MDMA and fenfluramine reduce L-DOPA-induced dyskinesia via indirect 5-HT1A receptor stimulation

• Published in: The European journal of neuroscience 2006-05, Vol.23 (10), p.2669-2676
• Main Authors: Bishop, Christopher, Taylor, Jennifer L., Kuhn, Donald M., Eskow, Karen L., Park, John Y., Walker, Paul D.
• Format: Article
• Language: English
• Subjects: 6-hydroxydopamine; Adrenergic Agents - toxicity; Animals; Antiparkinson Agents - adverse effects; basal ganglia; Chromatography, High Pressure Liquid; dopamine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced - prevention & control; Fenfluramine - therapeutic use; Levodopa - adverse effects; Male; N-Methyl-3,4-methylenedioxyamphetamine - therapeutic use; Oxidopamine - toxicity; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - drug therapy; rat; Rats; Receptor, Serotonin, 5-HT1A - drug effects; serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin Agents - therapeutic use; WAY100635
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2006.04790.x

Chronic l‐3,4‐dihydroxyphenylalanine (L‐DOPA) pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as dyskinesia. Clinical and experimental studies indicate that indirect serotonin agonists can suppress dyskinesia without affecting the efficacy of L‐DOPA. While the mechanism by which these effects occur is not clear, recent research suggests that serotonin 5‐HT1A receptors may play a pivotal role. To test this, male Sprague–Dawley rats with unilateral 6‐hydroxydopamine medial forebrain bundle lesions received 1 week of daily treatment with L‐DOPA (12 mg/kg, i.p.) plus benserazide (15 mg/kg, i.p.). Beginning on the 8th day of treatment and every 3rd or 4th day thereafter, rats were pretreated with vehicle (0.9% NaCl), the serotonin and dopamine releaser 3,4‐methylenedioxymethamphetamine (MDMA; 0.25 or 2.5 mg/kg, i.p.) or the serotonin releaser fenfluramine (FEN; 0.25 or 2.5 mg/kg, i.p.) 5 min prior to L‐DOPA, after which abnormal involuntary movements (AIMs) and rotations were quantified every 20th minute for 2 h. Pretreatment with 2.5 mg/kg of either MDMA or FEN reduced AIMs. To determine the contribution of the 5‐HT1A receptor to these effects, another group of L‐DOPA‐primed 6‐hydroxydopamine‐lesioned rats were pretreated with the 5‐HT1A antagonist WAY100635 (0.5 mg/kg, i.p.), MDMA + WAY100635 (2.5 + 0.5 mg/kg, i.p.) or FEN + WAY100635 (2.5 + 0.5 mg/kg, i.p.) 5 min prior to L‐DOPA and subsequent AIMs and rotation tests. The antidyskinetic effects of MDMA and FEN were reversed by cotreatment with WAY100635. These results suggest that 5‐HT‐augmenting compounds such as MDMA and FEN probably convey antidyskinetic properties in part via stimulation of 5‐HT1A receptors.