Targeting PAI-1 with TM5441 Mitigates Chronic Social Stress-Induced Anxiety-Like Behavior and Stress-Induced Increases in Ethanol Intake and Preference.

Chronic stress promotes alcohol use and relapse, yet the mechanisms linking stress-induced anxiety to excessive ethanol consumption remain poorly understood. Plasminogen activator inhibitor-1 (PAI-1), a stress-responsive regulator of neuroplasticity, has recently emerged as a potential therapeutic target; however, its role in stress-induced alcohol-related behaviors remains unknown. This study investigated whether TM5441, a selective inhibitor of plasminogen activator inhibitor-1 (PAI-1), modulates anxiety-like behavior and ethanol consumption following chronic social stress. Male mice were subjected to social defeat chronic stress (SDCS) and treated with TM5441. Behavioral assessments included the elevated plus maze (EPM), open field test (OFT), and two-bottle choice paradigms to assess voluntary intake of ethanol, saccharin, and quinine. Blood ethanol concentration (BEC) was measured to evaluate pharmacokinetic parameters. TM5441 significantly attenuated SDCS-induced anxiety-like behaviors and restored stress-induced increases in ethanol intake and preference toward control levels. These effects were specific to ethanol, as neither TM5441 nor stress altered saccharin or quinine consumption. Importantly, pharmacokinetic analyses revealed no differences in ethanol absorption or clearance, and BEC did not correlate with ethanol intake or preference, indicating that the observed behavioral effects are unlikely to result from differences in ethanol pharmacokinetics. Correlational analyses supported a functional link between anxiety-like behavior and increased ethanol consumption under stress. Together, these findings suggest that PAI-1 may contribute to the link between stress-induced anxiety and alcohol consumption and support further investigation of PAI-1 as a potential target for stress-related alcohol use disorders.