Nonmotor Symptoms of Parkinson's Disease Revealed in an Animal Model with Reduced Monoamine Storage Capacity

Center for Neurodegenerative Disease and Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2009; 29(25):8103-13. DOI: 10.1523/JNEUROSCI.1495-09.2009
Source: PubMed


Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.

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Available from: P. Michael Iuvone, Oct 02, 2015
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    • "Environmental toxin modeling À þ (25% increase of NREM sleep selectively during the active dark phase of light/ dark cycle) À À 39% increase during active phase -Slight reduction in the number of orexinergic neurons. -No other potential alterations were reported [85] VMAT 2 deficient mice Loss of vesicular monoamine transporter 2 NR NI À NI NI Alteration of monoamine neurotransmission [196] Gracile axonal dystrophy (gad) mice Deletion of Ubiquitin cterminal hydrolase NI NI þ NI NI Slight reduction in the number of orexinergic neurons [197] "
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    ABSTRACT: Parkinson disease is one of the neurodegenerative diseases that benefited the most from the use of non-human models. Consequently, significant advances have been made in the symptomatic treatments of the motor aspects of the disease. Unfortunately, this translational success has been tempered by the recognition of the debilitating aspect of multiple non-motor symptoms of the illness. Alterations of the sleep/wakefulness behavior experienced as insomnia, excessive daytime sleepiness, sleep/wake cycle fragmentation and REM sleep behavior disorder are among the non-motor symptoms that predate motor alterations and inevitably worsen over disease progression. The absence of adequate humanized animal models with the perfect phenocopy of these sleep alterations contribute undoubtedly to the lack of efficient therapies for these non-motor complications. In the context of developing efficient translational therapies, we provide an overview of the strengths and limitations of the various currently available models to replicate sleep alterations of Parkinson's disease. Our investigation reveals that although these models replicate dopaminergic deficiency and related parkinsonism, they rarely display a combination of sleep fragmentation and excessive daytime sleepiness and never REM sleep behavior disorder. In this light, we critically discuss the construct, face and predictive validities of both rodent and non-human primate animals to model the main sleep abnormalities experienced by patients with PD. We conclude by highlighting the need of integrating a network-based perspective in our modeling approach of such complex syndrome in order to celebrate valid translational models. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Sleep Medicine Reviews 02/2015; DOI:10.1016/j.smrv.2015.02.005 · 8.51 Impact Factor
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    • "The phenotype was robust, emerging by 3 months of age and persisting through 11 months. Taylor et al. (2009) reported significant hyposmia in a VMAT2-deficient mouse (VMAT2- Lo). These mice express only 5% of wild-type levels of VMAT2 and express features of Parkinson disease such as neuronal loss in the SNc, oxidative stress, and motor impairments. "
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    ABSTRACT: The motor impairments of Parkinson disease are its most salient feature, and thus these symptoms receive the most attention. However, many nonmotor symptoms are also prevalent and may range in severity from mild to incapacitating. Cognitive impairment, for example, affects more than half of Parkinson patients (Ebmeier et al., 1990; Williams-Gray et al., 2007). Psychiatric conditions such as anxiety, depression, impulsivity, and sleep disorders are also common among Parkinson patients. Indeed, Weintraub and Burn (2011) suggest that psychiatric complications are so common among Parkinson patients that the disease might be better conceptualized as a neurocognitive/psychiatric disorder. Although these symptoms are gaining more recognition clinically, modeling of nonmotor symptoms lags behind. Behaviorally, many well-validated tasks exist that can assess a range of complex psychiatric and neurological conditions that are comorbid with Parkinson disease. However, it is important to determine whether manipulations that model the motor symptoms of Parkinson disease also alter nonmotor behaviors, to investigate how treatments for the motor impairments affect the nonmotor symptoms, and to understand how the standard treatments for nonmotor symptoms interact with treatments for the motor symptoms. This chapter will review the methods and techniques used to assess the nonmotor symptoms in animals, along with the relevant biology in animal models of Parkinson disease. 23.2 ANXIETY Anxiety is considered first for several reasons. First, anxiety disorders are highly prevalent in Parkinson disease, affecting up to half of patients (reviewed in Gallagher and Schrag, 2012). Second, chronic anxiety
    Movement Disorders: Genetics and Models, 2nd edited by M. S. LeDoux, 10/2014: chapter 23: pages 387-412; Elsevier Academic Press., ISBN: 978-0-12-405195-9
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    • "The present results are more in line with work performed in VMAT2-depleted mice (Taylor et al., 2009) and indicate that the combined manifestation of depression and anxiety can be successfully modeled in a toxin-based mouse model of PD. "
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    ABSTRACT: Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.
    Frontiers in Behavioral Neuroscience 08/2014; 8:290. DOI:10.3389/fnbeh.2014.00290 · 3.27 Impact Factor
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