Ibudilast perpetuates stress-induced anxiety-like behavior and fear memory expression in adult Sprague-Dawley rats

The relationship between neuroinflammatory processes and stress-related disorders is complex with neuroinflammation both resulting from, and contributing to, the stress response. Findings from both preclinical studies and clinical trials suggest that ibudilast (IBUD), a glial cell activation attenuator and phosphodiesterase inhibitor, has shown promise for mitigating the adverse behavioral effects of stress exposure and stress-related neuropsychiatric disorders. The objective of the present study was to determine the effect of IBUD administration on anxiety-like behavioral performance and fear memory expression in rats following stressor exposure. Here, adult male Sprague-Dawley rats were behaviorally tested in the elevated plus maze (EPM) and acoustic startle response tests 2 days before (day 1) and 2 days after (day 5) exposure to a stressor (inescapable footshock). Five days after stressor exposure, IBUD (0-10 mg/kg, i.p.) was administered 1 hour prior to a daily fear expression test session (days 8-11). Behavioral performance in the EPM and acoustic startle test was measured again on the following day (day 12). Following this, multiplex immunoassays were used to determine neuroinflammatory cytokine/chemokine levels in various brain regions. In a separate experiment, the effects of IBUD on locomotor activity and anxiety-like behavior were characterized in an open field test in rats with no history of stressor exposure. Stress exposure significantly (P < .05) reduced open arm exploration in the EPM-effects that were prolonged following IBUD treatment in a dose-dependent manner. Pretest administration of IBUD resulted in significantly (P < .05) greater freezing behavior during the fear expression tests with no evidence of fear extinction, whereas fear extinction was evident in vehicle-treated control rats. In nonstressed rats, IBUD reduced total locomotor activity and center exploration in the open field in a dose-dependent manner. Neuroinflammatory marker levels in the prefrontal cortex and amygdala were positively correlated with anxiety-like behavioral performance outcomes. Together, results suggest IBUD perpetuates stress-induced anxiety-like behavior and stress-associated fear memory expression (ie, hinders fear memory extinction). Further investigations into the interactions between IBUD administration and stressor exposure are needed to understand the implications of administering this drug in the context of stress exposure. SIGNIFICANCE STATEMENT: Ibudilast, a glial cell inhibitor and promising treatment candidate for various psychiatric disorders, was found to prolong fear expression and anxiety-like behavior in stress-exposed rats. Results suggest added characterization and consideration of its interactions with traumatic stress is needed.