Lack of a role for the D 3 receptor in clozapine induction of c-fos demonstrated in D 3 dopamine receptor-deficient mice

Abstract

The role of the D 3 dopamine receptor in mediating the effects of clozapine was analysed using in situ hybridization histochemistry to measure the induction of the immediate early gene c-fos in different brain areas of mice lacking a functional D 3 dopamine receptor compared to wild type mice. Clozapine treatment (15 and 30 mg/kg, s.c.) resulted in a dose-dependent pattern of induction of c-fos messenger RNA in the striatum, accumbens and septal area, with a non-significant increase in the prefrontal cortex. There was no difference detected in any of these areas in the level of induction between mice lacking the D 3 receptor (D 3−/−) and wild type (D 3+/+). To determine which types of neurons in the striatum and accumbens displayed clozapine (30 mg/kg) induction of c-fos messenger RNA, a double-labeling experiment was performed using a radioactive c-fos messenger RNA probe and a digoxigenin-labeled enkephalin messenger RNA probe, the latter used as a marker of D 2-containing neurons. Clozapine-induced c-fos was detected in 20% of enkephalin-positive striatal neurons and 15% of enkephalin-positive accumbens neurons, and in both areas in about 10% of enkephalin-negative, putative D 1 neurons, in both D 3+/+ and D 3−/− mice. These results demonstrate that clozapine induction of c-fos messenger RNA is not dependent on the D 3 dopamine receptor subtype in the striatum or nucleus accumbens.