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Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self-administration and withdrawal.
Neuropharmacology 2018; 128:1-10N

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28919080

Citation

Kim, Ronald, et al. "Regulation of Glutamate Transporter 1 (GLT-1) Gene Expression By Cocaine Self-administration and Withdrawal." Neuropharmacology, vol. 128, 2018, pp. 1-10.
Kim R, Sepulveda-Orengo MT, Healey KL, et al. Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self-administration and withdrawal. Neuropharmacology. 2018;128:1-10.
Kim, R., Sepulveda-Orengo, M. T., Healey, K. L., Williams, E. A., & Reissner, K. J. (2018). Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self-administration and withdrawal. Neuropharmacology, 128, pp. 1-10. doi:10.1016/j.neuropharm.2017.09.019.
Kim R, et al. Regulation of Glutamate Transporter 1 (GLT-1) Gene Expression By Cocaine Self-administration and Withdrawal. Neuropharmacology. 2018;128:1-10. PubMed PMID: 28919080.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self-administration and withdrawal. AU - Kim,Ronald, AU - Sepulveda-Orengo,Marian T, AU - Healey,Kati L, AU - Williams,Emily A, AU - Reissner,Kathryn J, Y1 - 2017/09/14/ PY - 2017/04/14/received PY - 2017/09/06/revised PY - 2017/09/11/accepted PY - 2017/9/19/pubmed PY - 2018/7/14/medline PY - 2017/9/19/entrez KW - Cocaine KW - GLT-1 KW - Glutamate KW - Methylation KW - Self-administration KW - Transporter SP - 1 EP - 10 JF - Neuropharmacology JO - Neuropharmacology VL - 128 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28919080/Regulation_of_glutamate_transporter_1__GLT_1__gene_expression_by_cocaine_self_administration_and_withdrawal_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30436-7 DB - PRIME DP - Unbound Medicine ER -