Differential reversal of various dopamine antagonists by anticholinergics in Sidman avoidance: possible relationship to adrenergic blockade.

Various dopamine receptor antagonists have divergent clinical and neurochemical properties. The relative ability of anticholinergics (benztropine and scopolamine) to reverse these drugs was assessed in squirrel monkeys and rats performing a Sidman avoidance task. In monkeys, benztropine markedly attenuated the effects of oxiperomide, metoclopramide, halopemide, tiapride and mezilamine as well as haloperidol. Chlorpromazine and fluphenazine were antagonized to a moderate extent; thioridazine and perlapine were not antagonized; and clozapine was actually potentiated by benztropine. In the rat, benztropine antagonized haloperidol strongly but reversed fluphenazine, thioridazine or clozapine only weakly or not at all. The overall effects of scopolamine in both species were similar to those of benztropine. The dopamine receptor antagonists that were most completely reversed by benztropine were found to inhibit 3H-spiroperidol more strongly than 3H-WB-4101 binding in calf caudate, while the reverse was true for drugs that were antagonized only moderately or not at all by benztropine. These results support a previous suggestion that anticholinergic reversal is less marked against dopamine antagonists with alpha-adrenergic blocking properties. Benztropine reversal of experimental dopamine receptor antagonists in the squirrel monkey Sidman avoidance test may contribute to their preclinical characterization.