**5. Interaction between β-endorphin and sex in acute EtOH exposure**

Recent studies suggest that sex differences may play a moderating role in acute EtOH sensitivity differences. It is widely appreciated that females have lower incidence of alcoholism than males (Hunt and Zakhari, 1995), and these differences are theorized to manifest differences in coping response between sexes (Hettema et al., 2003). A burgeoning body of research supports the contention that females are more sensitive to stress than males (see Kleim et al., 2010; Maestripieri et al., 2010; Paris et al., 2010; Pratchett et al., 2010 for recent reviews of the human literature and Bangasser et al., 2010; Mogil et al., 1997; and Palanza 2001 for some basic research findings). For example, females, whose use and abuse of alcohol are increasing dramatically, also appear to be more sensitive to stress-induced changes in EtOH sensitivity (see Greenfield et al., 2010; Hudson & Stamp, 2010; Przybycien-Szymanska et al., 2010; Sartor et al., 2010).

Sex differences in stress sensitivity appear to result, at least in part, from differences in hypothalamic-pituitary-adrenal (HPA) functioning mediated by an interaction between gonadal hormones and -endorphin (Hudson and Stamp, 2010). In β-endorphin deficient animals, stress response to EtOH becomes increasingly more hormone dependent (Barfield et al., 2010). In addition to main effects of both sex and β-endorphin on measures of stressinduced behavior, the effect of EtOH was most profound in females deficient in endorphin. This triple interaction between peptide, sex and EtOH sensitivity on stress response was evident in females during their sexually-receptive phase, but not at other times in their estrous cycle.

These data suggest a biologic mechanism for sexually-dimorphic coping responses to stress that is β-endorphin dependent. Unfortunately, there is a paucity of basic biomedical research on sex differences (Beery and Zucker, 2010) but these data suggest the need for future studies to examine the role the estrous cycle plays in the interaction between stress response and alcohol to further understand differences between males and females.

inversely related to time spent in the open or light areas of the assay apparatuses. In naïve subjects, the amount of time spent in the open arms of the Plus Maze or Light-Dark Box was inversely correlated with the amount of basal β-endorphin. These findings are consistent with the suggestion that β-endorphin release produces a calming and relaxing effect and thus lower levels of β-endorphin result in less regulation of HPA axis stress response (Gianoulakis, 1998; Sarkar et al., 2007). It follows that those with low basal β-endorphin levels, and therefore exaggerated stress responses, would be more inclined to self medicate with drugs of abuse, specifically anxiolytics such as EtOH (Zalewska-Kaszubska and

Similar experiments were also conducted following acute exposure to EtOH (Grisel et al., 2008). Here, despite more anxious behavior at baseline, β-endorphin-deficient mice exhibited an exaggerated anxiolytic response after EtOH administration in both the plus maze and light-dark box in comparison to controls. These data may help explain the clinical relationship between this peptide and the propensity for alcoholism by suggesting that individuals with chronic β-endorphin deficiency have an increased sensitivity to the

Recent studies suggest that sex differences may play a moderating role in acute EtOH sensitivity differences. It is widely appreciated that females have lower incidence of alcoholism than males (Hunt and Zakhari, 1995), and these differences are theorized to manifest differences in coping response between sexes (Hettema et al., 2003). A burgeoning body of research supports the contention that females are more sensitive to stress than males (see Kleim et al., 2010; Maestripieri et al., 2010; Paris et al., 2010; Pratchett et al., 2010 for recent reviews of the human literature and Bangasser et al., 2010; Mogil et al., 1997; and Palanza 2001 for some basic research findings). For example, females, whose use and abuse of alcohol are increasing dramatically, also appear to be more sensitive to stress-induced changes in EtOH sensitivity (see Greenfield et al., 2010; Hudson & Stamp, 2010; Przybycien-

Sex differences in stress sensitivity appear to result, at least in part, from differences in hypothalamic-pituitary-adrenal (HPA) functioning mediated by an interaction between gonadal hormones and -endorphin (Hudson and Stamp, 2010). In β-endorphin deficient animals, stress response to EtOH becomes increasingly more hormone dependent (Barfield et al., 2010). In addition to main effects of both sex and β-endorphin on measures of stressinduced behavior, the effect of EtOH was most profound in females deficient in endorphin. This triple interaction between peptide, sex and EtOH sensitivity on stress response was evident in females during their sexually-receptive phase, but not at other times in their

These data suggest a biologic mechanism for sexually-dimorphic coping responses to stress that is β-endorphin dependent. Unfortunately, there is a paucity of basic biomedical research on sex differences (Beery and Zucker, 2010) but these data suggest the need for future studies to examine the role the estrous cycle plays in the interaction between stress

response and alcohol to further understand differences between males and females.

rewarding properties of EtOH, at least in part, because it alleviates their anxiety.

**5. Interaction between β-endorphin and sex in acute EtOH exposure** 

Czarnecka, 2004).

Szymanska et al., 2010; Sartor et al., 2010).

estrous cycle.
