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

The role of the D-3 dopamine receptor in mediating the effects of clozapine was analysed using in situ hybridization histochemistry to measure the ind uction of the immediate early gene c-fos in different brain areas of mice l acking a functional D-3 dopamine receptor compared to wild type mice. Cloza pine treatment (15 and 30 mg/kg, s.c.) resulted in a' dose-dependent patter n 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 betw een mice lacking the D-3 receptor (D-3-/-) and wild type (D-3+/+) To determ ine which types of neurons in the striatum and accumbens displayed clozapin e (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 digoxige nin-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 enke phalin-positive striatal neurons and 15% of enkephalin-positive accumbens n eurons, 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 i s not dependent on the D-3 dopamine receptor subtype in the striatum or nuc leus accumbens.