In situ hybridization histochemistry was used to study the expression of preprosomatostatin (PPSOM) and preprotachykinin A (PPT-A) mRNA in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAC) and the caudate putamen (CP) of the rat after chronic (21 days) treatment with the classical antipsychotic drug haloperidol (1 mg/kg i.p.), the atypical antipsychotic drugs clozapine (15 mg/kg i.p.) and amperozide (5 mg/kg i.p.), and the selective dopamine (DA)-D2/D3 receptor antagonist raclopride (2 mg/kg i.p.). Whereas amperozide markedly elevated the numerical density of PPSOM mRNA expressing neurons in the mPFC (52%), the other drugs did not significantly affect PPSOM mRNA levels in any of the brain regions studied. Amperozide also altered PPT-A mRNA expression in the mPFC, i.e. a decrease (22%) was found. Of the other drugs tested only haloperidol significantly decreased PPT-A mRNA levels in the NAC shell (14%), in the dorso-lateral CP (19%) and in the medial CP (15%). In view of the differences between amperozide and the other drugs studied, as regards both pre-clinical and clinical characteristics, we suggest that the specific effects of amperozide on PPSOM and PPT-A mRNA in the mPFC may be related to its 5-HT releasing action in the frontal cortex, an effect possibly caused by its alpha2-adrenoceptor blocking activity. This effect, in turn, may be related to an antidepressant-like action that this compound exhibits in animal studies. The decrease in PPT-A mRNA levels seen after the haloperidol treatment is probably due to its potent DA-D2 receptor antagonism and may be related to side-effects, rather than therapeutic effects of this drug.