Despite the high rates of comorbidity between alcohol use disorder (AUD) and post traumatic stress disorder (PTSD) there is a substantial gap in our knowledge concerning how these disorders interact to cause significant deficits in behavior and cognition. Specifically, there has been little investigation into how the neural mechanisms underlying PTSD drive subsequent alcohol use. Conversely, the impact of alcohol abuse on PTSD-related fear memories is not well known. Both clinical and pre-clinical findings show a complex behavioral interaction between alcohol abuse and PTSD. For example, exposure to PTSD-related cues increases anxiety that promotes alcohol abuse, while this repeated alcohol abuse leads to an enhancement of PTSD memories making them more resistant to treatment. This pattern results in a damaging cycle that consists of PTSD-induced alcohol consumption that strengthens PTSD memories, which, in turn, promote escalated alcohol abuse ultimately leading to an AUD. The establishment of AUD/PTSD comorbidity leads to neurobiological changes resulting in cognitive deficits that further sustain alcohol abuse and exaggerated responses to fear cues. Furthermore, there is little known about mechanisms underlying sex differences associated with co-occurring AUD/PTSD. Clinical findings indicate that the prevalence of PTSD is twice as high in women as in men and the motives to use alcohol differ between men and women with PTSD. With the use of established animal models, our preliminary data demonstrate that exposure to chronic intermittent ethanol (CIE) after fear conditioning leads to deficits in the extinction of fear-related behaviors, increased alcohol consumption in response to fear cues, and deficits in cognitive flexibility. In addition, we show that modulation of mGluR5 attenuates CIE-induced deficits in fear extinction learning suggesting that glutamatergic mechanisms play a role in these processes. We have designed a comprehensive set of studies to test the overarching hypothesis of this proposal that the combination of CIE/Fear conditioning alters specific neurocircuitry involved in learning, extinction, and memory reconsolidation. The proposed studies involve a multifaceted approach including behavioral pharmacology and optogenetics to test the following hypotheses:
Aim 1) CIE exposure alters fear memory extinction that is attenuated through mGluR5 potentiation in regions of the PFC and amygdala;
Aim 2) Repeated exposure to fear cues diminishes PFC function leading to increased alcohol intake in a model of AUD/PTSD;
Aim 3) Disruption of a fear memory during reconsolidation can attenuate CIE-induced deficits in fear extinction;
Aim 4) The combination of CIE/Fear conditioning leads to deficits in executive function that mediate flexible behavior. Findings from these studies will contribute to a better understanding of the neural mechanisms underlying the complex interactions between AUD and PTSD that contribute to significant behavioral and cognitive deficits. They will also provide potential therapeutic targets that will aide in the development of more effective treatments for AUD/PTSD comorbidity.

Public Health Relevance

The data collected from the proposed studies will increase not only our understanding of the behaviors associated with alcoholism/PTSD comorbidity, but also the brain changes that result from these extraordinarily motivating alcohol- and fear-related memories. As a result, there is great potential to identify novel therapeutic targets for treatment of these commonly co-occurring disorders.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Grakalic, Ivana
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Medical University of South Carolina
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Cannady, Reginald; McGonigal, Justin T; Newsom, Ryan J et al. (2017) Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior. J Neurosci 37:4359-4369
Gass, J T; McGonigal, J T; Chandler, L J (2017) Deficits in the extinction of ethanol-seeking behavior following chronic intermittent ethanol exposure are attenuated with positive allosteric modulation of mGlu5. Neuropharmacology 113:198-205
Macht, Victoria A; Kelly, Sandra J; Gass, Justin T (2017) Sex-specific effects of developmental alcohol exposure on cocaine-induced place preference in adulthood. Behav Brain Res 332:259-268