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

Abstract

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.

Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats

“…Moreover, it has been recently described that serotonin mesencephalic neuron transplants exacerbate levodopa-induced dyskinesia in 6-OHDA-lesioned rats . It is thus conceivable that inhibition of serotonin release as a consequence of 5-HT 1A agonist action of sarizotan might alleviate dyskinesias (Ba et al 2007;Bibbiani et al 2001;Bishop et al 2006;Carta et al 2007;Dekundy et al 2007;Dupre et al 2008;Eskow et al 2007;Lunblad et al 2005). The present results extend previous findings in MPTP monkeys (Bedard et al 2006;Bibbiani et al 2001) and PD patients (Bara-Jimenez et al 2005;Olanow et al 2004) where systemic administration of the 5-HT 1A agonist sarizotan can attenuate levodopa-induced dyskinesias without worsening parkinsonian symptoms.…”

“…It is well established that stimulation of presynaptic 5-HT 1A receptors diminishes nerve impulse activity in serotoninergic neurons leading to a decrease of serotonin release in the striatum (Gobert et al 1995;Kreiss and Lucki 1994). It is thus conceivable that inhibition of serotonin release, as a consequence of 5-HT 1A agonists administration, might alleviate dyskinesias (Ba et al 2007;Bibbiani et al 2001;Bishop et al 2006;Carta et al 2007;Eskow et al 2007).…”

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

“…The dose of L-DOPA and the length of priming have been extensively utilized in our lab to produce prominent and stable abnormal AIMs expression (Taylor et al 2005;Bishop et al 2006;Eskow et al 2007). L-DOPA and benserazide were dissolved in vehicle (0.9% NaCl + 0.1% ascorbic acid) and administered at a volume of 1.0 ml/ kg.…”

“…Rats were monitored for AIMs using a procedure slightly modified from that described in Lundblad et al (2002) and Bishop et al (2006). The AIMs model of dyskinesia utilizes distinct behavioral measures and demonstrates face validity with known anti-dyskinetic compounds (Lundblad et al 2002;Taylor et al 2005).…”

Oral administration of (±)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques

“…For example trials have recently been planned or initiated in the US, Switzerland and Israel to use MDMA in the treatment of Post-Traumatic Stress Disorder and for anxiety in late stage cancer (Doblin, 2006;Mithoefer, 2006a;Mojeiko, 2006;Oehen, 2006). Furthermore, some recent findings from animal models suggest that MDMA may be therapeutically useful in Parkinson's Disease (Bishop et al, 2006;Iravani et al, 2003;Sotnikova et al, 2005) thereby increasing the potential for additional human trials and eventual clinical use of MDMA. Other amphetamines are already in current clinical use, for example METH is marketed as Desoxyn® for indications such as ADHD and obesity.…”