Dopamine D 3 receptor is decreased and D 2 receptor is elevated in the striatum of Parkinson's disease

The mesolimbic dopamine (DA) system preferentially innervates the D 3 receptor, whereas the D 2 receptor is, in addition, a target of the nigrostriatal DA system. In human brain D 3 receptors and D 3 mRNA‐expressing neurons are largely segregated to brain regions that are the targets of the mesolimbic DA system and the efferents of the “limbic striatum.” Thus, D 3 receptors may regulate effects of DA on the “limbic” cortico‐striatal‐pallidal‐thalamic‐cortical loop. The nigrostriatal DA system is considerably more damaged in Parkinson's disease (PD) than the mesolimbic DA system. We report here, using radioligands selective for the D 2 and D 3 receptor, that these receptors are independently changed in PD. Tissue collected at autopsy from nine subjects with a diagnosis of PD and eight age‐matched subjects with no evidence of a neurologic disorder was processed for [ 125 I]epidepride binding to D 2 receptors, [ 125 I] trans ‐7‐OH‐PIPAT binding to D 3 receptors, [ 125 I]RTI‐55 for the DA transporter (DAT), and immunoautoradiography for tyrosine hydroxylase (TH) using autoradiographic methods. Dopaminergic innervation to the caudal putamen was profoundly reduced and to a lesser extent in the rostral putamen in PD. DAT sites but not TH protein levels were reduced in the nucleus accumbens (NAS) in PD compared with age‐matched control subjects. This is consistent with a loss of dopaminergic innervation from the mesolimbic DA system but elevation in TH production. D 3 receptors were significantly reduced in PD by 40–45% particularly in the NAS and putamen. D 2 receptors were elevated in PD in the dorsal putamen by 15%. The reduction in D 3 receptor number was not observed in PD cases with a diagnosis of less than 10 years. The changes in DA D 3 receptor number is interesting in light of the development of antiparkinsonian agents that are D 3 ‐preferring agonists.