reflect an action upon different subtypes of functionally coupled DA D2 receptors.
Ogren
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Astra Arcus AB, CNS Preclinical R&D, Södertälje, Sweden.
Archer
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D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D008568:Memory / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D001058:Apomorphine