INVESTIGATING VULNERABILITY TO TRAUMATIC STRESS AND SUSCEPTIBILITY TO ETHANOL CONSUMPTION AND SUBSEQUENT NEUROCHEMICAL CHANGES

Abstract

Post-traumatic stress disorder (PTSD) is initiated by traumatic-stress exposure and manifests into a collection of symptoms including increased anxiety, sleep disturbances, enhanced response to triggers, and increased sympathetic nervous system arousal. PTSD often co-occurs with alcohol use disorder. Only some individuals experiencing traumatic stress develop PTSD and a subset of individuals with PTSD develop co-occurring alcohol use disorder. Both men and women are at risk to develop PTSD and co-occurring alcohol use disorder when exposed to a traumatic event. Age at which the traumatic event occurred is also a major factor in developing PTSD and co-occurring alcohol use disorder. If exposure occurs during childhood or adolescence, individuals may be more resilient to these stresses compared to older individuals. Factors including sex and age have shown individual differences in developing PTSD and co-occurring alcohol use disorder and severity of disorders. However, what factors following traumatic stress exposure that predict resilience or vulnerability remain unknown. To investigate the basis of the individual responses to traumatic stress, single prolonged stress (SPS) a validated rodent model of traumatic stress was applied to young adult male and female rats and adolescent female rats. Individual behavioral responses to traumatic stress were characterized using anxiety-like behaviors with open field and elevated plus maze tests, fear-like behaviors with cue-reactivity, and depression-like behaviors with the forced swim test. Ethanol consumption following traumatic stress or control handling was measured by allowing individual rats to self-administer ethanol using an intermittent two bottle choice procedure for 8 weeks. Correlations within age and sex were used to determine which behavioral factors were predictive of ethanol consumption. Results demonstrate that different behavioral endpoints were predictive of subsequent drinking in males and females, and in adult and adolescent groups. Fear-like behavior was predictive of drinking in young adult males. Depression-like behavior was predictive of adolescent female ethanol consumption. Anxiety-like behavior was predictive of ethanol drinking in young adult females. These results indicate that resilience and vulnerability manifest differently after traumatic stress exposure depending on age and biological sex. Young adult females were further analyzed using an artificial intelligence algorithm that was developed to predict resilient and vulnerable individuals based on data from anxiety testing and ethanol consumption. Using the algorithm with the factors of time in center on the open field test and open arm entries on the elevated plus maze revealed that the population consisted of 3 groups with 24% classified as resilient and 41% classified as susceptible to high ethanol drinking. The artificial intelligence model was implemented in a second experiment to identify resilient and vulnerable adult female rats before ethanol exposure. Using the resilient and vulnerable animals identified from the artificial intelligence algorithm, analyses of neuropeptide Y (NPY) and its receptors Y1 and Y2 in the central nucleus of the amygdala (CeA), basolateral amygdala (BLA), and bed nucleus stria terminalis (BNST) were performed. The CeA, BLA, and BNST are important regions for PTSD and co-occurring alcohol use disorder. Results demonstrate that resilient rats had higher expression of Y2 mRNA in the CeA compared with vulnerable and control rats. In the BLA, the vulnerable rats had higher levels of Y1 compared to controls. In the BNST, NPY was elevated in resilient animals compared to controls. The results of the study show that an artificial intelligence algorithm can identify individual differences in response to traumatic stress and subsequent ethanol drinking, and the NPY pathway is differentially altered following traumatic stress exposure in resilient and vulnerable populations. Understanding neurochemical alterations following traumatic-stress exposure is critical in developing prevention strategies for the vulnerable phenotype and will help further development of novel therapeutic approaches for individuals suffering from PTSD and alcohol use disorder.