Age- and sex-dependent effects of footshock stress on subsequent alcohol drinking and acoustic startle behavior in mice selectively bred for high-alcohol preference

Background: Exposure to stress during adolescence is known to be a risk factor for alcohol‐use and anxiety disorders. This study examined the effects of footshock stress during adolescence on subsequent alcohol drinking in male and female mice selectively bred for high‐alcohol preference (HAP1 lines). Acoustic startle responses and prepulse inhibition (PPI) were also assessed in the absence of, and immediately following, subsequent footshock stress exposures to determine whether a prior history of footshock stress during adolescence would produce enduring effects on anxiety‐related behavior and sensorimotor gating. Methods: Alcohol‐naïve, adolescent (male, n = 27; female, n = 23) and adult (male, n = 30; female, n = 30) HAP1 mice were randomly assigned to a stress or no stress group. The study consisted of 5 phases: (1) 10 consecutive days of exposure to a 30‐minute footshock session, (2) 1 startle test, (3) one 30‐minute footshock session immediately followed by 1 startle test, (4) 30 days of free‐choice alcohol consumption, and (5) one 30‐minute footshock session immediately followed by 1 startle test. Results: Footshock stress exposure during adolescence, but not adulthood, robustly increased alcohol drinking behavior in both male and female HAP1 mice. Before alcohol drinking, females in both the adolescent and adult stress groups showed greater startle in phases 2 and 3; whereas males in the adolescent stress group showed greater startle only in phase 3. After alcohol drinking, in phase 5, enhanced startle was no longer apparent in any stress group. Males in the adult stress group showed reduced startle in phases 2 and 5. PPI was generally unchanged, except that males in the adolescent stress group showed increased PPI in phase 3 and females in the adolescent stress group showed decreased PPI in phase 5. Conclusions: Adolescent HAP1 mice appear to be more vulnerable to the effects of footshock stress than adult mice, as manifested by increased alcohol drinking and anxiety‐related behavior in adulthood. These results in mice suggest that stress exposure during adolescence may increase the risk for developing an alcohol‐use and/or anxiety disorder in individuals with a genetic predisposition toward high alcohol consumption.