Relation between corticosterone and fear-related behavior in mice selectively bred for high or low alcohol preference.

Blunted cortisol responses to stress or trauma have been linked with genetic (familial) risk for both alcoholism and post-traumatic stress disorder (PTSD). Mouse lines selectively bred for high (HAP) or low (LAP) alcohol preference may be a relevant model of genetic risk for co-morbid alcoholism and PTSD in humans. HAP mice show greater fear-potentiated startle (FPS), a model used to study PTSD, than LAP mice. The relation between corticosterone (CORT) and FPS behavior was explored in four experiments. Naïve male and female HAP2 and LAP2 mice received fear-conditioning or control treatments, and CORT levels were measured before and immediately after fear-conditioning or FPS testing. In two other experiments, HAP2 mice received CORT (1.0, 5.0 or 10.0 mg/kg) or a glucocorticoid receptor antagonist (mifepristone; 25.0 and 50.0 mg/kg) 30 minutes before fear conditioning. HAP2 mice exposed to fear conditioning and to control foot shock exposures showed lower CORT after the fear-conditioning and FPS testing sessions than LAP2 mice. A trend toward higher FPS was seen in HAP2 mice pretreated with 10.0 mg/kg CORT, and CORT levels were the lowest in this group, suggesting negative feedback inhibition of CORT release. Mifepristone did not alter FPS. Overall, these results are consistent with data in humans and rodents indicating that lower cortisol/CORT levels after stress are associated with PTSD/PTSD-like behavior. These findings in HAP2 and LAP2 mice suggest that a blunted CORT response to stress may be a biological marker for greater susceptibility to develop PTSD in individuals with increased genetic risk for alcoholism.

Effects of cross-fostering on alcohol preference and correlated responses to selection in high- and low-alcohol-preferring mice.

BACKGROUND: Selectively bred rodent lines are valuable tools for investigating gene × environment interactions related to risk for alcoholism in humans. Early maternal environment is one particular factor known for critically influencing neural, hormonal, and behavioral outcomes in adulthood. Cross-fostering is a procedure that may be used to explore the role of genotype-dependent maternal influences on phenotypic variability in adulthood. The purpose of these experiments was to examine the effects of cross-fostering on free-choice alcohol drinking and correlated responses to selection for alcohol preference in mice selectively bred for high (HAP2) and low (LAP2) alcohol preference. METHODS: Mice were assigned to one of the following treatments: SHAM (pups that were fostered to their original biological mother), IN (pups that were fostered to a different mother of the same line), and CROSS (pups that were fostered to a mother of a different line). Mice were tested in adulthood for (i) free 24-hour access to alcohol for a period of 28 days; (ii) the expression of the acoustic startle response and fear-potentiated startle (FPS); and (iii) handling-induced convulsions (HICs) during acute alcohol withdrawal. RESULTS: Overall, the expression of the alcohol preference selection phenotype was robust in all groups (HAP2 > LAP2). Cross-fostering produced a moderate but significant reduction in g/kg alcohol drinking and preference scores in HAP2 mice (CROSS < SHAM) but had no effect in LAP2 mice. Cross-fostering did not affect the expression of correlated responses to selection: acoustic startle response (HAP2 > LAP2), FPS (HAP2 > LAP2), HICs (LAP2 > HAP2). CONCLUSIONS: It appears that maternal environment can modify the expression of the high-alcohol-preference phenotype in HAP2 selectively bred mice. These results suggest a gene × environment interaction with respect to the expression of the high-alcohol-preference selection phenotype but not correlated responses to selection.

Effects of alcohol on the acquisition and expression of fear-potentiated startle in mouse lines selectively bred for high and low alcohol preference.

RATIONALE: Anxiety disorders and alcohol use disorders frequently co-occur in humans perhaps because alcohol relieves anxiety. Studies in humans and rats indicate that alcohol may have greater anxiolytic effects in organisms with increased genetic propensity for high alcohol consumption. OBJECTIVES AND METHODS: The purpose of this study was to investigate the effects of moderate doses of alcohol (0.5, 1.0, 1.5 g/kg) on the acquisition and expression of anxiety-related behavior using a fear-potentiated startle (FPS) procedure. Experiments were conducted in two replicate pairs of mouse lines selectively bred for high- (HAP1 and HAP2) and low- (LAP1 and LAP2) alcohol preference; these lines have previously shown a genetic correlation between alcohol preference and FPS (HAP > LAP; Barrenha and Chester, Alcohol Clin Exp Res 31:1081-1088, 2007). In a control experiment, the effect of diazepam (4.0 mg/kg) on the expression of FPS was tested in HAP2 and LAP2 mice. RESULTS: The 1.5 g/kg alcohol dose moderately decreased the expression of FPS in both HAP lines but not LAP lines. Alcohol had no effect on the acquisition of FPS in any line. Diazepam reduced FPS to a similar extent in both HAP2 and LAP2 mice. CONCLUSIONS: HAP mice may be more sensitive to the anxiolytic effects of alcohol than LAP mice when alcohol is given prior to the expression of FPS. These data collected in two pairs of HAP/LAP mouse lines suggest that the anxiolytic response to alcohol in HAP mice may be genetically correlated with their propensity toward high alcohol preference and robust FPS.

Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.

RATIONALE: Alcohol-use disorders often occur together with anxiety disorders in humans which may be partly due to common inherited genetic factors. Evidence suggests that the endocannabinoid system (ECS) is a promising therapeutic target for the treatment of individuals with anxiety and/or alcohol-use disorders. OBJECTIVES: The present study assessed the effects of a novel endocannabinoid uptake inhibitor, LY2183240, on anxiety- and alcohol-seeking behaviors in a unique animal model that may represent increased genetic risk to develop co-morbid anxiety and alcohol-use disorders in humans. Mice selectively bred for high alcohol preference (HAP) show greater fear-potentiated startle (FPS) than mice selectively bred for low alcohol preference (LAP). We examined the effects of LY2183240 on the expression of FPS in HAP and LAP mice and on alcohol-induced conditioned place preference (CPP) and limited-access alcohol drinking behavior in HAP mice. RESULTS: Repeated administration of LY2183240 (30 mg/kg) reduced the expression of FPS in HAP but not LAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhanced the expression of alcohol-induced CPP and this effect persisted in the absence of the drug. LY2183240 did not alter limited-access alcohol drinking behavior, unconditioned startle responding, or locomotor activity. CONCLUSIONS: These findings suggest that ECS modulation influences both conditioned fear and conditioned alcohol reward behavior. LY2183240 may be an effective pharmacotherapy for individuals with anxiety disorders, such as post-traumatic stress disorder, but may not be appropriate for individuals with co-morbid anxiety and alcohol-use disorders.

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.

Acoustic startle at baseline and during acute alcohol withdrawal in replicate mouse lines selectively bred for high or low alcohol preference.

BACKGROUND: Previous data in both rat and mouse genetic models suggest that there is a genetic relationship between acute alcohol withdrawal responses and innate alcohol drinking behavior. The purpose of the present study was to examine whether acute alcohol withdrawal responses, as measured by acoustic startle and prepulse inhibition (PPI) of acoustic startle, may be genetically related to innate differences in alcohol preference in 2 mouse lines selectively bred for high (HAP1 and HAP2) or low (LAP1 and LAP2) alcohol preference. Line differences in startle responses at baseline, prior to alcohol or saline treatment, were also measured. METHODS: Alcohol-naive, male and female HAP1 (n = 35) and LAP1 (n = 32) and HAP2 (n = 43) and LAP2 (n = 40) mice were tested under baseline conditions and during withdrawal from a single injection of 4.0 g/kg alcohol or equal volume of saline at 4, 8, and 12 hours post-injection. RESULTS: On most trial types, baseline startle responses and PPI were greater in both HAP lines than in both LAP lines, and startle responses were greater in males than in females. During acute alcohol withdrawal, both male LAP lines, and LAP1 females, showed reduced startle responses at the 4-hour time point during acute alcohol withdrawal. In contrast, both HAP1 males and females showed a trend toward enhanced startle at 4 hours in withdrawal. No clear differences in PPI during withdrawal were evident. CONCLUSIONS: These findings indicate good evidence for a genetic relationship between greater baseline acoustic startle responses and PPI and high alcohol preference. Modest support for a genetic correlation between low alcohol preference and reduced startle responses at 4 hours in withdrawal was found in male mice. The suppression in acoustic startle during acute alcohol withdrawal in male LAP lines but not in male HAP lines suggests that a genetic propensity toward low alcohol preference may be related to greater sensitivity to alcohol as measured by acoustic startle responses during acute alcohol withdrawal.

Genetic correlation between innate alcohol preference and fear-potentiated startle in selected mouse lines.

BACKGROUND: There is a high rate of co-occurrence between anxiety and alcohol-use disorders in humans that may arise from the inheritance of common genes that increase the risk for both psychiatric disorders. The purpose of this study was to investigate whether a genetic relationship exists between innate alcohol preference and propensity to develop learned fear, using the fear-potentiated startle (FPS) paradigm, in 2 mouse lines selectively bred for high or low alcohol preference. METHODS: Alcohol-naïve, male, and female mice from replicate pairs of lines selectively bred for high alcohol preference and low alcohol preference were randomly assigned to a fear-conditioned or control group. Mice in the fear-conditioned group received 20 pairings of a light stimulus and footshock; the control group received the same number of exposures to light and footshock, except that these stimuli were explicitly unpaired. During testing for FPS, acoustic stimuli were presented both in the presence and in the absence of the light stimulus. RESULTS: In both replicate pairs of lines, mice selectively bred for high alcohol preference showed greater FPS than mice selectively bred for low alcohol preference. No sex differences in FPS were found in any line. Control groups did not show FPS. CONCLUSION: These findings suggest that common genes mediate both innate alcohol preference and propensity to develop learned fear in these selected mouse lines.