Reduced D2 dopamine and muscarinic cholinergic receptor densities in caudate specimens from fluctuating parkinsonian patients

Abstract

Binding of spiperone and 3-quinuclidinyl benzilate (QNB), both labeled with hydrogen 3 (3H), were measured in caudate tissue obtained from 8 living parkinsonian patients at the time of cerebral transplantation. This was clinically homogeneous group of patients. All remained predominantly responsive to levodopa, although with marked disability secondary to clinical fluctuations (short-duration responses) and medication-induced dyskinesias; all were receiving substantial doses of levodopa and 6 of the 8 patients were additionally receiving bromocriptine or pergolide. Binding densities of dopamine D2 receptors, as measured by [3H]spiperone binding, were reduced in this group of patients, compared to caudate specimens from autopsy control subjects. This findings may reflect medication-induced receptor downregulation. Parallel changes occurred with muscarinic cholinergic receptors; [3H]QNB binding was significantly reduced, compared to autopsy control values. This reduction of muscarinic receptors might be due to loss of nigrostriatal terminals that are known to contain muscarinic receptors. Alternatively, muscarinic receptors may have been downregulated by increased corticostriatal glutamatergic input to cholinergic cells, inferred to be present based on the prominent levodopa-induced dyskinesias. Finally, receptor deficits could have been a reflection of more widespread degenerative cerebral disease, although levodopa-refractory symptoms were generally not pronounced in these patients.

Effect of age and disease duration on parkinsonian motor scores under levodopa therapy

“…Availability of endogenous dopamine and dopamine receptor density decline with increasing age (Marksman et al, 1979;Cot6 and Kremzner, 1983;De Keyser et al, 1990;Martin et al, 1989) and the combined age-and disease-related changes in the dopaminergic neurotransmission might insufficiently be compensated by dopaminergic therapy (Lloyd and Hornykiewicz, 1970;Lloyd et al, 1975;Melamed et al, 1981;Leenders et al, 1986;Hornykiewicz and Kish, 1986;Ahlskog et al, 1991;Brooks et al, 1992).…”

Decline of striatal dopamine release in parkin‐deficient mice shown by ex vivo autoradiography

“…Intriguingly, parkin deficiency was associated with marked elevation of both D 1 and D 2 receptors. Indeed, previous studies reported that although striatal D 2 binding increased in untreated patients with PD, adaptive postsynaptic mechanisms and treatment decreased this as the condition advanced (Ahlskog et al,1991; Brooks et al,1992; Ichise et al,1999). In a study of AR‐JP patients, Scherfler et al (2004) reported a global decrease in D 2 receptor and argued for parkin genetic defect itself or susceptibility to receptor downregulation after long‐term exposure to dopaminergic agents.…”

Pathophysiology of motor response complications in Parkinson's disease: Hypotheses on the why, where, and what

“…[39][40][41][42] The same, however, does not appear to be the case in the striatum of levodopa-treated patients in which either normal or decreased dopamine receptor binding/density has been reported. [41][42][43][44][45] Furthermore, in a recent PET study of levodopa-treated patients with PD with and without dyskinesias, no differences in D1 and D2 receptor binding between the two groups were observed. 42 In recent years, the role of nondopaminergic pathways in the pathogenesis of MRCs has received increasing investigative attention.…”