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

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.

Sex Differences in Animal Models: Focus on Addiction

“…In light of this, particularly intriguing was a gene expression profile approach to the study of withdrawal seizure-prone and withdrawal seizureresistant mice. A prominent common gene regulatory node in the medial prefrontal cortex that was activated during acute withdrawal for both sexes was the nuclear factor kB transcription factor, but the immune response was dramatically sexually dimorphic, with females presenting a proinflammatory gene expression profile and males presenting an anti-inflammatory gene expression profile (Wilhelm et al, 2014). The authors suggested that each stage of the addiction cycle is differentially influenced by sex versus genetic background, and they argued for the development of stageand sex-specific therapies for alcohol withdrawal and relapse prevention.…”

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males

“…Mice were exposed to ethanol continuously for 72 h in vapor inhalation chambers as previously described (44,119). This paradigm has been characterized as a vulnerability model [see (119)], with a single chronic exposure to high intoxication, followed by synchronized withdrawal.…”

“…Nevertheless, increased vulnerability to EtOH-induced neurotoxicity in females remains controversial [reviewed in (51)] with additional studies needed to support or refute this hypothesis. This finding is buttressed by the observation that chronic ethanol exposure is associated with a strongly sexually dimorphic transcriptional response (44,118,119). In those studies, significantly regulated transcripts included several genes that are exclusively or predominantly expressed in astrocytes, suggesting that a component of the neuroadapative response in the brain after ethanol exposure reflects changes in astrocyte gene expression that are distinct between males and females.…”

“…Importantly, astrocytes can produce potentially neurotoxic inflammatory mediators including tumor necrosis factor (TNF) (55). We have recently shown that following chronic intoxication in vivo, females exhibit a pro-inflammatory response in the medial prefrontal cortex that includes increased Tnf expression, while males show a pattern consistent with immune suppression (118,119). Associated with this pro-inflammatory tone, females also exhibit increased neurotoxicity (44,118).…”

Transitioning from First Drug Use to Dependence Onset: Illustration of a Multiparametric Approach for Comparative Epidemiology

“…Additionally, pursuing general NIH program interest in male-female differences, we considered how parameter estimates might differ for male and female drug users (Mello N.K., 1986;Sartor et al, 2014;Wagner and Anthony, 2007;Wetherington, 2007;Wilhelm et al, 2014). In prior work, female-male contrasts for risk of becoming dependent assume that age is held constant (e.g., Chen and Kandel, 2002) or hold constant elapsed time since first onset of drug use (e.g., Sartor et al, 2014;Wagner and Anthony, 2007).…”