Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

Clare Wilhelm, J. G. Hashimoto, M. L. Roberts, Mustafa (Kemal) Sonmez, Kristine Wiren

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety.

Original languageEnglish (US)
Pages (from-to)168-186
Number of pages19
JournalNeuroscience
Volume279
DOIs
StatePublished - Sep 4 2014

Fingerprint

Genotype
Alcoholism
Phenotype
Seizures
Ethanol
Alcohols
Sexual Development
Premature Mortality
Brain Death
Genetic Models
Prefrontal Cortex
Computational Biology
Animal Models
Maintenance
Genetic Background
Therapeutics

Keywords

  • Astrocytes
  • Ethanol
  • Inflammation
  • Low level response to alcohol
  • Prefrontal cortex
  • Sexual dimorphism

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Understanding the addiction cycle : A complex biology with distinct contributions of genotype vs. sex at each stage. / Wilhelm, Clare; Hashimoto, J. G.; Roberts, M. L.; Sonmez, Mustafa (Kemal); Wiren, Kristine.

In: Neuroscience, Vol. 279, 04.09.2014, p. 168-186.

Research output: Contribution to journalArticle

Wilhelm, Clare ; Hashimoto, J. G. ; Roberts, M. L. ; Sonmez, Mustafa (Kemal) ; Wiren, Kristine. / Understanding the addiction cycle : A complex biology with distinct contributions of genotype vs. sex at each stage. In: Neuroscience. 2014 ; Vol. 279. pp. 168-186.
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