Abstract

The present study was designed to determine the involvement of cholinergic projections to the ventral tegmental area in the rewarding effects of cocaine. Bilateral intracranial injections of the muscarinic receptor antagonist atropine into the ventral tegmental area attenuated the rewarding effects of intravenous cocaine self-administered on either fixed ratio or progressive ratio schedules of reinforcement. Low doses of atropine sulphate, the lipophilic form of the drug, produced a compensatory increase in cocaine intake while the administration of higher doses of atropine sulphate extinguished responding for intravenous cocaine on a fixed ratio schedule of reinforcement. Bilateral microinjections of atropine methyl nitrate, the lipophobic form of the drug, into the ventral tegmental area also attenuated the rewarding effects of intravenous cocaine self-administered on a progressive ratio schedule of reinforcement. Responding following the injection of low doses of atropine resembled responding when saline was substituted for cocaine, breaking points were established rapidly and there was no post-reinforcement pause. The priming effect of the cocaine administered during "loading" was abolished by the highest dose of atropine; breaking points were reduced. Enhanced locomotion was the predominant effect on activity induced by the administration of atropine into the ventral tegmental area. Atropine sulphate initially induced a period of immobility that did not occur following the administration of atropine methyl nitrate. Microdialysis techniques were used to assess extracellular dopamine levels in the shell of the nucleus accumbens, the terminal region for mesolimbic dopamine neurons originating in the ventral tegmental area. The injection of atropine methyl nitrate into the ventral tegmental area elevated extracellular levels of dopamine and its metabolites in the ipsilateral nucleus accumbens. Thus blockade of muscarinic receptors in the ventral tegmental area reduces cocaine reward, but increases locomotion and mesolimbic dopamine levels. As cocaine reward is believed to be dopamine-dependent, these findings suggest that separate populations of mesolimbic dopamine neurons underlie cholinergic actions on locomotion and reward.