Ventral striatal D3 receptors and Parkinson's Disease

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Abstract

Antiparkinsonian drugs are thought to act largely through the D2 receptor family that includes the D2 and D3 receptors. D2 and D3 receptors exhibit both complementary and overlapping expression at the macro and cellular level. The D3 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 D2 receptor. In Parkinson's Disease it has been determined that loss of dopaminergic innervation results in elevation of the D2 receptor but reduced levels of the D3 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 D3 receptor, and not that of the D2 receptor, is associated with the loss of response to l-dopa and other antiparkinsonian drugs. The reduction of D3 receptor is also related to the presence of dementia. An elevation of D3 receptors was evident in those Parkinson's Disease cases with continued good response to l-dopa. Thus, we believe that reduced D3 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.

Section snippets

D2 Receptors are functionally relevant in PD

Parkinson's disease (PD) is a neurodegenerative disorder with an insidious onset and a prolonged course over many years. The primary cause of the symptoms of this illness is the neuronal death of dopamine (DA)-producing neurons of the substantia nigra (SN) and the resultant depletion of DA in the striatum [1]. The therapeutic intervention for PD is based on the assumption that activation of postsynaptically located DA receptors will provide some return of balance to the system. The preferred

Changes in expression of D3 receptors in PD

In vivo imaging by PET and SPECT in PD has shown a reduction in D2-like receptor binding of radioligands with increased disease duration [37], [38], [39] and/or complicated response to l-dopa [40], [41], [42]. This has led to the speculation that the loss of D2 receptors contributes to a deteriorated response to l-dopa in PD [41]. We [43] and others [44], [45], [46] have observed 25–35% increase of D2 receptors in post-mortem studies of PD regardless of the duration of illness. As the

Acknowledgements

Funded by Federal Grant NS40669 and Arizona Alzheimers Disease Research Grant to JNF, and Mayo Foundation Grant to CHA.

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