ELIMINATION OF COCAINE-INDUCED HYPERACTIVITY AND DOPAMINE-MEDIATED NEUROPHYSIOLOGICAL EFFECTS IN DOPAMINE D1 RECEPTOR MUTANT MICE

The brain mesoaccumbens dopamine system is intricately Involved in the psychomotor stimulant activities of cocaine. However, the extent to w hich different dopamine receptors mediate these effects has not yet be en firmly established. The present study used dopamine D1 receptor mut ant mice produced by gene targeting to investigate the role of this re ceptor in the effects induced by cocaine. In contrast with wild-type m ice, which showed a dose-dependent increase in locomotion, D1 mutant m ice exhibited a dose-dependent decrease. Electrophysiological studies of dopamine-sensitive nucleus accumbens neurons demonstrated a marked reduction in the inhibitory effects of cocaine on the generation of ac tion potentials. In addition, the inhibitory effects of dopamine as we ll as D1 and D2 agonists were almost completely abolished, whereas tho se of serotonin were unaffected. DS-like dopamine receptor binding was also normal. These results demonstrate the essential role of the D1 r eceptor in the locomotor stimulant effects of cocaine and in dopamine- mediated neurophysiological effects within the nucleus accumbens.