Serotonin 2A receptor antagonist treatment reduces dopamine D1 receptor-mediated rotational behavior but not l-DOPA-induced abnormal involuntary movements in the unilateral dopamine-depleted rat

Abstract

Previous experiments have demonstrated that serotonin (5-HT) 2A receptor antagonists suppress hyperkinetic behaviors associated with dopamine (DA) D1 receptor supersensitivity in rats with 6-hydroxydopamine (6-OHDA) lesions. Since l-DOPA induced dyskinesia (LID) may be mediated by oversensitive D1-mediated signaling, the present study examined the effects of the selective 5-HT2A antagonist M100907 on LID behaviors in DA-depleted rats. Adult male Sprague–Dawley rats with unilateral 6-OHDA lesions received daily l-DOPA treatments to produce dyskinetic behaviors as measured by abnormal involuntary movements (AIMs) testing. In these animals, M100907 (0.01, 0.1 or 1.0 mg/kg, ip) given 30 min before l-DOPA did not alter the appearance or intensity of AIMs behaviors. Because l-DOPA induced AIMs in rats are dependent upon D1 and D2 receptor activation, a second study was performed to determine if M100907 could suppress D1- or D2-mediated rotational behaviors. Contralateral rotations induced by the D1 agonist SKF82958 were significantly reduced by pre-treatment with M100907. However, M100907 was ineffective in reducing rotations induced by the D2 agonist quinpirole. The finding that M100907 suppresses rotations induced by D1, but not D2, agonists may provide a partial explanation for the lack of effect of a selective 5-HT2A antagonist on l-DOPA-induced AIMs behaviors.

Introduction

Dopamine (DA) replacement therapy with l-DOPA is the common treatment for the alleviation of motor impairments associated with Parkinson's Disease (PD). Unfortunately, prolonged l-DOPA treatment leads to l-DOPA-induced dyskinesia (LID) characterized by abnormal and excessive movements in 40% of patients within 4–6 years of treatment and as much as 90% by 9–15 years (Ahlskog and Muenter, 2001). One factor hypothesized to underlie LID is the development of supersensitive DA D1 receptors – a mechanism suggested to contribute to the problem of LID in PD patients, MPTP-treated primates, and 6-hydroxydopamine-lesioned rats (Pifl et al., 1992, Cai et al., 2002, Gerfen et al., 2002, Corvol et al., 2004, Aubert et al., 2005, Taylor et al., 2005). As such, methods for reducing abnormal D1 signaling may also decrease the problem of LID and enhance the therapeutic efficacy of l-DOPA treatment.

Recent studies suggest that 5-HT2A receptor-mediated signaling may contribute to hyperkinetic behaviors and abnormal striatal gene expression patterns observed in DA-depleted rats treated with D1 agonists. D1 and 5-HT2 agonist treatments produce a synergistic induction of striatonigral gene expression in the DA-lesioned rat while no such effect is observed in the intact animal (Gresch and Walker, 1999b, Campbell et al., 2001). This observation is consistent with behavioral studies showing hyperlocomotion following combined D1 and 5-HT2 agonist infusion into the DA-depleted striatum at low doses that had no effect on behavior when administered separately (Bishop and Walker, 2003). More recently, the selective 5-HT2A receptor antagonist M100907 was found to suppress hyperactive locomotor behaviors induced by intrastriatal infusion of the D1 agonist SKF82958 (Bishop et al., 2005). Interestingly, both experimental and clinical studies suggest that LID is reduced by atypical antipsychotics with 5-HT2A receptor antagonist abilities (Meco et al., 1998, Grondin et al., 1999, Oh et al., 2002, Durif et al., 2004), as well as the 5-HT2 receptor antagonist ritanserin (Maertens de Noordhout and Delwaide, 1986, Meco et al., 1988). Thus, it is possible that 5-HT2A receptor antagonist treatment may also have LID suppressing effects in l-DOPA-treated rats since LID behaviors have been shown to be dependent, at least in part, upon D1 receptor activation (Taylor et al., 2005). To address this question, the present studies examined the effects of 5-HT2A antagonist treatment with M100907 on l-DOPA-induced abnormal involuntary movements (AIMs) in adult rats with unilateral DA lesions. In addition, experiments also measured the effects of M100907 on contralateral rotational behavior induced by selective D1- and D2-receptor agonists to determine if 5-HT2A antagonist treatment was differentially effective in blocking supersensitive effects at one or both receptors.