EFFECTS OF BENZTROPINE ON BEHAVIORAL AND TOXIC EFFECTS OF COCAINE - COMPARISON WITH ATROPINE AND THE SELECTIVE DOPAMINE UPTAKE INHIBITOR HENYLMETHOXY)ETHYL]-4-(3-PHENYL-PROPYL)-PIPERAZINE

Behavioral effects of cocaine that are relevant to its abuse have been associated with pharmacological actions at the dopamine uptake carrie r. Benztropine (Cogentin) is an antiparkinson agent that has limited a buse despite its ability to block dopamine uptake, and has been sugges ted as a candidate for the treatment of cocaine dependence. Preclinica l studies were conducted to assess the behavioral and toxic effects of benztropine alone and in conjunction with cocaine, Because of the mix ed pharmacology of benztropine which includes antimuscarinic as well a s dopaminergic actions, results obtained from parallel experiments wit h atropine and the selective dopamine uptake inhibitor, GBR 12935 nylm ethoxy)ethyl]-4-(3-phenyl-propyl)-piperazine}, were performed, All of the drugs stimulated locomotor activity of mice, but atropine and benz tropine had much lower efficacy. Nonstimulatory doses of GBR 12935 enh anced the locomotor stimulant effects of cocaine, whereas benztropine and atropine did not share this effect. GBR 12935, benztropine and coc aine increased fixed-interval responding, whereas atropine decreased f ixed-interval response rates in rats. Only GBR 12935 and cocaine incre ased responding during timeout periods. GBR 12935, but not benztropine or atropine, fully reproduced the discriminative stimulus effects of cocaine (10 mg/kg). GBR 12935 and atropine augmented the discriminativ e stimulus effects of lower cocaine doses in rats. Only GBR 12935 and cocaine had convulsant effects and only GBR 12935 significantly enhanc ed the convulsant effects of cocaine in mice. These results document a behavioral and toxicity profile for benztropine distinct from that of classical dopamine uptake blockers. The data underscore further the p otential of benztropine as a candidate for clinical evaluation in the treatment of cocaine dependence.