Sex differences in incentive motivation and the relationship to the development and maintenance of alcohol use disorders

Abstract

Despite considerable evidence of higher rates of alcohol use disorders (AUDs) in men than in women, there is a dearth of research into the underlying causes of this disparity. As the gap in high risk drinking between men and women closes, it is critical to disentangle the biological factors that may place men and women at different risk for the development of AUDs as well as AUD-associated health problems. While sex differences in alcohol drinking have been reported in animal models and in human alcoholics, it increasingly seems that consummatory behavior may be dissociated from propensity toward inflexible and cue-elicited drug seeking and taking that characterize alcohol use disorders. While much of this work was initially performed in males a growing, yet limited, body of literature suggests that there are sex differences in both cue reactivity, and further, the relationship between cue reactivity and the maintenance of addictive behavior, indicating that males may be at greater risk for the development of a subset of addiction-related behaviors independent of alcohol consumption. Here, we will review the current literature on sex effects on the relationship between incentive motivation and addictive behavior and discuss unanswered questions that we expect will inform the development of individualized and sex-specific treatment and prevention strategies for AUDs. We believe that a greater understanding of how sex interacts with in cue reactivity to independently mediate the drug taking and risk for the development of uncontrolled drug or alcohol-seeking and -taking will inform the development of individualized treatment and prevention strategies for addiction.

Keywords: Alcohol use disorders; Female; Incentive salience; Pavlovian-to-instrumental transfer; Sex differences; Sign- and goal-tracking.

Figure 1

(a) The four core genotypes (FCG) mouse model. In order to study the influence of sex chromosome complement and gonadal sex independently, MF1 FCG mice, in which the testis-determining gene, Sry, is deleted from the Y chromosome, were used. In breeders, an Sry transgene is inserted onto an autosome, resulting in testis formation. Because the Sry transgene is on an autosome, it segregates independently of sex chromosome. The activational effects of gonadal hormones were not considered as all mice underwent gonadectomy (GDX) or sham GDX at 45 days of age. (b) Sex chromosome predicts the relationship between incentive motivation and cue-induced reinstatement. FCG mice were XXF (gonadal and chromosomal females), XXM (chromosomal female, gonadal males), XYF (chromosomal male, gonadal female) and XYM (chromosomal and gonadal males). All mice were gonadectomized. High PIT mice show greater cue-induced reinstatement than Low PIT mice only in XY (chromosomal male) mice. There is no relationship between PIT status and reinstatement in XX mice. *p<.05, **p<.01. Error bars ± SEM. A three-way ANOVA (gonad × chromosome × PIT status) revealed an interaction between chromosome (XX vs. XY) and PIT (Low PIT vs. High PIT) on normalized responding in reinstatement (active response rate during the reinstatement session normalized to response rate on the last day of extinction; F_2,33= 5.518, p=.028). Post-hoc analyses indicate that only in XY mice does High PIT predict elevated reinstatement (p=.03), while in XX mice no difference was seen between reinstatement in High and Low PIT mice (p=.2). These data indicate that the observed relationship between PIT status and cue-induced reinstatement is only true in chromosomal males and that this relationship is lacking in chromosomal females.