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

被引:52
作者
Bishop, Christopher
Taylor, Jennifer L.
Kuhn, Donald M.
Eskow, Karen L.
Park, John Y.
Walker, Paul D.
机构
[1] SUNY Binghamton, Dept Psychol, Behav Neurosci Program, Binghamton, NY 13902 USA
[2] Wayne State Univ, Dept Psychiat & Behav Neurosci, Cellular & Clin Neurobiol Program, Detroit, MI 48201 USA
[3] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA
[4] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA
关键词
6-hydroxydopamine; basal ganglia; dopamine; rat; serotonin; WAY100635;
D O I
10.1111/j.1460-9568.2006.04790.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:2669 / 2676
页数:8
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