Modulation of l-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus
Introduction
Dopamine (DA) replacement with l-DOPA has remained the most widely used and effective treatment for Parkinson's disease (PD) since its introduction in the 1960's (Katzenschlager and Lees, 2002, Hauser, 2009). However, long-term l-DOPA use is associated with the emergence of a debilitating, hyperkinetic motor side effect known as l-DOPA-induced dyskinesia (LID) (Jankovic, 2005). While the primary cause of LID is not fully understood, it is generally accepted that LID involves excessive release of l-DOPA-derived DA and stimulation of sensitized DA receptors leading to aberrant striatal signaling pathway activity (Huot et al., 2013). Attempts to reduce LID by pharmacologically manipulating the DA system, either by blocking DA receptors or reducing l-DOPA dosage, are frequently complicated by the return of primary PD symptoms (Grondin et al., 1999, Elliott et al., 1992, Goetz et al., 1982). An alternative to this has been the exploration of non-dopaminergic targets which interact with central motor circuits.
There is a growing body of evidence implicating the norepinephrine (NE) system in the expression of LID. NE levels are frequently reduced in the PD brain (Zarow et al., 2003) and l-DOPA treatment has been shown to enhance central NE concentrations (Chalmers et al., 1971, Bianco et al., 2008). Recent experimental evidence reported LID expression temporally coincides with l-DOPA-derived striatal NE efflux in l-DOPA-primed, hemiparkinsonian rats (Wang et al., 2014). As such, a number of compounds targeting the NE system, and α2-adrenoceptors (α2R) specifically, have shown promise for the treatment of LID. Paradoxically, systemic treatment with either agonists or antagonists for the α2R has been shown to reduce LID symptoms, but demonstrate equivocal effects on l-DOPA's therapeutic benefits. The classic α2R agonist clonidine relieves LID but blocks l-DOPA's anti-parkinsonian motor effects (Gomez-Mancilla and Bedard, 1993, Dekundy et al., 2007). In contrast, several classic α2R antagonists including idazoxan, yohimbine, and fipamezole reduce the severity or duration of LID in experimental and clinical populations (Dekundy et al., 2007, Lundblad et al., 2002, Buck et al., 2010, Barnum et al., 2012, Savola et al., 2003, Grondin et al., 2000, Rascol et al., 2001) without interfering with l-DOPA's antiparkinsonian motor benefits (Johnston et al., 2010, Henry et al., 1999). In fact, co-treatment with the α2R-antagonist idazoxan actually extends l-DOPA's antiparkinsonian benefits.
The precise anatomical site of action for these effects has not yet been determined. α2R are abundantly expressed throughout central motor nuclei including the striatum and the rest of the basal ganglia (Rosin et al., 1996, Alachkar et al., 2011); however, it is has been suggested that α2R regulate l-DOPA's effects via a presynaptic mechanism since α2R antagonists influence l-DOPA-, but not DA-agonist-, induced dyskinesias (Fox et al., 2001). The locus coeruleus (LC), the main noradrenergic nucleus in the brain, is a promising candidate since basal firing activity of NE neurons in the locus coeruleus (LC) was positively correlated with dyskinesia severity in a rodent model of LID (Miguelez et al., 2011). NE neurotransmission from the LC is regulated by a class of inhibitory somatodendritic α2-autoreceptors (Norenberg et al., 1997) and stimulation or blockade of these receptors have been shown to influence monoamine efflux and neurotransmitter signaling in motor regions implicated in LID (Yavich et al., 1997, Yavich et al., 2003, Nutt et al., 1994, Bucheler et al., 2002).
Progress in understanding the role of α2R in LID has been slowed due to the limited number of receptor-specific ligands. Atipamezole is a highly potent and selective α2R antagonist demonstrating 100 times greater affinity for the α2R than other α2R antagonists commonly investigated in LID like idazoxan or yohimbine (Pertovaara et al., 2005). In order to clarify the pharmacological and neuroanatomical underpinnings of α2R action in LID and PD, we first evaluated the consequence of systemic administration of atipamezole, or the classic α2R agonist clonidine, on l-DOPA's dyskinetic, antiparkinsonian, and general motor-activating properties. The second goal was to determine whether these effects were mediated by α2R within the LC using site-specific microinfusions. Collectively, the current work demonstrated that α2R modify l-DOPA's motor actions in part due to a population of receptors located in the LC.
Section snippets
Animals
Adult male Sprague–Dawley rats (N = 43; 225–250 g upon arrival; Harlan, USA) were housed in plastic cages (22 cm high, 45 cm deep, and 23 cm wide) with free access to water and standard lab chow (Rodent Diet 5001; Lab Diet, Brentwood, MO, USA). The colony room was maintained at 22–23 °C on a 12 h light/dark cycle (lights on at 0700 h). Animals were cared for in accordance with the guidelines of the Institutional Animal Care and Use Committee at Binghamton University and the “Guide for the Care
Monoamine and metabolite levels
The effects of 6-OHDA lesion on concentrations of NE, DA, and DOPAC levels in the lesioned (left) versus intact (right) striatum are reported in Table 2.
As expected, unilateral 6-OHDA injection into the MFB produced significant (∼99%) reductions in DA and the DA metabolite DOPAC in the lesioned striatal hemisphere of all rats compared to the intact striatal hemisphere (t25 = −9.51; 9.15, p < 0.001). Despite desipramine pretreatment ∼80% reductions in striatal NE levels were also observed
Discussion
Although α2R have received attention in recent years as a target for modulating l-DOPA's effects in the PD brain, their mechanism(s) of action have remained elusive. In the present work, employing the selective α2R antagonist atipamezole allowed us to differentiate the specific contribution of α2R in l-DOPA's dyskinesia- and motor-inducing effects. Systemic α2R blockade with atipamezole extended the dyskinetic and pro-locomotor actions of a low dose of l-DOPA. Conversely, α2R stimulation with
Acknowledgments
This work was supported by funds from R01-NS059600 (CB) and the Center for Development and Behavioral Neuroscience at Binghamton University (CB).
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