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Neuropharmacology. 2018 Jan;128:1-10. doi: 10.1016/j.neuropharm.2017.09.019. Epub 2017 Sep 14.

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

Author information

1
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: kreissne@email.unc.edu.

Abstract

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.

KEYWORDS:

Cocaine; GLT-1; Glutamate; Methylation; Self-administration; Transporter

PMID:
28919080
PMCID:
PMC5714670
[Available on 2019-01-01]
DOI:
10.1016/j.neuropharm.2017.09.019
[Indexed for MEDLINE]

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