mGlu5 modulation prevents and attenuates deficits in a model of PTSD/AUD comorbidity

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Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two of the most common mental health disorders and are highly comorbid. Unfortunately, the incidence rate of PTSD is significantly greater in the Veteran population. Even worse, Veterans with PTSD are almost twice as likely to develop issues with alcohol abuse and AUD. Both disorders are thought to arise from “aberrant learning” resulting in deficits in the ability to adjust behavior (e.g. impaired cognitive flexibility) that ultimately drives continued drug abuse or fear behavior. Recent evidence further suggests that the neurocircuitry of fear and anxiety disorders and the neurocircuitry of drug addiction have many common characteristics. A prominent feature of both disorders is dysfunctional top- down control of behavior by the prefrontal cortex (PFC). Alterations in prefrontal-mediated cognitive processes that regulate behavior likely contribute to the high comorbidity of the disorders. Of particular clinical importance, this comorbidity is associated with significantly worse prognosis of recovery when compared to non-comorbid individuals. There is also evidence that PTSD symptoms are a significant risk factor for development of AUD that, in turn, interfere with PTSD treatment and contributes to increased functional impairment. This application will examine three separate aims that contain novel questions about PTSD/AUD comorbidity and utilize state-of- the-art techniques to answer them. We propose that the combination of stress and alcohol exposure alters many factors associated with the disorder including drug use, relapse behavior, cognitive deficits, and vulnerability to future traumas. The overarching hypothesis of this proposal is that stress and alcohol exposure alter subsequent drug, cognitive, and stress-related behaviors through glutamatergic mechanisms in subregions of the PFC. To test this, we will use a multi-faceted approach that incorporates behavioral pharmacology, optogenetics, and telemetry to investigate the interactions between a traumatic stressor and chronic alcohol exposure to identify certain brain mechanisms that may mediate the resulting changes in behavior. Aim 1 will examine the result of stress and chronic exposure on alcohol-related behaviors including intake, relapse-like behavior, and consolidation of extinction memories. We will use recent developments in technology to monitor some of the same measurements in rats that are often used in human studies. Radiotelemetry sensors will be implanted in the rats to determine whether stress-induced alterations in alcohol behaviors are associated with deficits in heart rate variability (HRV: a physiological measure that reflects coping ability). In this aim, and the remaining aims, will attempt to either attenuate or prevent stress- and alcohol-induced behavioral deficits through manipulation of glutamatergic signaling in the PFC and its projections to other brain regions. Finally, to better understand the neural mechanisms involved we will measure inflammatory makers in the PFC. Aim 2 will examine a component of PTSD/AUD that has not been investigated sufficiently in the field. These are cognitive-based tasks that measure behaviors often seen in the clinical population such as changes in normal decision-making processes. Thus, we will assess the impact of stress and chronic alcohol on future “risky” behaviors that often precede drug abuse and the development of PTSD. In Aim 3 we will determine how exposure to the combination of stress and chronic alcohol leads to significant increases in neuroinflammation in specific brain regions. This is critical because it provides a potential mechanism for the behavioral effects observed in this population. Importantly, we have data showing that modulation of mGlu5 can reduce stress/alcohol-induced neuroinflammation and this provides a novel target for drug treatment. When combined, this set of experiments lays the foundation to examine PTSD/AUD from multiple perspectives, highlight potential neural mechanisms, and develop novel treatment options.