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

Abstract

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.

Effect of acute swim stress on plasma corticosterone and brain monoamine levels in bidirectionally selected DxH recombinant inbred mouse strains differing in fear recall and extinction

“…However, lower corticosterone levels and a blunted corticosterone response to stress are typical hallmarks of PTSD (Chester et al, 2013; Zoladz and Diamond, 2013), which more closely resembles the endocrine findings in our H-FSS mice. The hypothesis that H-FSS mice suffer from a condition resembling PTSD or a principal fear disorder can be tested with a thorough analysis of the HPA axis, e.g., by presenting various stressors and measuring hormone levels at different time points following acute stress exposure and/or delivery of chronic stressors known to provoke PTSD symptoms in rodent models.…”

Genetic correlation between alcohol preference and conditioned fear: Exploring a functional relationship

“…This finding, which is similar to results reported in humans with a family history of AUDs (Sher & Levenson, 1982; Sinha, Robinson, & O’Malley, 1998), suggested that greater sensitivity to the anxiolytic, and therefore, reinforcing, effects of alcohol in people with a genetic propensity toward AUDs may be one of the mechanisms that contributes to the high rate of co-morbidity between AUD and PTSD. These mouse lines also show differences in the HPA axis response to stress (lower corticosterone levels after foot shock and fear-related cues) that correlate with their genetically influenced divergent alcohol-drinking behavior (Chester et al, 2014), and match data reported in humans with PTSD (Yehuda, 2001) and in other rodent models of PTSD-like behavior (Cohen et al, 2006). Overall, our data in these lines suggest they are a unique model for identifying genetic and biological factors that contribute to AUD and PTSD comorbidity in humans.…”

“…Alcohol-naïve HAP lines (1 and 2) show greater fear potentiated startle (FPS), a model for fear-related disorders such as PTSD, compared to LAP lines (Barrenha & Chester, 2007; Barrenha, Coon, & Chester, 2011; Chester, Kirchhoff, & Barrenha, 2014). Fear-conditioning models such as FPS are commonly used to study mechanisms that contribute to fear-related disorders such as PTSD (Kim & Jung, 2006).…”

Substance abuse, memory, and post-traumatic stress disorder

“…Due to the significant overlap between the underlying mechanisms, fear conditioning in rodents is commonly used to study aspects of anxiety and fear-related disorders, such PTSD (Chester, Kirchhoff, & Barrenha, 2013; Kim & Jung, 2006). Several paradigms of inescapable shock delivery in unpredictable patterns have been shown to create PTSD-like states in rodents (Foa, Zinbarg, & Rothbaum, 1992; Maier, 2001; Siegmund & Wotjak, 2007), and prior exposure to multiple shocks enhances the subsequent learning of conditioned fear (Rau, DeCola, & Fanselow, 2005).…”

“…Alcohol also has well-documented effects on several forms of learning and memory, including fear-conditioned behaviors (Alijan-pour et al, 2012; Weissenborn & Duka, 2003; Alijan-pour et al, 2012). Genetic rodent models for drinking also show distinctive phenotypes for fear-conditioned behaviors, such as FPS (Barrenha, Coon, & Chester, 2011; Chester et al, 2013). This suggests that common genes regulate alcohol preference and the propensity toward fear-related behavior, thus implicating a shared underlying mechanism in these processes.…”