Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self-administration and withdrawal

NEUROPHARMACOLOGY

卷:128

Article

Kim, Ronald¹  Sepulveda-Orengo, Marian T.¹  Healey, Kati L.¹  Williams, Emily A.¹  Reissner, Kathryn J.¹ 

[1] Univ North Carolina Chapel Hill, Dept Psychol & Neurosci, CB 3270, Chapel Hill, NC 27599 USA

关键词: Glutamate;    Transporter;    GLT-1;    Cocaine;    Self-administration;    Methylation;   

DOI  :  10.1016/j.neuropharm.2017.09.019

来源: Elsevier

【 摘 要 】

Downregulation of the astroglial glutamate transporter GLT-1 is observed in the nucleus accumbens (NAc) following administration of multiple drugs of abuse. The decrease in GLT-1 protein expression following cocaine self-administration is dependent on both the amount of cocaine self-administered and the length of withdrawal, with longer access to cocaine and longer withdrawal periods leading to greater decreases in GLT-1 protein. However, the mechanism(s) by which cocaine downregulates GLT-1 protein remains unknown. We used qRT-PCR to examine gene expression of GLT-1 splice isoforms (GLT-1A, GLT-1B) in the NAc, prelimbic cortex (PL) and basolateral amygdala (BLA) of rats, following two widely used models of cocaine self-administration: short-access (ShA) self-administration, and the long-access (LgA) self-administration/incubation model. While downregulation of GLT-1 protein is observed following ShA cocaine self-administration and extinction, this model did not lead to a change in GLT-1A or GLT-1B gene expression in any brain region examined. Forced abstinence following ShA cocaine self-administration also was without effect. In contrast, LgA cocaine self-administration and prolonged abstinence significantly decreased GLT-1A gene expression in the NAc and BLA, and significantly decreased GLT-1B gene expression in the PL. No change was observed in NAc GLT-1A gene expression one day after LgA cocaine self-administration, indicating withdrawal-induced decreases in GLT-1A mRNA. In addition, LgA cocaine self-administration and withdrawal induced hypermethylation of the GLT-1 gene in the NAc. These results indicate that a decrease in NAc GLT-1 mRNA is only observed after extended access to cocaine combined with protracted abstinence, and that epigenetic mechanisms likely contribute to this effect. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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