Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems

NEUROPHARMACOLOGY

卷:76

Article

Hall, F. S.¹  Itokawa, K.²  Schmitt, A.³  Moessner, R.³  Sora, I.⁴  Lesch, K. P.³  Uhl, G. R.¹ 

[1] NIDA, NIH, DHHS, Mol Neurobiol Branch,Intramural Res Program, Baltimore, MD 21224 USA

[2] Saitama Med Sch, Dept Neurol, Saitama, Japan

[3] Univ Wurzburg, Dept Psychiat, Wurzburg, Germany

[4] Tohoku Univ, Grad Sch Med, Dept Neurosci, Div Psychobiol, Sendai, Miyagi 980, Japan

关键词: Transgenic mice;    Gene knockout;    Dopamine;    Aging;    Amphetamine;    Cocaine;   

DOI  :  10.1016/j.neuropharm.2013.07.031

来源: Elsevier

【 摘 要 】

Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLOA6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be exacerbated by other factors that affect the metabolism of cytosolic DA. (C) Published by Elsevier Ltd.

【 授权许可】

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