Differential regional and cellular distribution of dopamine D2-like receptors: An immunocytochemical study of subtype-specific antibodies in rat and human brain

Dopamine D2-like receptors (D2, D3, and D4) are major targets for action of typical and atypical neuroleptics, commonly used in the treatment of schiz ophrenia. To understand their individual functional contribution, subtype-s elective anti-peptide antibodies were raised against D2, D3, and D4 recepto r proteins. The antibodies were shown to be specific on immunoblots of rat brain membranes and immunoprecipitated the solubilized native dopamine rece ptors in an antibody concentration-dependent manner. In addition, they also bind selectively to the respective recombinant D2, D3, and D4 receptor mem brane proteins from cDNA transfected cells. Immunolocalization studies show that the D2-like receptor proteins had differential regional and cellular distribution in the cerebral cortex, hippocampus, basal ganglia, cerebellum , and midbrain, thus providing anatomical substrate for area-specific regul ation of the dopamine neurotransmission. In cortical neurons, D4 receptor p rotein was found in both pyramidal and nonpyramidal cells, whereas D2 and D 3 seem to be mostly associated with nonpyramidal interneurons. In rat hippo campus, the expression pattern of Da-like receptors (D4>D3>D2) mirrored tha t obtained with immunoprecipitation studies. D2 and D4 receptor immunolabel ing was observed in the thalamic reticular nucleus, which was negative for the D3 subtype. Species differences were also observed; for example, the D4 subtype receptor is the most highly expressed protein in the rat cortex, w hereas it is significantly less in human cortex. Differential patterns of D 2, D3, and D4 receptor expression in rat and human brain should shed light on the therapeutic actions of neuroleptic drugs and may lead to the develop ment of more specifically targeted antipsychotic drugs. J. Comp. Neurol. 40 2:353-371, 1998. (C) 1998 Wiley-Liss, Inc.