ALOCHOL WITHDRAWAL ALTERS NEGATIVE AFFECT, MOTIVATION, AND MESOCORTICOLIMBIC ENDOCANNABINOIDS IN A  SEXUALLY DIMORPHIC MANNER

Angela Marie Henricks

Alcohol dependence is associated with major perturbations in affect and motivation. During withdrawal, alcohol-dependent individuals experience increased anxiety and depression, which contributes to loss of control over drinking. Considerable sex differences exist in the way men and women express the symptoms of alcohol dependence, but preclinical research almost exclusively examines male animals, likely contributing to the ineffectiveness of many pharmacotherapies aimed at treating addiction. The endocannabinoid (ECB) system moderates both the motivational and affective symptoms of alcohol dependence, and there is bidirectional relationship between ovarian hormones and ECBs, making it an important pharmacotherapeutic target. Thus, the present experiments aimed to evaluate how chronic intermittent alcohol (CIA) alters affect and mesocorticolimbic ECBs in intact male and female rats, as well as in ovariectomized (OVX) female rats with or without estradiol (E2) replacement, during acute withdrawal. Compared to control males, intact alcohol-dependent male rats showed enhanced negative affect and escalated alcohol consumption during acute withdrawal, which was coupled with widespread reductions in basolateral amygdala (BLA), ventromedial prefrontal cortex (vmPFC), and nucleus accumbens (NAc) ECBs. While CIA significantly reduced the frequency of proestrus and estrus in intact females, behavioral and ECB-related changes were significantly less pronounced during acute withdrawal compared to intact males. Alcohol consumption was enhanced in intact females, but drinking behavior did not depend on CIA exposure, collectively demonstrating that CIA produces considerable sexually dimorphic changes in behavior and mesocorticolimbic ECBs. Similar to what was seen in males, CIA exposure in OVX females resulted in enhanced negative affect and depressions in BLA and vmPFC ECB mRNA compared to controls, which was not rescued by E2. In the NAc, E2 and alcohol interacted to modulate ECB biosynthesis and degradation, possibly contributing to the sex differences observed in drinking behavior. Thus, E2 may initially protect females against the negative affective symptoms and ECB reductions observed in males during withdrawal, but removal of ovarian hormones leads to male-like affective behavior and alterations in ECBs. Overall, these experiments suggest a mechanism by which men and women express the symptoms of alcohol dependence differentially, which could ultimately facilitate the development of more efficacious pharmacotherapies for alcoholism.

ALOCHOL WITHDRAWAL ALTERS NEGATIVE AFFECT, MOTIVATION, AND MESOCORTICOLIMBIC ENDOCANNABINOIDS IN A SEXUALLY DIMORPHIC MANNER

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