guanosine-5--o-(3-thiotriphosphate) and Parkinsonian-Disorders

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D(1) and D(2) dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa-induced dyskinesia, we report changes affecting D(1) and D(2) dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D(1) receptor expression itself is not related to dyskinesia, D(1) sensitivity per D(1) receptor measured by D(1) agonist-induced [(35)S]GTPgammaS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that levodopa-induced dyskinesia results from increased dopamine D(1) receptor-mediated transmission at the level of the direct pathway.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analysis of Variance; Animals; Antiparkinson Agents; Autoradiography; Behavior, Animal; Blotting, Western; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Female; Guanosine 5'-O-(3-Thiotriphosphate); Immunohistochemistry; In Situ Hybridization; Isotopes; Levodopa; Macaca fascicularis; Membrane Glycoproteins; Membrane Transport Proteins; Motor Activity; Nerve Tissue Proteins; Nortropanes; Parkinsonian Disorders; Phosphoproteins; Radioligand Assay; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Substantia Nigra; Time Factors; Tyrosine 3-Monooxygenase

Long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease leads to dyskinesias in the majority of patients. The underlying molecular mechanisms for L-DOPA-induced dyskinesias (LIDs) are currently unclear. However, the findings that there are alterations in opioid peptide mRNA and protein expression and that opioid ligands modulate dyskinesias suggest that the opioid system may be involved. To further understand its role in dyskinesias, we mapped opioid receptor-stimulated G-protein activation using [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) autoradiography in the basal ganglia of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned squirrel monkeys administered water or L-DOPA. Subtype-selective opioid receptor G-protein coupling was investigated using the mu-opioid agonist [D-Ala, N-Me-Phe, Gly-ol]-enkephalin, delta-agonist SNC80 and kappa-agonist U50488H. Our data show that mu-opioid receptor-mediated G-protein activation is significantly enhanced in the basal ganglia and cortex of L-DOPA-treated dyskinetic monkeys, whereas delta- and kappa-receptor-induced increases were limited to only a few regions. A similar pattern of enhancement was observed in both MPTP-lesioned and unlesioned animals with LIDs suggesting the effect was not simply due to a compromised nigrostriatal system. Opioid receptor G-protein coupling was not enhanced in non-dyskinetic L-DOPA-treated animals, or lesioned monkeys not given L-DOPA. The increases in opioid-stimulated [35S]GTPgammaS binding are directly correlated with dyskinesias. The present data demonstrate an enhanced subtype-selective opioid-receptor G-protein coupling in the basal ganglia of monkeys with LIDs. The positive correlation with LIDs suggests this may represent an intracellular signaling mechanism underlying these movement abnormalities.

Topics: Animals; Antiparkinson Agents; Autoradiography; Behavior, Animal; Brain; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesias; Female; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Levodopa; Male; Membrane Glycoproteins; Membrane Transport Proteins; Naloxone; Narcotic Antagonists; Narcotics; Nerve Tissue Proteins; Parkinsonian Disorders; Protein Binding; Receptors, Opioid; Saimiri; Sulfur Isotopes