Fear conditioning enhances subsequent cocaine self-administration and amygdala neuronal activity only in male rats.

Pathological fear resulting from traumatic experiences plays a critical role in the development of post-traumatic stress disorder (PTSD) and substance use disorders (SUDs), which frequently co-occur and worsen clinical outcomes. However, the neuronal mechanisms underlying fear memory interactions with drug-seeking behaviors remain poorly understood. In this study, we employed a novel rodent model combining Pavlovian fear conditioning and cocaine self-administration to investigate the behavioral effects and neuronal mechanisms underlying the interaction between fear conditioning and substance use. We hypothesized that pre-existing fear memories would enhance subsequent cocaine-related behaviors and alter neuronal activity in the basolateral amygdala (BLA), a key brain region involved in fear and reward memory processing. Our results showed that in male, but not female, rats prior cued fear conditioning increased cocaine intake and cue-induced cocaine seeking. These effects were specific to cue-dependent fear learning, as rats exposed to unpaired footshocks did not exhibit similar increases in cocaine-associated behaviors. Electrophysiological recordings from the BLA revealed distinct patterns of neuronal activity. Cocaine self-administration enhanced synaptic activity independent of footshock exposure, while fear conditioning increased intrinsic activity independent of cocaine exposure. These findings indicate that persistent fear memory enhances cocaine-mediated behaviors in male rats through distinct changes in the BLA, providing new insights into the neurobiological basis of comorbid PTSD and SUD.