Characterization of alcohol interoceptive effects following predator odor exposure: relevance to PTSD

Project Summary Individuals who suffer from post-traumatic stress disorder (PTSD) are often at higher risk for developing comorbid alcohol use disorder (AUD). Studying individual differences in response to stress is important as not everyone who experiences trauma or witnesses a traumatic event develops PTSD. In preclinical models, exposure to the scent of a predator is commonly used for the study of PTSD-like phenotypes. During the current funding period and in this renewal we use exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) a synthetically derived component of fox feces as the predator odor stressor. We find individual differences in stress reactivity specifically in the engagement of digging in the bedding and immobility behavior during the TMT exposure. While most rats engage primarily in immobility behavior (TMT-1 subgroup), we find a subset of rats engage in a high degree of digging behavior and less immobility (TMT-2 subgroup). This TMT-2 subgroup also shows heightened corticosterone in response to TMT, persistent escalation in alcohol self-administration, and increased TMT- contextual conditioning whereas rats in the TMT-1 subgroup do not. Moreover, while several factors contribute to alcohol drinking, the interoceptive effects associated with drinking are important to study as these are a key part of the drinking experience and can drive ongoing drinking. Further, dysregulation of interoceptive processing is a common feature in several mental health disorders, including PTSD. As such, it is important to consider that escalations in alcohol drinking that emerge following a stressor exposure, may be related to changes in sensitivity to the interoceptive effects of alcohol. Therefore, it is highly significant that we find potentiated sensitivity to the interoceptive effects of alcohol (as measured in a Pavlovian drug discrimination procedure) 2 weeks after TMT exposure, driven by the TMT-2 subgroup. We also find changes in GABAA and NMDA receptor gene expression, primary components of alcohol interoceptive effects, in the anterior insular cortex (aIC) and the nucleus accumbens core (AcbC), key circuitry that we have identified as underlying alcohol interoceptive effects. Lastly, there is a growing body of PTSD literature implicating dysregulated glutamatergic systems in PTSD pathology. We find that treatment with a metabotropic glutamate receptor subtype 3 (mGlu3) negative allosteric modulator (NAM) prior to TMT exposure attenuates some of the adaptations in GABAA and NMDA receptors. Overall, we hypothesize that 1) decreased activity of aICAcbC projections influenced by changes in GABAA and NMDA receptor expression, drive potentiated sensitivity to alcohol 2 weeks after TMT exposure, and 2) that mGlu3 signaling during TMT exposure contributes to these lasting changes. These innovative studies will allow for a broader understanding of the consequences of stressor exposure on alcohol interoceptive effects, as this can lead to a better understanding of interoceptive processing in PTSD, which may influence alcohol drinking.