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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    • "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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    • "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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