Anticholinergic drugs potentiate dopamine D1 but not D2 antagonists on a conditioned avoidance task in rats

The present study investigated whether blockade of conditioned avoidance responding (CAR) in rats by selective D1 and D2 receptor antagonists could be differentially affected by anticholinergics. The results show that atropine and scopolamine dose-relatedly antagonized the effects on CAR of two specific D2 receptor blockers, haloperidol and raclopride, but potentiated the effects of three specific D1 receptor antagonists, SCH 23390, SCH 39166 and NO-01-0756. Of the less specific dopamine receptor antagonists tested, scopolamine blocked the effects of clozapine and cis-flupenthixol, but did not alter the effects of chlorpromazine, thioridazine or cis-piflutixol. Although the mechanisms involved in the differential shifts by the anticholinergics are unknown, the results are consistent with the view that CAR antagonism by the specific D2 vs. D1 receptor antagonists involves unique and separate mechanisms of action. With respect to the less specific dopamine receptor antagonists, the CAR blockade seen with clozapine and cis-flupenthixol might reflect predominant D2 receptor blockade because their effects were blocked by atropine. In contrast, the CAR blockade by chlorpromazine, thioridazine and cis-piflutixol antagonists might be mediated by equal degrees of D1 and D2 receptor blockade inasmuch as they were not blocked or potentiated by atropine. The antagonism of CAR in rats by the D1 receptor antagonists suggests that these drugs have potential antipsychotic activity in humans. However, they do not appear to enhance central cholinergic transmission and therefore may be devoid of the side effects produced by the antipsychotics in clinical use.