Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation.

The ability of chronic treatment with the atypical neuroleptic clozapine to induce functional dopaminergic hypersensitivity in laboratory rats was assessed. The intracranial electrical self-stimulation paradigm, known to be sensitive to changes in functional dopaminergic sensitivity, was used. Animals with electrodes in the ventral tegmental nucleus (mesolimbic dopamine cell body area) showed a marked increase in self-stimulation rate following 3 weeks of chronic clozapine. This increase was similar in magnitude and duration to that shown by animals given 3 weeks of chronic haloperidol. In contrast, animals with electrodes in the substantia nigra (nigrostriatal dopamine cell body area) showed no change in self-stimulation rate following 3 weeks of chronic clozapine. These data are interpreted in the light of previous suggestions that clozapine and other atypical neuroleptics may possess functional selectivity for the mesolimbic dopamine system.