The partial 5-HT1A agonist buspirone reduces the expression and development of I-DOPA-induced dyskinesia in rats and improves I-DOPA efficacy

Dopamine (DA) replacement therapy with I-DOPA remains the standard pharmacotherapy for Parkinson's disease (PD). Unfortunately, chronic 1-DOPA treatment is accompanied by development of motor fluctuations and 1-DOPA-induced dyskinesia (LID). While serotonin (5-HT)tA agonists acutely reduce these complications, their prophylactic and long-term effects are not well-delineated. To test this, male Sprague-Dawley rats received unilateral 6-hydroxydopamine (6-OHDA) lesions. In experiment 1, I-DOPA-primed rats were pre-treated with Vehicle (0.9% NaCl), various doses of the partial 5-HT1A agonist, buspirone (0.25, 1.0 or 2.5 mg/kg, ip) or buspirone (2.5 mg/kg, ip)+ the 5-HT1A antagonist, WAY100635 (0.5 mg/kg, ip) 5 min prior to 1-DOPA (12 mg/kg+ 15 mg/kg benserazide, ip). Rats were tested for LID using the abnormal involuntary movements (AIMs) scale and otor performance using the forepaw adjusting steps test (FAS). In experiment 2,1-DOPA-naive rats received co-administration of 1-DOPA+buspirone (1.0 or 2.5 mg/kg, ip) for 2 weeks. AlMs and FAS were measured throughout. In I-DOPA-primed rats, buspirone dose-dependently reduced LID and improved 1-DOPA-related motor performance due to action at the 5-HT1A receptor. In 1-DOPA-naive rats, buspirone delayed LID development while improving 1-DOPA's anti-parkinsonian efficacy indicating the potential long-term benefits of 5-HT1A agonists for reduction of 1-DOPA-related side effects. (c) 2007 Elsevier Inc. All rights reserved.