INVESTIGATION OF PREDATOR ODOR STRESSOR ON LASTING CHANGES TO ALCOHOL INTEROCEPTIVE SENSITIVITY

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly comorbid. Exposure to the scent of a predator, such TMT, is a well-established model of traumatic stress in rodents with relevance to PTSD. Interoceptive sensitivity to alcohol influences alcohol intake and is related to risk of developing AUD. The present work focuses on the GABA-A and NMDA receptor-mediated components of the interoceptive stimulus of alcohol, which are thought to produce the stimulatory and the sedative interoceptive effects of alcohol, respectively. First, gene expression analyses were conducted after TMT exposure. The overall pattern of findings showed differentially expressed genes (DEGs) related to HPA-axis activation at early time points (6 hrs and 2 days), and DEGs related to excitatory and inhibitory neuronal signaling at late time points (2 days, 2 weeks, and 4 weeks). Next, we show that TMT exposure potentiated the interoceptive effects of alcohol when tested 2-weeks after the exposure in males using an operant drug discrimination procedure. This finding was replicated using Pavlovian drug discrimination in males, but this effect was not observed in females. We next tested substitution for alcohol using GABA-A positive modulators and NMDA receptor antagonists. Both systemic and site-specific prelimbic cortex (PrL) GABA-A modulation produced greater substitution for alcohol in the TMT group compared to controls in males. Again, this effect was not found in females, but interestingly female rats appear to have greater sensitivity to the GABA-A mediated interoceptive effects of alcohol. Follow up molecular experiments suggest that the GABA-A receptor adaptations in the PrL may increase the level of disinhibition by alcohol on PrL projection neurons, and as a result increase the stimulatory effects of alcohol. Because greater sensitivity to the stimulatory effects of alcohol is associated with increased alcohol intake and risk of AUD development, we propose that this effect of TMT exposure may account for the escalated alcohol self-administration following TMT exposure that our lab has previously shown. These findings serve as a plausible mechanism by which traumatic stress can lead to increased alcohol use and risk for AUD. This work could help us better understand PTSD-AUD comorbidity.Doctor of Philosoph