DIFFERENTIAL FOS-PROTEIN INDUCTION IN RAT FOREBRAIN REGIONS AFTER ACUTE AND LONG-TERM HALOPERIDOL AND CLOZAPINE TREATMENT

Both acute and long-term effects of haloperidol and clozapine on Fos-l ike immunoreactive nuclei in several rat forebrain areas were quantifi ed. Rats were treated with saline (1 ml/kg.day, control), haloperidol (1 mg/kg.day) and clozapine (20 mg/kg.day) i.p. for 21 days. Two hours before perfusion fixation a single (acute treatment) or last (long-te rm treatment) dose of the drug was given. Drug-induced catalepsy and g ain in body weight were also measured. A single dose of haloperidol pr oduced large increases in Fos-like immunoreactive nuclei in the striat um, the nucleus accumbens and central amygdala. Following long-term tr eatment these increases were reduced in all nuclei studied, except the lateral septum. Acute clozapine treatment had slight (if any) effects on the number of Fos-like immunoreactivity-expressing nuclei in the s triatum, but the increases in the nucleus accumbens, the lateral septu m, the paraventricular and supraoptic nuclei of the hypothalamus and t he central amygdala were substantial. Long-term clozapine treatment re duced the acute response significantly in all the areas except the nuc leus accumbens. Both haloperidol and clozapine treatment reduced the w eight gain of the rats. Haloperidol, but not clozapine, induced catale psy that remained maximal during the long-term haloperidol treatment. These results indicate that in most brain areas high Fos-protein level s are not necessary to maintain antipsychotic activity or side-effects . The persisting effect of clozapine in the nucleus accumbens may be o f significance to the efficacy of this drug in treatment-refractory sc hizophrenia.