Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats

Abstract

Serotonin 1A receptor (5-HT_1AR) agonists reduce both l-DOPA- and D1 receptor (D1R) agonist-mediated dyskinesia, but their anti-dyskinetic mechanism of action is not fully understood. Given that 5-HT_1AR stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT_1AR agonists may diminish dyskinesia in part through modulation of pro-dyskinetic striatal glutamate levels. To test this, rats with unilateral medial forebrain bundle dopamine or sham lesions were primed with l-DOPA (12 mg/kg + benserazide, 15 mg/kg, sc) or the D1R agonist SKF81297 (0.8 mg/kg, sc) until abnormal involuntary movements (AIMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT_1AR agonist ± 8-OH-DPAT (1.0 mg/kg, sc), followed by l-DOPA or SKF81297, or intrastriatal ± 8-OH-DPAT (7.5 or 15 mM), followed by l-DOPA. In some cases, the 5-HT_1AR antagonist WAY100635 was employed to determine receptor-specific effects. In vivo microdialysis was used to collect striatal samples for analysis of extracellular glutamate levels during AIMs assessment. Systemic and striatal ± 8-OH-DPAT attenuated l-DOPA-induced dyskinesia and striatal glutamate efflux while WAY100635 reversed ± 8-OH-DPAT's effects. Interestingly, systemic ± 8-OH-DPAT diminished D1R-mediated AIMs without affecting glutamate. These findings indicate a novel anti-dyskinetic mechanism of action for 5-HT_1AR agonists with implications for the improved treatment of Parkinson's disease.

Introduction

Chronic dopamine (DA) replacement therapy with l-3,4-dihydroxyphenylalanine (l-DOPA) for Parkinson's disease (PD) patients often results in abnormal and excessive movements known as l-DOPA-induced dyskinesia (LID; Jankovic, 2005). Although the mechanisms of LID are not fully understood, it is believed that following DA depletion, serotonergic neurons of the raphe nuclei convert exogenously administered l-DOPA to DA and release it into the striatum in a pulsatile, unregulated manner (Carta et al., 2007, Eskow et al., 2009, Lindgren et al., 2010). This aberrant release of DA is believed to stimulate supersensitive DA D1 (D1R) and D2 (D2R) receptors located in the DA-depleted striatum (Pavese et al., 2006, Cenci, 2007). While both receptor subtypes appear to be involved in LID, it is likely that striatal D1R have a more prominent role (Westin et al., 2007). For instance, striatal D1R expression and signaling have been shown to be significantly enhanced in dyskinetic animals and humans (Cenci et al., 1998, Gerfen et al., 2002, Aubert et al., 2005, Guigoni et al., 2007), and D1R agonists induce dyskinesia in both experimental and clinical models of PD (Rascol et al., 2001, Rascol et al., 2006, Delfino et al., 2007, Dupre et al., 2007, Dupre et al., 2008a).

It is well known that serotonin (5-HT) 1A receptor (5-HT_1AR) agonists diminish LID (Dekundy et al., 2007, Eskow et al., 2007, Eskow et al., 2009) and these results have been mostly attributed to stimulation of raphe 5-HT_1AR that temper striatal DA release. Interestingly, there is also evidence that stimulation of 5-HT_1AR located directly within the striatum attenuates both l-DOPA- (Bishop et al., 2009) and D1R-mediated dyskinesia (Dupre et al., 2008a) and improves movement in DA-depleted rats (Mignon and Wolf, 2002, Matsubara et al., 2006, Dupre et al., 2008a). The mechanism(s) surrounding these striatally-mediated 5-HT_1AR effects are not yet known. One possibility is that activation of these receptors, located presynaptically on corticostriatal glutamate neurons, attenuate the release of glutamate into the striatum (Antonelli et al., 2005, Mignon and Wolf, 2005). Indeed, upon DA depletion and subsequent l-DOPA or D1R agonist treatment, augmentation of striatal glutamate levels (Jonkers et al., 2002, Robelet et al., 2004) and increased expression of striatal glutamate receptors have been postulated to result in dyskinetic behaviors (Calon et al., 2002, Ouattara et al., 2010). In support of this, a number of ionotropic and metabotropic glutamate receptor antagonists have been shown to reduce LID and improve D1R-mediated locomotor activity (Goodwin et al., 1992, Ferré et al., 1994, Bibbiani et al., 2005, Rylander et al., 2010, Kobylecki et al., 2010). Thus, whether striatal 5-HT_1AR stimulation attenuates LID and D1R agonist-induced dyskinesia through modulation of local glutamate release remains an important mechanistic and translational question.

The aim of the current study was to investigate the effects of systemic and local 5-HT_1AR stimulation on extracellular striatal glutamate levels in hemiparkinsonian rats rendered dyskinetic by either l-DOPA or the D1R agonist SKF81297. Using in vivo microdialysis, the full 5-HT_1AR agonist (±)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide (± 8-OH-DPAT) was administered systemically or striatally perfused prior to l-DOPA (12 mg/kg, sc + benserazide, 15 mg/kg, sc) or administered systemically prior to R(+)-SKF-81297 hydrobromide (SKF81297; 0.8 mg/kg, sc) in unilaterally DA-depleted and sham-lesioned rats. Striatal sample fractions were collected for analysis of glutamate and dyskinesia was measured using the abnormal involuntary movements (AIMs) scale (Lundblad et al., 2002). The present results indicate that the anti-dyskinetic effect of 5-HT_1AR stimulation coincides with a reduction in extracellular striatal glutamate levels with l-DOPA, but not D1R agonist, treatment. These findings implicate a novel glutamatergic mechanism by which 5-HT_1AR agonists work to reduce LID with implications for the treatment of PD.