Combined stress and alcohol exposure: Synergistic effects on alcohol-seeking behaviors and neuroinflammation.

Posttraumatic stress disorder and alcohol use disorder are frequently co-occurring conditions that can create a synergistic effect, worsening symptoms of both disorders. This heightened comorbidity suggests a shared pathological basis rooted in maladaptive learning process that amplifies drug- and fear-related behaviors. The present study investigates the combined effects of stress and chronic alcohol exposure on alcohol-seeking behaviors and neuroinflammation in male and female rats. Additionally, we investigate the potential of metabotropic glutamate receptor type 5 (mGlu5) modulation as a therapeutic strategy for this co-occurring condition. Adult Wistar rats received restraint stress (Stress), chronic intermittent ethanol (CIE) vapor inhalation, both (Stress + CIE), or no exposure (Control). We assessed ethanol self-administration, extinction learning, reinstatement of alcohol-seeking behavior, and tumor necrosis factor-⍺ protein expression in the infralimbic (IfL) and prelimbic subregions of the prefrontal cortex. Additionally, we examined the effects of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), a mGlu5 positive allosteric modulator, on these outcomes. Stress + CIE exposure significantly increased ethanol self-administration, impaired extinction learning, and heightened reinstatement compared with all other groups. Interestingly, CDPPB treatment improved extinction learning and reduced reinstatement in males but not females. Furthermore, Stress + CIE exposure elevated tumor necrosis factor-⍺ levels specifically in the IfL, and CDPPB normalized this effect in males only. The current study demonstrates a synergistic effect of stress and alcohol exposure on alcohol-seeking behaviors and suggests a potential role for neuroinflammation in the IfL. Our findings also highlight sex-specific therapeutic strategies targeting mGlu5 signaling to prevent relapse in individuals with comorbid posttraumatic stress disorder and alcohol use disorder. SIGNIFICANCE STATEMENT: This research demonstrates that combined stress and alcohol exposure worsen alcohol-seeking behavior in rats, potentially via neuroinflammation in the infralimbic cortex, a region known to be involved in extinction learning. Notably, metabotropic glutamate receptor type 5 modulation was able to prevent alcohol-seeking behaviors and inflammation in a sex-dependent manner. These findings pave the way for developing personalized treatments to prevent relapse in individuals with co-occurring posttraumatic stress disorder/alcohol use disorder.