Effect of chronic L-DOPA treatment on 5-HT1A receptors in parkinsonian monkey brain

After chronic use of L-3,4-dihydroxyphenylalanine (L-DOPA), most Parkinson's disease (PD) patients suffer from its side effects, especially motor complications called L-DOPA-induced dyskinesia (LID). 5-HT1A agonists were tested to treat LID but many were reported to worsen parkinsonism. In this study, we evaluated changes in concentration of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and of 5-HT1A receptors in control monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, dyskinetic MPTP monkeys treated chronically with L-DOPA, low dyskinetic MPTP monkeys treated with L-DOPA and drugs of various pharmacological activities: Ro 61-8048 (an inhibitor of kynurenine hydroxylase) or docosahexaenoic acid (DHA) and dyskinetic MPTP monkeys treated with L-DOPA + naltrexone (an opioid receptor antagonist). Striatal serotonin concentrations were reduced in MPTP monkeys compared to controls. Higher striatal 5-HIAA/serotonin concentration ratios in L-DOPA-treated monkeys compared to untreated monkeys suggest an intense activity of serotonin axon terminals but this value was similar in dyskinetic and nondyskinetic animals treated with or without adjunct treatment with L-DOPA. As measured by autoradiography with [H-3]8-hydroxy-2-(di-n-propyl) aminotetralin (8-OH-DPAT), a decrease of 5-HT1A receptor specific binding was observed in the posterior/dorsal region of the anterior cingulate gyrus and posterior/ventral area of the superior frontal gyrus of MPTP monkeys compared to controls. An increase of 5-HT1A receptor specific binding was observed in the hippocampus of MPTP monkeys treated with L-DOPA regardless to their adjunct treatment. Cortical 5-HT1A receptor specific binding was increased in the L-DOPA-treated MPTP monkeys alone or with DHA or naltrexone and this increase was prevented in low dyskinetic MPTP monkeys treated with L-DOPA and Ro 61-8048. These results highlight the importance of 5-HT1A receptor alterations in treatment of PD with L-DOPA. (C) 2012 Elsevier Ltd. All rights reserved.