Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors

• Published in: Brain research Vol. 955; no. 1-2; pp. 138 - 152
• Main Authors: JOYCE, J. N, RYOO, H. L, BEACH, T. B, CAVINESS, J. N, STACY, Mark, GUREVICH, E. V, REISER, Mark, ADLER, C. H
• Format: Journal Article
• Language: English
• Published: London Elsevier 15.11.2002; Amsterdam; New York, NY
• Subjects: Aged; Aged, 80 and over; Analysis of Variance; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dementia - drug therapy; Dementia - enzymology; Dementia - metabolism; Dementia - pathology; Female; Humans; Levodopa - pharmacology; Levodopa - therapeutic use; Male; Medical sciences; Middle Aged; Neuropharmacology; Parkinson Disease - drug therapy; Parkinson Disease - enzymology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Pharmacology. Drug treatments; Receptors, Dopamine D2 - physiology; Receptors, Dopamine D3; Retrospective Studies; RNA, Messenger - metabolism; Tyrosine 3-Monooxygenase - metabolism; Human; Nervous system diseases; Parkinson's disease; Parkinson disease; Antiparkinson agent; D3 Dopamine receptor; Cerebral disorder; D2 Dopamine receptor; Dopamine D, receptor; Central nervous system disease; Degenerative disease; Levodopa; Extrapyramidal syndrome
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(02)03396-6

Previous data suggest a relationship between the loss of response to levodopa in Parkinson's disease (PD) patients with the co-occurrence of dementia, but the role of alterations in the dopamine system has not been explored. We measured the extent of striatal DA loss and changes in striatal DA D(2) and D(3) receptors in postmortem striatum of PD patients who historically had or had not lost their clinical response to dopaminergic drugs and/or had an additional diagnosis of dementia. Clinical evaluation and retrospective chart reviews for PD and dementia, and neuropathological diagnoses were obtained. All PD cases (+/-dementia), regardless of response to dopaminergic drugs, exhibited a significant and similar degree and pattern of loss of tyrosine hydroxylase immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive neurons from the ventral midbrain. D(2) receptor concentrations were modestly elevated in the rostral striatum of all the PD cases (+/-dementia), whether or not they continued to respond to dopaminergic drugs. In contrast, loss of D(3) receptor concentration correlated with loss of response to dopaminergic drugs, independent of the presence or absence of dementia. A maintained response to dopaminergic drugs correlated with an elevation of D(3) receptors. Dementia with PD was highly correlated with a loss of response to dopaminergic drugs, and was also correlated with reduced D(3) receptors. The alterations in D(3) receptor concentrations were greatest in the nucleus accumbens, caudal striatum, and globus pallidus. Thus, loss of dopamine D(3) receptors may be a more important contributing factor to a loss of response to dopaminergic drugs than changes in the D(2) receptor.