Dopamine-Independent Locomotor Actions of Amphetamines in a Novel Acute Mouse Model of Parkinson Disease

Department of Cell Biology, Center for Models of Human Disease, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, USA.
PLoS Biology (Impact Factor: 9.34). 09/2005; 3(8):e271. DOI: 10.1371/journal.pbio.0030271
Source: PubMed


Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

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    • "Importantly, PLCβ inhibition suppressed spontaneous locomotor hyperactivity in hyperdopaminergic mice lacking the dopamine transporter (DAT) and antagonized the effects of amphetamine, cocaine, SKF 81297 and apomorphine on forward locomotion. Furthermore, the restoration of locomotion by L-DOPA in dopamine-depleted mice (Sotnikova et al., 2005) is also reduced by inhibition of PLCβ resulting in mostly vertical activity following these treatments (Medvedev et al., 2013). These data strongly support a contribution of PLC in mediating the effects of dopamine on forward locomotion. "
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    ABSTRACT: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
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    • "In short, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD (Martinez and Greenamyre, 2012). As mentioned earlier, Sotnikova et al. (2005) were able to reverse parkinsonian motor features resulting from acute dopamine depletion (e.g., akinesia, rigidity, tremor). The acute lesion or dopamine deficiency is not progressive, and in fact, many animal models, including primates, can recover from unilateral MPTP lesions (Boulet et al., 2008; Meredith and Rademacher, 2011). "
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    ABSTRACT: Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder that results in a variety of debilitating symptoms, including bradykinesia, resting tremor, rigidity, and postural instability. Research spanning several decades has emphasized basal ganglia dysfunction, predominantly resulting from dopaminergic cell loss, as the primarily cause of the aforementioned parkinsonian features. But, why those particular features manifest themselves remains an enigma. The goal of this paper is to develop a theoretical framework that parkinsonian motor features are behavioral consequence of a long-term adaptation to their inability (inflexibility or lack of capacity) to meet energetic demands, due to neural metabolic deficits arising from mitochondrial dysfunction associated with PD. Here, we discuss neurophysiological changes that are generally associated with PD, such as selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, in conjunction with metabolic and mitochondrial dysfunction. We then characterize the cardinal motor symptoms of PD, bradykinesia, resting tremor, rigidity and gait disturbance, reviewing literature to demonstrate how these motor patterns are actually energy efficient from a metabolic perspective. We will also develop three testable hypotheses: (1) neural metabolic deficits precede the increased rate of neurodegeneration and onset of behavioral symptoms in PD, (2) motor behavior of persons with PD are more sensitive to changes in metabolic/bioenergetic state, and (3) improvement of metabolic function could lead to better motor performance in persons with PD. These hypotheses are designed to introduce a novel viewpoint that can elucidate the connections between metabolic, neural and motor function in PD.
    Frontiers in Systems Neuroscience 01/2014; 8. DOI:10.3389/fnsys.2014.00242
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    • "To study the role of GRK6 under conditions of severe acute DA deficiency, we developed GRK6-deficient DDD mice26. For this purpose, we first generated DAT/GRK6 double KO mice by crossing heterozygous mice for dopamine transporter (DAT) and GRK6, and then crossing double heterozygous mice for DAT/GRK6 to obtain double DAT/GRK6 KO mice. "
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    ABSTRACT: G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D(2) dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA.
    Scientific Reports 03/2012; 2:301. DOI:10.1038/srep00301 · 5.58 Impact Factor
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