Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease

https://doi.org/10.1016/j.pnpbp.2016.05.004Get rights and content

Highlights

  • A novel model of impulsivity associated with Parkinson's disease is described.

  • Dose-related effects of continuously released pramipexole in this model are revealed.

  • Pramipexole effects on motor dysfunction were distinct from effects on impulsivity.

  • Mirtazapine altered impulsivity, but not motor benefits, of pramipexole.

  • The model may help identify adjunct therapy to reduce unwanted side effects of pramipexole.

Abstract

Pramipexole and ropinirole are dopamine agonists that are efficacious in treating motor disturbances of neuropathologies, e.g., Parkinson's disease and restless legs syndrome. A significant portion of treated patients develop impulsive/compulsive behaviors. Current treatment is dose reduction or switching to an alternative dopamine replacement, both of which can undermine the motor benefits. Needed is a preclinical model that can assist in identifying adjunct treatments to dopamine agonist therapy that reduce impulsive/compulsive behaviors without interfering with motor benefits of the dopamine agonist. Toward that objective, the current study implemented a rat model of Parkinson's disease to behaviorally profile chronically administered pramipexole. This was accomplished with male Sprague-Dawley rats wherein (i) 6-hydroxydopamine-induced lesions of the dorsolateral striatum produced Parkinson's disease-like akinesia, measured in the forelimbs, (ii) intracranial self-stimulation–mediated probability discounting indicated impulsivity/risk-taking, and (iii) two doses of pramipexole were continuously administered for 14–28 days via osmotic minipumps to mirror the chronic, stable exposure achieved with extended release formulations. The atypical antidepressant, mirtazapine, is known to reduce behaviors associated with drug addiction in rats; thus, we demonstrated model utility here by determining the effects of mirtazapine on pramipexole-induced motor improvements versus probability discounting. We observed that forelimb akinesia subsequent to striatal lesions was attenuated by both pramipexole doses tested (0.3 and 1.2 mg/kg/day) within 4 h of pump implant dispensing 0.3 mg/kg/day and 1 h by 1.2 mg/kg/day. By contrast, 12–14 days of infusion with 0.3 mg/kg/day did not alter discounting, but increases were obtained with 1.2 mg/kg/day pramipexole, with 67% of 1.2 mg/kg/day-treated rats meeting categorical criteria for ‘high risk-taking’. Insertion of a second minipump delivering mirtazapine did not alter motor function during 14 days of co-administration with pramipexole, but was sufficient to attenuate risk-taking. These outcomes revealed distinct probability discounting and anti-akinesia profiles for pramipexole, indicating that pharmacotherapy, (e.g., mirtazapine treatments), can be developed that reduce risk-taking while leaving motor benefits intact.

Introduction

Agonists of the dopamine D2 receptor family (D2R) (e.g., pramipexole (PPX), ropinirole) are efficacious in treating motor deficits of Parkinson's disease (PD) and restless legs syndrome. However, dopamine agonist therapy is associated with the development of impulsive/compulsive disorders (ICDs) in a significant portion of treated patients (Voon et al., 2011, Callesen et al., 2014, Weintraub et al., 2010). These disorders can be emotionally and financially devastating for the afflicted individuals and their families. Therapeutic regimens that treat motor deficits but do not induce ICDs are needed; however, relevant alternatives include adjunct treatments that can mitigate established ICDs, without impacting the capacity of a dopamine agonist to improve PD. For this to be feasible, the brain substrates engaged by D2R agonists that mediate motor benefits must differ from those that mediate ICDs. To functionally dissect these brain substrates, we developed a sophisticated paradigm that allows for concurrent testing of PD-like motor pathology (akinesia) and impulsivity related to ICDs observed in vulnerable dopamine agonist-treated PD patients.

Impulsiveness includes a greater tendency for risk-taking. This tendency can be quantified using probability discounting procedures; a cross-species assessment in which the subject chooses between a small reinforcer (SR) delivered at a high probability, and a large reinforcer (LR) delivered at a low probability. Typically, the subjective value of the LR is discounted when its probability is low, and individuals then select the smaller, yet more certain reinforcer. In western cultures, problem/pathological gambling, hypersexuality, and impulsive/compulsive shopping and eating, are the most frequently reported ICDs in PD (Voon et al., 2011, Callesen et al., 2014, Weintraub et al., 2010). Those who suffer from these disorders are less sensitive to low probabilities than healthy individuals, and they more frequently select the LR even when the odds to obtain the reward are very low (Raylu and Oei, 2002, Madden et al., 2009, Lawyer, 2008, Miedl et al., 2012, Hendrickson and Rasmussen, 2013). Discounting tasks also have been implemented in rats, using food (St Onge and Floresco, 2009) or intracranial self-stimulation (ICSS) (Rokosik and Napier, 2012, Rokosik and Napier, 2011, Tedford et al., 2014, Tedford et al., 2015) as positive reinforcers. We demonstrated that ICSS protocols allow for repeated testing without changing feeding status, and we have implemented this procedure in a rat model of PD (i.e., rats with 6-hydroxydopamine (6OHDA)-induced lesions of the dorsolateral striatum (DLS)) (Hendrickson and Rasmussen, 2013, Rokosik and Napier, 2012, Rokosik and Napier, 2011). We also determined that repeated, intermittent intraperitoneal treatments of relatively high doses of PPX increases ICSS-mediated probability discounting (Rokosik and Napier, 2012). Outbred rats exhibit differential sensitivities to moderate doses of indirect acting dopamine agonists, e.g., cocaine and amphetamine, and the treated rats are commonly categorized as high or low responders (Kabbaj, 2006). Accordingly, we postulated here that moderate doses of PPX might enhance risk-taking only in a subset of (more sensitive) rats. Such a scenario would parallel the human condition wherein only some PPX-treated PD patients develop ICDs (Callesen et al., 2014, Weintraub et al., 2010).

The present study was designed to determine if, in an outbred strain of rats, a dose of PPX that mitigated 6OHDA-induced forelimb akinesia in all rats would concurrently increase probability discounting only in some. As motor benefits of agonist therapy in PD are typically realized long before diagnosis of ICDs (Shannon et al., 1997), we also determined the onset of PPX-induced effects on akinesia and probability discounting. Extended release formulations of PPX are frequently used for human patients to provide relatively stable exposure to the drug during chronic therapy (Eisenreich et al., 2010). To emulate this therapeutic approach in rats, we evaluated continuously delivered PPX using subcutaneously (sc) implanted osmotic minipumps.

Currently, there are no FDA-approved pharmacotherapies for ICDs with neurological comorbidities. Accordingly, another objective of the current study was to validate the utility of our PD/risk-taking model to help identify putative adjunct therapies that maintain dopamine agonist-mediated motor improvement but reduce ICD-like behaviors. Brain and behavioral substrates of ICDs are similar to those engaged during substance use disorders and drug addiction (Engel and Caceda, 2015). Thus, we postulated that therapies which hold promise for addiction may provide relief from ICDs. Mirtazapine, an atypical antidepressant, reduces behaviors associated with substance use disorders in rats (Graves and Napier, 2011, Herrold et al., 2009, Voigt et al., 2011, Voigt and Napier, 2011, Graves et al., 2012a) and humans (Yoon et al., 2006, Graves et al., 2012b). Moreover, mirtazapine has been used to treat anxiety, depression, and psychosis in PD patients, and is well-tolerated by PD patients on dopamine agonist therapy with little to no effect on the motor benefits afforded by the agonist (Gordon et al., 2002, Pact and Giduz, 1999, Hagikura et al., 2012, Nagata et al., 2013, Tagai et al., 2013, Godschalx-Dekker and Siegers, 2014). This latter feature likely reflects the lack of mirtazapine binding to dopaminergic receptors (de Boer et al., 1988, Fernandez et al., 2005). Based on this backdrop, we tested the utility of mirtazapine to diminish PPX-induced risk-taking in rats.

The hypotheses for the study were that (i) chronic, continuous delivery of low to moderate doses of PPX will reverse forelimb akinesia induced by 6OHDA lesions of the DLS, (ii) some treated rats will exhibit increased risk-taking in the probability discounting task, and (iii) mirtazapine will attenuate risky behavior, but not the motor benefits of PPX.

Section snippets

Animals and surgical procedures

Male Sprague-Dawley (outbred) rats (250–300 g; Harlan Laboratories, Indianapolis, IN) were pair-housed under environmentally controlled conditions under a 12 h light/dark cycle (lights on at 07:00); food and water were available ad libitum. Experimental procedures were approved by the IACUC at Rush University Medical Center and in accordance with the National Institutes of Health “Guide for the Care and Use of Laboratory Animals”. Experimental timelines are illustrated in Fig. 1.

A commonly used

Results

We (Rokosik and Napier, 2012, Tedford et al., 2015) and others (Chang et al., 1999) show that deficits in the forelimb step task (i.e., akinesia) reflect substantial reductions of DLS TH (lesion illustrated in Fig. 1C). Likewise, here, intra-DLS 6OHDA produced akinesia, (i.e., an ~ 80% reduction in stepping) in all rats, and this was attenuated with PPX infusion at 0.3 and 1.2 mg/kg/day (e.g., Fig. 2A). Evaluating effect onset; there was a main effect of time (F6,78 = 144.86, p < 0.0001), and a dose × 

Discussion

This study demonstrates in rats (i) the utility of a minipump chronic administration protocol, (ii) the ability of PPX to reduce forelimb akinesia imposed by 6OHDA-induced lesions of the DLS (iii) vs. promoting risk-taking behavior, and (iv) the utility of a non-food motivated, probability discounting task. Study outcomes support the possibility that dopamine agonists engage different neuronal systems and/or biochemical processes for these two behavioral functions. The efficacy of this novel

Conclusion

In conclusion, we confirmed the differing pharmacological profiles for akinesia and risk-taking following PPX treatment in DLS-lesioned rats, a rat model of PD. PPX-induced risk-taking was blunted by the concomitant administration of mirtazapine while the motor benefits remained intact. These results illustrate the utility of this rat model of PPX-induced motor benefits and risk-taking/ICDs in PD patients. The results also indicate the merit of additional research into the potential utility of

Author roles

NAH was involved in the conception and organization of the research project, its design and execution, statistical analyses, and the writing of the manuscript.

SET was involved in the conception of the research project, its design and execution, statistical analyses, review and the writing of this manuscript.

ALP was involved in the conception of the research project, its design and execution, statistical analyses, writing, review and critique of the manuscript.

SAG was involved in data

Conflict of interest

All authors report no financial conflict of interest with respect to the content of this manuscript.

Acknowledgements

The authors thank Dr. Sandra (Rokosik) Kletzel for providing the photomicrograph of TH immunohistochemistry illustrated in this manuscript.

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  • Cited by (0)

    Sources: Work was supported by a grant from Michael J. Fox Foundation (TCN), and by USPHSGs NS087559 (TCN and ALP), and DA033121 (SET and TCN).

    1

    These authors contributed equally to this report.

    2

    Previously published as A.L. Mickiewicz.

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