The effect of dopamine depletion or pharmacological blockade of dopamine receptors on striatal and accumbens dopamine D2 mRNA and receptor levels was assessed by in situ hybridization histochemistry and receptor autoradiography. The time course of pharmacological blockade with haloperidol demonstrates a complex mode of regulation of dopamine D2 mRNA and receptor levels. By day 8 of haloperidol treatment, D2 mRNA and receptor levels were decreased (up to 20%) in the medial and anterior aspects of the caudate-putamen (mCPU and aCPU) and the nucleus accumbens (NAc). However, by day 21 of haloperidol treatment, D2 mRNA and receptor were increased relative to vehicle-injected controls. Likewise, unilateral dopamine depletion due to 6-hydroxydopamine (6-OHDA) lesions of mesencephalic dopaminergic neurons resulted in decreased levels of D2 receptor mRNA by day 8 post-lesion in the ipsilateral mCPU, aCPU and the NAc. However, at days 14 or 21 post-lesion, there was a reversal of the effect with increases of up to 22% in all brain regions ipsilateral to the lesion. Although no decreases in receptor level were observed at day 8, significant increases in receptor level in all three brain regions were detected at days 14 and 21 post-lesion. The results demonstrate that midbrain dopaminergic innervation exerts tonic effects on the levels of dopamine D2 receptor and mRNA in the caudate-putamen and the nucleus accumbens of the rat. Changes in receptor level are frequently accompanied by comparable changes in mRNA level, indicating a mass action relationship between receptor level and receptor biosynthesis in these forebrain regions in the rat.