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Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain's Reward Circuitry.

Authors :
Walker DM
Cates HM
Loh YE
Purushothaman I
Ramakrishnan A
Cahill KM
Lardner CK
Godino A
Kronman HG
Rabkin J
Lorsch ZS
Mews P
Doyle MA
Feng J
Labonté B
Koo JW
Bagot RC
Logan RW
Seney ML
Calipari ES
Shen L
Nestler EJ
Source :
Biological psychiatry [Biol Psychiatry] 2018 Dec 15; Vol. 84 (12), pp. 867-880. Date of Electronic Publication: 2018 Apr 25.
Publication Year :
2018

Abstract

Background: Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD).<br />Methods: We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes.<br />Results: We focused on three patterns of gene expression that reflect responses to 1) acute cocaine, 2) context re-exposure, and 3) drug + context re-exposure. These patterns revealed region-specific regulation of gene expression. Further analysis revealed that each of these gene expression patterns correlated with an addiction index-a composite score of several addiction-like behaviors during cocaine SA-in a region-specific manner. Cyclic adenosine monophosphate response element binding protein and nuclear receptor families were identified as key upstream regulators of genes associated with such behaviors.<br />Conclusions: This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.<br /> (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1873-2402
Volume :
84
Issue :
12
Database :
MEDLINE
Journal :
Biological psychiatry
Publication Type :
Academic Journal
Accession number :
29861096
Full Text :
https://doi.org/10.1016/j.biopsych.2018.04.009