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

Abstract

Dopamine D2-like receptors (D2, D3, and D4) are major targets for action of typical and atypical neuroleptics, commonly used in the treatment of schizophrenia. To understand their individual functional contribution, subtype-selective anti-peptide antibodies were raised against D2, D3, and D4 receptor proteins. The antibodies were shown to be specific on immunoblots of rat brain membranes and immunoprecipitated the solubilized native dopamine receptors in an antibody concentration-dependent manner. In addition, they also bind selectively to the respective recombinant D2, D3, and D4 receptor membrane 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 regulation of the dopamine neurotransmission. In cortical neurons, D4 receptor protein was found in both pyramidal and nonpyramidal cells, whereas D2 and D3 seem to be mostly associated with nonpyramidal interneurons. In rat hippocampus, the expression pattern of D2-like receptors (D4>D3>D2) mirrored that obtained with immunoprecipitation studies. D2 and D4 receptor immunolabeling 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, whereas it is significantly less in human cortex. Differential patterns of D2, 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 development of more specifically targeted antipsychotic drugs.

Altered Behavioral Response to Dopamine D3 Receptor Agonists 7-OH-DPAT and PD 128907 Following Repetitive Amphetamine Administration

“…The D3 receptor has wide expression throughout limbic brain regions, with densest expression in islands of Calleja and other regions of dorsal and ventral striatum (Diaz et al, 2000;Khan et al, 1998;Larson and Ariano, 1995;Ariano and Sibley, 1994). D3 receptor binding characteristics (B max and K D ) in dorsal and ventral striatum were unchanged by AMPH treatment in our study.…”

Chronic Carbamazepine Administration Attenuates Dopamine D2-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

“…Quinpirole significantly increased k* in 35 regions, many of which belong to dopaminergic circuits containing D 2 receptors (e.g. caudate-putamen and substantia nigra) [33], D 3 receptors (e.g. nucleus accumbens and olfactory tubercle) [50] or D 4 receptors (e.g.…”

A Simple Method to Measure Baseline Occupancy of Neostriatal Dopamine D2 Receptors by Dopamine In Vivo in Healthy Subjects

“…7. A significant number of D 2 R are located extrasynaptically (Khan et al 1998) where the DA concentration is lower than in the synapse (Fisher et al 1995). Thus, DA may occupy a smaller percentage of extrasynaptic receptors compared to those within the synapse and there may be interindividual differences in the proportion of synaptic versus extrasynaptic D 2 R. 8.…”