Dopamine D3 receptor is decreased and D2 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 [I-125]epidepride binding to D-2 receptors, [I-125] trans-7-OH-PIPAT binding to D-3 receptors. [I-125]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.