Enhancement of self-stimulation behavior in rats and monkeys after chronic neuroleptic treatment: evidence for mesolimbic supersensitivity.

The effect of chronic neuroleptic drug treatment on self-stimulation of the mesolimbic dopamine system was tested. Rats with electrodes implanted into the ventral tegmental nucleus (A10 cell body area) were treated with haloperidol for three weeks. Afterwards, the rats showed a 35% increase in self-stimulation rate, as compared to pre-drug control rates. This increase persisted for three weeks after drug withdrawal before returning to baseline rates. Rats treated for three weeks with the atypical neuroleptic, clozapine, also showed an increase, the duration and magnitude of which was similar to that seen in the haloperidol group. In addition, four rhesus monkeys with electrodes in the nucleus accumbens (one of the terminal projection areas of the A10 mesolimbic dopamine system) were given a three week treatment with haloperidol, after which all animals showed a significant, long-lasting decrease in self-stimulation threshold, as measured by a rate-independent reward paradigm. Taken together, these results suggest the induction of receptor supersensitivity in the mesolimbic dopamine system by long-term treatment with neuroleptic drugs.