Elsevier

Neuropharmacology

Volume 95, August 2015, Pages 215-225
Neuropharmacology

Modulation of l-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus

https://doi.org/10.1016/j.neuropharm.2015.03.008Get rights and content

Highlights

  • Clonidine suppressed l-DOPA-induced motor activity and dyskinesia in rats.

  • Atipamezole enhanced l-DOPA-induced motor activity and dyskinesia in rats.

  • Locus coeruleus α2-noradrenergic receptors regulated l-dopa-induced dyskinesia.

Abstract

Long-term l-DOPA use for Parkinson's disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as l-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the α2-adrenoceptors (α2R) in l-DOPA's therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic α2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and l-DOPA's therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of α2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic l-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with l-DOPA's antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate l-DOPA's antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that α2R play an important modulatory role in l-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target.

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).

References (85)

  • K.B. Dupre et al.

    Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat

    Neuropharmacology

    (2008)
  • P.J. Elliott et al.

    Dopamine D1 and D2 receptor interactions in the MPTP-treated marmoset

    Neurosci. Lett.

    (1992)
  • P. Ernsberger et al.

    Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla

    Eur. J. Pharmacol.

    (1987)
  • K.L. Eskow et al.

    The partial 5-HT(1A) agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy

    Pharmacol. Biochem. Behav.

    (2007)
  • P. Hertel et al.

    Idazoxan preferentially increases dopamine output in the rat medialprefrontal cortex at the nerve terminal level

    Eur. J. Pharmacol.

    (1999)
  • M. Holmberg et al.

    Adrenergic alpha2C-receptors reside in rat striatal GABAergic projection neurons: comparison of radioligand binding and immunohistochemistry

    Neuroscience

    (1999)
  • P. Huot et al.

    5-HT(1A) receptor stimulation and L-DOPA-induced dyskinesia in Parkinson's disease: bridging the gap between serotonergic and glutamatergic mechanisms

    Exp. Neurol.

    (2011)
  • M. Huotari et al.

    Effects of histamine H(3)-ligands on the levodopa-induced turning behavior of hemiparkinsonian rats

    Park. Relat. Disord.

    (2000)
  • J.B. Koprich et al.

    The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques

    Prog. Neuro-psychopharmacol. Biol. Psychiatry

    (2013)
  • S.Z. Langer

    Presynaptic regulation of catecholamine release

    Biochem. Pharmacol.

    (1974)
  • A. Lee et al.

    alpha2A-adrenergic receptors in the rat nucleus locus coeruleus: subcellular localization in catecholaminergic dendrites, astrocytes, and presynaptic axon terminals

    Brain Res.

    (1998)
  • S. Navailles et al.

    Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson's disease

    Neurobiol. Dis.

    (2011)
  • C.Y. Ostock et al.

    Role of the primary motor cortex in L-Dopa-induced dyskinesia and its modulation by 5-HT1A receptor stimulation

    Neuropharmacology

    (2011)
  • M. Scheinin et al.

    Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain

    Brain Res. Mol. Brain Res.

    (1994)
  • T.H. Svensson et al.

    Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine

    Brain Res.

    (1975)
  • J.L. Taylor et al.

    Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat

    Pharmacol. Biochem. Behav.

    (2005)
  • L. Yavich et al.

    Alpha2-adrenergic control of dopamine overflow and metabolism in mouse striatum

    Eur. J. Pharmacol.

    (1997)
  • L. Yavich et al.

    Atipamezole, an alpha2-adrenoceptor antagonist, augments the effects of L-DOPA on evoked dopamine release in rat striatum

    Eur. J. Pharmacol.

    (2003)
  • A. Alachkar et al.

    Changes in the mRNA levels of alpha(2A) and alpha(2C) adrenergic receptors in rat models of Parkinson's disease and L-DOPA-induced dyskinesia

    J. Mol. Neurosci.

    (2011)
  • A. Arai et al.

    Reuptake of L-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter

    Synapse

    (2008)
  • L.E. Bianco et al.

    Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats

    J. Neurochem.

    (2008)
  • C. Bishop et al.

    Contribution of the striatum to the effects of 5-HT1A receptor stimulation in L-DOPA-treated hemiparkinsonian rats

    J. Neurosci. Res.

    (2009)
  • K. Buck et al.

    The selective alpha1 adrenoceptor antagonist HEAT reduces L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

    Synapse

    (2010)
  • K. Buck et al.

    The alpha(2) adrenoceptor antagonist idazoxan alleviates L-DOPA-induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6-hydroxydopamine-lesioned rats

    J. Neurochem.

    (2010)
  • M. Carta et al.

    Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats

    Brain : A J. Neurol.

    (2007)
  • M.A. Cenci et al.

    Ratings of L-DOPA-induced dyskinesia in the unilateral 6-OHDA lesion model of Parkinson's disease in rats and mice

    Curr. Protoc. Neurosci.

    (2007)
  • J.P. Chalmers et al.

    Effects of L-dopa on norepinephrine metabolism in the brain

    Proc. Natl. Acad. Sci. U. S. A.

    (1971)
  • P. Chopin et al.

    Effects of alpha-2 adrenoceptor agonists and antagonists on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway

    J. Pharmacol. Exp. Ther.

    (1999)
  • T. Chotibut et al.

    Norepinephrine transporter inhibition with desipramine exacerbates L-DOPA-induced dyskinesia: role for synaptic dopamine regulation in denervated nigrostriatal terminals

    Mol. Pharmacol.

    (2014)
  • C. Colosimo et al.

    Noradrenergic drugs for levodopa-induced dyskinesia

    Clin. Neuropharmacol.

    (2003)
  • A. Convents et al.

    [3H]rauwolscine labels alpha 2-adrenoceptors and 5-HT1A receptors in human cerebral cortex

    Eur. J. Pharmacol.

    (1989)
  • I. Coupry et al.

    Different affinities of alpha 2-agonists for imidazoline and alpha 2-adrenergic receptors

    Am. J. Hypertens.

    (1989)
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