DA and PD for Salahpour - Open access freely available...

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Dopamine-Independent Locomotor Actions of Amphetamines in a Novel Acute Mouse Model of Parkinson Disease Tatyana D. Sotnikova 1 , Jean-Martin Beaulieu 1 , Larry S. Barak 1 , William C. Wetsel 2 , Marc G. Caron 1* , Raul R. Gainetdinov 1 1 Department of Cell Biology, Center for Models of Human Disease, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, United States of America, 2 Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina, United States of America 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. Citation: Sotnikova TD, Beaulieu JM, Barak LS, Wetsel WC, Caron MG, et al. (2005) Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease. PLoS Biol 3(8): e271. Introduction The phenylethylamine derivative dopamine (DA) is crit- ically involved in a wide variety of vital functions such as locomotion, feeding, emotion, and reward [1–3]. Major DA systems in the brain originate from brainstem DA neurons located in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). SNc neurons project mainly to the caudate/putamen or dorsal striatum (nigrostriatal system), whereas VTA neurons send their axons to the ventral striatum including the nucleus accumbens, as well as certain other limbic (mesolimbic system) and cortical areas (meso- cortical system). Small DA-containing cell groups located primarily in the hypothalamus comprise the tuberoinfundib- ular DA system [4–6]. DA is synthesized from tyrosine by the rate-limiting enzyme tyrosine hydroxylase (TH), to produce L-DOPA which is quickly decarboxylated by L -aromatic acid decarboxylase (L-AADC) to DA [1,3]. Intraneuronal DA is accumulated into synaptic vesicles by the vesicular mono- amine transporter-2 (VMAT2) [7,8]. DA released into the extracellular space exerts its physiological functions via activation of G protein-coupled D1-like and D2-like DA receptors [9]. Finally, DA in the extracellular space is subject
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