Genetic Model to Study the Co-Morbid Phenotypes of Increased Alcohol Intake and Prior Stress-Induced Enhanced Fear Memory.

ABSTRACT

Posttraumatic Stress Disorder (PTSD) is a complex illness, frequently co-morbid with depression, caused by both genetics, and the environment. Alcohol Use Disorder (AUD), which also co-occurs with depression, is often co-morbid with PTSD. To date, very few genes have been identified for PTSD and even less for PTSD comorbidity with AUD, likely because of the phenotypic heterogeneity seen in humans, combined with each gene playing a relatively small role in disease predisposition. In the current study, we investigated whether a genetic model of depression-like behavior, further developed from the depression model Wistar Kyoto (WKY) rat, is a suitable vehicle to uncover the genetics of co-morbidity between PTSD and AUD. The by-now inbred WKY More Immobile (WMI) and the WKY Less Immobile (WLI) rats were generated from the WKY via bidirectional selective breeding using the forced swim test, a measure of despair-like behavior, as the functional selector. The colonies of the WMIs that show despair-like behavior and the control strain showing less or no despair-like behavior, the WLI, are maintained with strict inbreeding over 40 generations to date. WMIs of both sexes intrinsically self-administer more alcohol than WLIs. Alcohol self-administration is increased in the WMIs without sucrose fading, water deprivation or any prior stress, mimicking the increased voluntary alcohol-consumption of subjects with AUD. Prior Stress-Enhanced Fear Learning (SEFL) is a model of PTSD. WMI males, but not females, show increased SEFL after acute restraint stress in the context-dependent fear conditioning paradigm, a sexually dimorphic pattern similar to human data. Plasma corticosterone differences between stressed and not-stressed WLI and WMI male and female animals immediately prior to fear conditioning predict SEFL results. These data demonstrate that the WMI male and its genetically close, but behaviorally divergent control the WLI male, would be suitable for investigating the underlying genetic basis of comorbidity between SEFL and alcohol self-administration.