The partial 5-HT_1A agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy

Abstract

Dopamine (DA) replacement therapy with l-DOPA remains the standard pharmacotherapy for Parkinson's disease (PD). Unfortunately, chronic l-DOPA treatment is accompanied by development of motor fluctuations and l-DOPA-induced dyskinesia (LID). While serotonin (5-HT)_1A 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, l-DOPA-primed rats were pre-treated with Vehicle (0.9% NaCl), various doses of the partial 5-HT_1A agonist, buspirone (0.25, 1.0 or 2.5 mg/kg, ip) or buspirone (2.5 mg/kg, ip) + the 5-HT_1A antagonist, WAY100635 (0.5 mg/kg, ip) 5 min prior to l-DOPA (12 mg/kg + 15 mg/kg benserazide, ip). Rats were tested for LID using the abnormal involuntary movements (AIMs) scale and motor performance using the forepaw adjusting steps test (FAS). In experiment 2, l-DOPA-naïve rats received co-administration of l-DOPA + buspirone (1.0 or 2.5 mg/kg, ip) for 2 weeks. AIMs and FAS were measured throughout. In l-DOPA-primed rats, buspirone dose-dependently reduced LID and improved l-DOPA-related motor performance due to action at the 5-HT_1A receptor. In l-DOPA-naïve rats, buspirone delayed LID development while improving l-DOPA's anti-parkinsonian efficacy indicating the potential long-term benefits of 5-HT_1A agonists for reduction of l-DOPA-related side effects.

Introduction

Dopamine (DA) replacement therapy with l-3,4-dihydroxyphenylalanine (l-DOPA) remains the standard pharmacotherapy for the treatment of movement deficit in patients with Parkinson's disease (PD; Obeso et al., 2000). Unfortunately, most PD patients eventually experience motor fluctuations, including “wearing off” and l-DOPA-induced dyskinesias (LID; Jankovic, 2005). The current necessity of DA replacement therapy and the debilitating nature of its side effects make non-dopaminergic adjunct treatments for the reduction of l-DOPA-induced motor complications indispensable for the health of PD patients.

One potential non-dopaminergic therapeutic target may prove to be the serotonin (5-HT) system. Following severe DA denervation, neuroadaptive changes in 5-HT raphestriatal projections and upregulated 5-HT receptors allow this system to more readily influence basal ganglia activity (Fox et al., 1998, Maeda et al., 2003, Bishop et al., 2004). Such findings have led to the suggestion that compounds targeting 5-HT neurotransmission may have therapeutic value for the reduction of problems that accompany chronic l-DOPA treatment (Nicholson and Brotchie, 2002, Scholtissen et al., 2006). In support of this assertion, the 5-HT/DA releaser, 3,4-methylenedioxymethamphetamine and the 5-HT releaser, fenfluramine have been shown to convey both anti-parkinsonian and anti-dyskinetic effects in experimental models of PD (Iravani et al., 2003, Bishop et al., 2006). While multiple 5-HT receptor subtypes may have contributed to these beneficial effects, accumulating evidence suggests an integral role for the 5-HT_1A receptor.

In recent years, investigations into the beneficial effects of 5-HT_1A receptor stimulation have yielded encouraging, though occasionally conflicting results. In rats with unilateral DA lesions, acute administration of the full 5-HT_1A agonists, ± 8-OH-DPAT and sarizotan was reported to reduce peak l-DOPA-induced rotations, but prolong response duration (Bibbiani et al., 2001, Ba et al., 2007). In MPTP-lesioned primates, acute administration of sarizotan was also shown to attenuate LID without affecting l-DOPA's efficacy (Bibbiani et al., 2001). These results were found to be specific to the drug's action at the 5-HT_1A receptor. In contrast, Iravani et al. (2006) reported that the more potent and selective enantiomer for the 5-HT_1A receptor, + 8-OH-DPAT squelched LID, but worsened movement disability, likely reflecting induction of a 5-HT-like syndrome. Clinically, various 5-HT_1A agonists such as tandospirone (Kannari et al., 2002) and sarizotan (Olanow et al., 2004) have been employed with moderate success. For example, sarizotan has been reported to attenuate LID at low doses (Goetz et al., 2007) and prolong l-DOPA's efficacy in patients with advanced PD (Bara-Jimenez et al., 2005). However, similar to results in preclinical work, higher doses of these compounds can worsen parkinsonian features (Kannari et al., 2002, Goetz et al., 2007) and may have influenced the recent decision to halt the development of sarizotan as an l-DOPA adjunct therapy following Phase III clinical trials.

Given these challenges, essential questions remain concerning the utility of chronic 5-HT_1A adjunct therapy for the treatment of l-DOPA-related side effects. One understudied question in this area of research is the differential effects of adjunct treatments on induction (initial development) and subsequent expression (continued behavioral manifestation) of LID. While the effect of adjunct treatments on expression of LID has been extensive, effects on induction of LID have been relatively ignored. For example, 5-HT_1A agonists may have prophylactic utility on the development of motor fluctuations and subsequent LID expression (Tomiyama et al., 2005, Hauser et al., 2006). Moreover, partial 5-HT_1A agonists may convey greater benefit with less risk by reducing the likelihood of side effects related to potent 5-HT_1A receptor stimulation. To answer these questions, we systematically investigated the effects of 5-HT_1A receptor stimulation on l-DOPA-related side effects in both l-DOPA-primed and l-DOPA-naïve unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. We employed the partial 5-HT_1A agonist, buspirone, a common anxiolytic that has been used with some success as an experimental adjunct therapy with l-DOPA in humans (Kleedorfer et al., 1991, Bonifati et al., 1994). To measure LID, we utilized the well-validated abnormal involuntary movements procedure (Lundblad et al., 2002) and the forelimb adjusting steps test (Olsson et al., 1995, Chang et al., 1999) to quantify changes in motor performance. The current findings suggest that in this preclinical model, buspirone administration can reduce both the development and expression of l-DOPA-induced motor complications.