At least five subtypes of DA receptors, D1-D5, have been identified While the receptor distribution and some functional sequelae of D1, D2, and D3 receptors are known, information regarding the physiological or pathological role of D4 receptors is scant Mounting evidence indicates potential involvement of these receptors in """"""""novelty-seeking"""""""" behaviors, psychostimulant effects, attention deficit hyperactivity disorder, Parkinson's disease and depression To clarify the role of this receptor subtype in primates, we developed a map of D4 receptor distribution in rhesus monkey brain and compared it with reported D4 mRNA sites Because of its reported selectivity for the D4 receptor, the D4 receptor probe [3H]U-101,958 (1-benzyl-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine) was custom-synthesized for the current study Autoradiography was conducted in triplicate in three separate animals (N=3) with adjacent coronal sections (20 um) to measure total ([3 H]U-101, 958, 1 nM) and nonspecific binding Specific binding was measured in the presence of clozapine or L-745,870 Data was generated from eight anterior-to-posterior coronal planes and 75 distinct subnuclei and cortical areas A region-specific distribution of [3H]U-101,958 binding was detected The highest densities (>20 pmol/g tissue equivalents) of [3H]U-101,958 binding sites (clozapine baseline) were found in areas 12, 14 and 9 of the prefrontal cortex High levels of [3H]U-101,958 binding sites (>17 pmol/g) were also observed in other prefrontal cortex regions, inferior temporal gyrus, subiculum, fusiform gyrus, uncus, paraventricular nucleus of thalamus, median eminence of the hypothalamus, medial longitudinal fasciculus, and hippocampus [3H]U-101,958 binding sites in caudate/putamen were clearly below levels observed in the prefrontal cortex and other cortical areas Lower levels (<12 pmol/g) of [3H]U-101,958 binding sites were found in specific nuclei of the thalamus, and the midbrain, pons, cerebellum and medulla The heterogeneity of [3H]U-101,958 binding within subnuclei of the thalamus, hippocampus, and cortex appear to reflect discreet localization of D4 dopamine receptors The following conclusions can be drawn from this study 1 The brain distribution of the D4 receptor, measured with [3H]U101,958, corresponds to the distribution reported for species; 2 The distribution is similar to, but not identical with D4 mRNA distribution; 3 [3H]U-101,958 binding in non-human primate brain appears to reflect D4 receptors, and therefore emerges as a suitable probe for investigation of D4 receptors in the brain; 4 D4 dopamine receptor density gradients do not correspond to dopamine levels or dopamine transporter gradients in brain, suggesting that dopamine level regulation at the D4 receptor may differ than for the D1 and D2 receptor The significance of a dense localization of D4 receptors in prefrontal cortex and hippocampus, and broad distributio n in other brain areas, allows for speculation on how these receptors may relate to specific neuropsychiatric disorders or effects produced by psychostimulants The autoradiographic map of D4 receptor distribution reported herein provides a detailed substrate for further investigation of the D4 receptor in nonhuman primates
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