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

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

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.

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / metabolism*
  • Conditioning, Operant / drug effects
  • DNA Methylation / drug effects
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Excitatory Amino Acid Transporter 2 / genetics
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Gene Expression Regulation / drug effects*
  • Male
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration

Substances

  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Transporter 2
  • RNA, Messenger
  • Slc1a2 protein, rat
  • Cocaine