Associative and limbic regions of monkey striatum express high levels of dopamine D₃ receptors: Effects of MPTP and dopamine agonist replacement therapies

The role of the dopamine D₃ receptor subtype in the central nervous system is still not well understood. It has a distinct and restricted distribution, mostly associated with limbic territories of the striatum (olfactory tubercle and the shell of nucleus accumbens) in rat brain. Dopaminergic denervation induced by a 6-hydroxydopamine lesion of the nigrostriatal system in rat down-regulates the expression of the D₃ receptor. In the present study, we investigated the functional neuroanatomy of the dopamine D₃ receptor subtype in the monkey (Macaca fascicularis) basal ganglia. We also studied the effect of administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic D₁-like (SKF 82958) or D₂-like (cabergoline) agonist treatments on dopamine D₃ receptor levels using receptor autoradiography. Our results clearly show that the distribution of D₃ receptors in the monkey is more closely related to associative and limbic components of the striatum (caudate-putamen), as compared with its sensorimotor counterpart. Hence, D₃ receptors may be more specifically involved in cognitive and motivational aspects of striatal functions, which are elaborated in prefrontal, temporal, parietal, cingulate and limbic cortices. Moreover, MPTP administration significantly decreased levels of D₃ receptors and this effect was reversed or compensated by a chronic treatment with a D₁-like, but not a D₂-like, receptor agonist. The D₃ receptor may represent an important target for adjunct or direct therapy designed to improve cognitive deficits observed in patients with Parkinson's disease, schizophrenia and other illnesses with frontal lobe cognitive disturbances.