Marked sex differences are observed in heroin acquisition and affective states in rats but converge to similar levels of footshock stress-induced reinstatement

RATIONALE: Negative affective states, particularly those driven by stress, are known to trigger the development of opioid addiction and relapse. Previous preclinical research has identified sex differences in vulnerability to stress and resulting compulsion to consume drugs. OBJECTIVES: To investigate sex differences in heroin self-administration, stress-induced reinstatement, and related affective state in rats. METHODS: 22- and 50-kHz ultrasonic vocalizations (USVs), reflecting negative and positive affective state, respectively, were recorded during a heroin self-administration and footshock stress-induced reinstatement model in Sprague-Dawley rats. We hypothesized that females would display increased vulnerability towards heroin use disorder-like profiles. RESULTS: Females showed elevated acquisition of heroin self-administration, but behavioral patterns were not linked to gonadal hormone levels. During heroin acquisition, males emitted significantly more 50 kHz calls compared to females, suggesting positive reinforcement-driven intake. We observed successful stress-induced reinstatement in both sexes, with males and females reaching similar overall numbers of active lever presses by the end of the reinstatement session. However, they appear to do so via different strategies, with females displaying "frontloading", rapidly lever pressing in the first 20 min of the behavioral session, perhaps indicating differential stress vulnerability or differences in underlying neural encoding of stressor/reward value. Successful stress-induced reinstatement in both sexes is accompanied by a distinct pattern of USVs, whereby a high number of anticipatory 50 kHz calls are emitted prior to the onset of reinstatement sessions, followed by 22 kHz call production by males during reinstatement sessions, perhaps reflecting drug seeking to relieve negative affect or negative affective responses to drug unavailability. CONCLUSIONS: These findings indicate sex-specific vulnerabilities to development of heroin use disorders.