Antiparkinsonian drugs are thought to act largely through the D2 receptor family that includes the D(2) and D(3) receptors. D(2) and D(3) receptors exhibit both complementary and overlapping expression at the macro and cellular level. The D(3) receptor appears to be a primary target of the mesolimbic dopamine system, is highly enriched in expression within the "limbic" striato-pallidal-thalamic loop, and is recognized as being regulated by dopaminergic activity in distinctly different ways from the D(2) receptor. In Parkinson's Disease it has been determined that loss of dopaminergic innervation results in elevation of the D(2) receptor but reduced levels of the D(3) receptor. In many late-stage Parkinson's Disease patients there is a loss of antiparkinsonian response to L-dopa and other antiparkinsonian drugs that is often correlated with clinical signs for dementia. We have determined that the reduction of D(3) receptor, and not that of the D(2) receptor, is associated with the loss of response to L-dopa and other antiparkinsonian drugs. The reduction of D(3) receptor is also related to the presence of dementia. An elevation of D(3) receptors was evident in those Parkinson's Disease cases with continued good response to L-dopa. Thus, we believe that reduced D(3) receptor number is correlated with certain subgroups of Parkinson's Disease and may also be related to a further diminishment in the mesolimbic DA system.