1. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.
- Author
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Farré D, Muñoz A, Moreno E, Reyes-Resina I, Canet-Pons J, Dopeso-Reyes IG, Rico AJ, Lluís C, Mallol J, Navarro G, Canela EI, Cortés A, Labandeira-García JL, Casadó V, Lanciego JL, and Franco R
- Subjects
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine pharmacology, Animals, Caudate Nucleus drug effects, Caudate Nucleus physiopathology, Corpus Striatum drug effects, Dimerization, Dopamine metabolism, Dopamine Agonists pharmacology, Dyskinesia, Drug-Induced etiology, Gene Expression Regulation drug effects, Levodopa toxicity, Macaca fascicularis, Male, Oxidopamine toxicity, Parkinsonian Disorders chemically induced, Putamen drug effects, Putamen physiopathology, Radioligand Assay, Rats, Rats, Wistar, Receptors, Dopamine D1 agonists, Receptors, Dopamine D1 biosynthesis, Receptors, Dopamine D1 genetics, Receptors, Dopamine D3 biosynthesis, Receptors, Dopamine D3 genetics, Corpus Striatum physiopathology, Dominance, Cerebral drug effects, Dyskinesia, Drug-Induced physiopathology, Levodopa pharmacology, Parkinsonian Disorders physiopathology, Receptors, Dopamine D1 physiology, Receptors, Dopamine D3 physiology
- Abstract
Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.
- Published
- 2015
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