Sex-specific effects of chronic stress prior to cocaine exposure on cue- vs drug-induced relapse after prolonged abstinence

The comorbidity between cocaine use disorder (CUD) and trauma/stressor-related disorders suggests a connection between neurophysiological changes induced by stress and those that lead to cocaine use. Due to the unexpected and sometimes uncontrollable nature and timing of stressful life events, their capacity to induce drug use poses a significant challenge for the administration of cocaine relapse therapy. This study aims to investigate the impact of chronic stress applied prior to cocaine acquisition on the development of cocaine-seeking behavior after different periods of drug abstinence in male and female rats. Rats were exposed to five days of inescapable footshocks (chronic stress) before undergoing extended access cocaine self-administration. Different groups then underwent forced abstinence periods of 1, 15, or 30 days before cue- and cocaine-induced seeking tests. Results showed that, after 30 days of abstinence, stressed females exhibited higher cue-induced, but not cocaine-induced seeking, compared to female controls and to males. In contrast, at 30 days, stressed males showed higher cocaine-, but not cue-induced seeking, versus controls. Such sex-dependent alterations in motivation and drug effects following prolonged abstinence highlight the importance of considering sex-specific differences in stress-related addiction research. Ongoing work should evaluate other stressors and self-administration models to elucidate neurophysiological and hormonal mechanisms underlying the incubation of cocaine craving. Identifying shared pathways between chronic stress and addiction could offer novel strategies for treating trauma/stress-related substance use disorders in a sex-specific manner.