Parkinson's disease as a model for changes in dopamine receptor dynamics with aging

Parkinson's disease ranks among the most prevalent neurological diseases in the elderly. The disease usually begins after the age of 50 years, and the risk of the disease rises steeply with advancing age. The primary etiology of Parkinson's disease is still unknown, although the aging process may be an important predisposing factor. There is some overlapping between Parkinson's disease and senile dementia of Alzheimer's type, although both seem to be disease entities. In Parkinson's disease, the most prominent and significant neuropathological change is the progressive loss of substantia nigra dopamine neurons. Studied of striatal dopamine receptors showed that the specific binding of 3H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the number of receptors, but no significant changes in the mean dissociation constant. Increased binding of 3H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3H-spiroperidol was found in patients treated with levodopa. The behavior of dopamine receptors in the nucleus accumbens was similar to that of dopamine receptors in the striatum. Clinically, the patients with low binding of 3H-spiroperidol in the striatum were more disabled and had lost the beneficial response to levodopa. Thus in some patients with Parkinson's disease a denervation supersensitivity seemed to develop and in others a loss of postsynaptic dopamine receptor sites in the neostriatum. The latter alteration may contribute to the decreased response of parkinsonian patients to long-term levodopa therapy. However, in patients with a deteriorating response to levodopa, there seem to be still enough dopamine receptors in the striatum for drugs stimulating the dopamine receptors to alleviate directly the parkinsonian disability. Indeed, dopaminergic agonists seem to be a significant and valuable adjuvant therapy to levodopa for parkinsonian patients with a deteriorating response and/or on-off phenomena.