Effects of noradrenergic denervation on L-DOPA-induced dyskinesia and its treatment by α- and β-adrenergic receptor antagonists in hemiparkinsonian rats

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Abstract

While L-3,4-dihydroxyphenylalanine (L-DOPA) remains the standard treatment for Parkinson's disease (PD), long-term efficacy is often compromised by L-DOPA-induced dyskinesia (LID). Recent research suggests that targeting the noradrenergic (NE) system may provide relief from both PD and LID, however, most PD patients exhibit NE loss which may modify response to such strategies. Therefore this investigation aimed to characterize the development and expression of LID and the anti-dyskinetic potential of the α2- and β-adrenergic receptor antagonists idazoxan and propranolol, respectively, in rats receiving 6-OHDA lesions with (DA lesion) or without desipramaine protection (DA + NE lesion). Male Sprague–Dawley rats (N = 110) received unilateral 6-hydroxydopamine lesions. Fifty-three rats received desipramine to protect NE neurons (DA lesion) and 57 received no desipramine reducing striatal and hippocampal NE content 64% and 86% respectively. In experiment 1, the development and expression of L-DOPA-induced abnormal involuntary movements (AIMs) and rotations were examined. L-DOPA efficacy using the forepaw adjusting steps (FAS) test was also assessed in DA- and DA + NE-lesioned rats. In experiment 2, DA- and DA + NE-lesioned rats received pre-treatments of idazoxan or propranolol followed by L-DOPA after which the effects of these adrenergic compounds were observed. Results demonstrated that moderate NE loss reduced the development and expression of AIMs and rotations but not L-DOPA efficacy while anti-dyskinetic efficacy of α2- and β-adrenergic receptor blockade was maintained. These findings suggest that the NE system modulates LID and support the continued investigation of adrenergic compounds for the improved treatment of PD.

Highlights

► Moderate NE loss reduces L-DOPA-induced dyskinesia and rotations. ► The α2-adrenergic antagonist idazoxan attenuates L-DOPA-induced dyskinesia. ► Propranolol, a b-adrenergic antagonist, reduces L-DOPA-induced dyskinesia. ► NE lesions do not alter anti-dyskinetic effects of adrenergic receptor antagonists.

Introduction

Parkinson's disease (PD) is widely recognized by the preferential loss of dopamine (DA) neurons located within the substantia nigra pars compacta (SNc) leading to motor deficits typified by rigidity, resting tremor, and akinesia (Dauer and Przedborski, 2003). DA replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) alleviates many of these motor impairments and has become the gold standard treatment for PD. Unfortunately, chronic pharmacotherapy with L-DOPA often results in side effects such as motor fluctuations and L-DOPA-induced dyskinesia (LID; Obeso et al., 2000).

In addition to SNc DA cell loss, norepinephrine (NE) neurons of the locus coeruleus (LC) degenerate, even preceding the death of DA neurons (Fornai et al., 2007, Hornykiewicz and Kish, 1987, McMillan et al., 2011, Zarow et al., 2003). Post-mortem estimates for NE loss in PD brains range from 60 to 90% (Zarow et al., 2003) and a number of preclinical studies suggest that NE cell death increases the vulnerability of DA neurons (Rommelfanger and Weinshenker, 2007, Srinivasan and Schmidt, 2003). Within the past few decades, there have been attempts to reduce motor symptoms of PD by increasing NE activity. For instance, Narabayashi and colleagues decreased akinesia with DL-threo-3,4-dihydroxyphenylserine (L-DOPS; Droxidopa), a precursor to NE that increases its activity (Narabayashi et al., 1984, Narabayashi et al., 1991). Still others have used the α2-adrenergic receptor antagonists such as idazoxan (IDZ), atipamezole and fipamezole to modulate NE function and improve PD treatment (Domino et al., 2003, Haapalinna et al., 2003, Johnston et al., 2010, Rascol et al., 2001, Yavich et al., 2003).

NE compounds have also been shown to modulate the expression of LID. For example, the non-selective β-adrenergic receptor antagonist (±)propranolol (PRO) significantly attenuated established LID in PD patients (Carpentier et al., 1996), an effect supported in both rodents (Buck and Ferger, 2010, Dekundy et al., 2007, Lindenbach et al., 2011) and primates (Gomez-Mancilla and Bedard, 1993). Anti-dyskinetic properties have also been shown with α1- and α2-adrenergic receptor antagonists (Buck and Ferger, 2010, Buck et al., 2010, Fox et al., 2001, Grondin et al., 2000, Rascol et al., 2001, Savola et al., 2003) and fipamezole, an α2-adrenergic receptor antagonist, has demonstrated therapeutic efficacy in persons suffering from LID and is currently in the process of being brought to market. Other drugs acting on NE transmission such as duloxetine, atomoxetine and droxidopa, are in various stages of development for the treatment of symptoms of PD (clinicaltrials.gov).

Still, there is much to be learned regarding the NE system and its role in LID. Indeed, studies investigating LID rarely consider NE cell loss as a modulatory factor in LID development, expression, or treatment or are contradictory. For example, in the abnormal involuntary movements (AIMs) rat model of LID, the NE reuptake inhibitor desipramine is often given to protect NE neurons during 6-hydroxydopamine (6-OHDA) lesion surgery (Barnum et al., 2008, Putterman et al., 2007). Other studies suggest that NE lesions either exacerbate L-DOPA and DA agonist-induced dyskinesia (Fulceri et al., 2007, Wang et al., 2010) or have no effect (Marin et al., 2008, Perez et al., 2009). Currently no studies have systematically addressed the effects of NE loss on adrenergic anti-dyskinetic efficacy. Therefore, we characterized the development and expression of LID and the anti-dyskinetic potential of the α2- and β-adrenergic receptor antagonists IDZ and PRO, respectively, in rats receiving 6-OHDA lesions with (DA lesion) or without desipramaine protection (DA + NE lesion).

Section snippets

Animals

Adult male Sprague–Dawley rats were used (225–250 g upon arrival; Taconic Farms, NY, USA). Animals were housed in plastic cages (22 cm high, 45 cm deep and 23 cm wide) and had free access to standard lab chow (Rodent Diet 5001; Lab Diet, Brentwood, MO, USA) and water. The colony room was maintained on a 12/12 h light/dark cycle (lights on at 0700 h) at a temperature of 22–23 °C. Animals were maintained in accordance with the guidelines of the Institutional Animal Care and Use Committee of Binghamton

Monoamine and metabolite levels

At least 48 h following the final L-DOPA treatment, rat striata and hippocampi were examined for NE, DA, DOPAC, 5-HT and 5-HIAA content via HPLC. A 2 (Side; Intact vs. Lesion) × 2 (Lesion; DA vs. DA + NE) ANOVA was used to analyze potential lesion-induced differences (Table 1). In striatum, main effects of Side (Intact vs. Lesion) were observed for DA, DOPAC (F1,31 = 652.2, p < 0.0001, F1,31 = 43.9, p < 0.0001) and 5-HIAA (F1,31 = 21.1, p < 0.0001) with post hocs indicating toxin-induced depletion ipsilateral

Discussion

In the current series of studies, we sought to clarify the contribution of the NE system to the development and expression of LID and determine how moderate NE loss affects the therapeutic benefits of NE antagonists in an animal model of LID. In order to modify NE, rats received unilateral MFB 6-OHDA lesions with or without the NE reuptake inhibitor desipramine. HPLC analysis demonstrated that striatal NE content in rats receiving desipramine did not differ from naïve control NE levels.

Acknowledgments

This work was supported by NIH NS059600 (C. Bishop) and the Center for Development and Behavioral Neuroscience at Binghamton University. The authors would especially like to thank Thomas Button for his technical assistance and Karen L. Eskow-Jaunarajs, Kristin B. Dupre, and Corinne Y. Ostock, for their help with behavioral scoring and surgery.

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