Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [ 125I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals

ABSTRACT The regional distribution and cellular localization of dopamine D3 receptors in the rat brain was examined using quantitative autoradiography. [ 125 I]7-OH-PIPAT bound in a saturable and reversible manner and exhibited subnanomolar affinity for a single population of GTP-insensitive sites. The pharmacological profile was characteristic of cloned D3 receptors and nonspecific binding was uniformly low. The highest levels of D3 receptors were measured in the islands of Calleja, nucleus accumbens, ventral pallidum, substantia nigra, and lobules 9 and 10 of the cerebellum. The high specific activity of this ligand also allowed detection of D3 receptors in other regions, including the serotonergic dorsal and median raphe nuclei, indicating that the distribution of this receptor is more widespread than previously appreciated. The cellular localization of D3 receptors in regions containing dopaminergic cells and terminals was examined by discrete injection of neurotoxins. Lesion of dopaminergic neurons with 6-hydroxydopamine produced 50% decreases in [ 125 I]7-OH-PIPAT binding in the nucleus accumbens and substantia nigra. Quinolinic acid lesion of neurons originating in the nucleus accumbens also produced approximately 50% decreases in D3 receptors in the nucleus accumbens, substantia nigra, and ventral pallidum. 5,7-Dihydroxytryptamine lesion of serotonergic cells and processes produced no changes in [ 125 I]7-OH-PIPAT binding. These results demonstrate the presence of D3 receptors in several brain regions not previously identified and suggest that D3 receptors are expressed at somatodendritic and terminal levels of both dopaminergic and nondopaminergic cells within the mesolimbic dopamine system. The neurotransmitter dopamine (DA) has been implicated in a variety of physiological functions and dysfunctions of dopaminergic systems are involved in several disorders, including Parkinson's disease and schizophrenia The physiological function(s) of the D3 receptor remains controversial, but several findings suggest that it may play an important role in neuropsychiatric and neurodegenerative disorders. For example, the density of D3 receptors is significantly elevated in the ventral striatum of cocaine overdose victims, suggesting that it plays a role in cocaine abus