Sex-specific effects of predator scent stress on fear, anxiety-like behavior and methamphetamine seeking in rats

Abstract

Methamphetamine use disorder (MUD) is frequently comorbid with other disorders, such as post-traumatic stress disorder (PTSD). Here, we used a rat model of PTSD+MUD to evaluate the influence of sex and stress on methamphetamine-seeking and on the activation of frontocortical regions during reinstatement of meth‑seeking. Male and female Sprague-Dawley rats were exposed to predator scent stress (PSS) or a control odor for 10 min, followed by anxiety testing one week later. Rats were re-exposed to the odor context three weeks after the exposure and then self-administered methamphetamine for 18 days. Rats underwent extinction training followed by a cue-primed reinstatement test. We found evidence for sex-specific fear and anxiety-like behaviors in PSS-exposed rats, with females exhibiting anxiety-like behavior in the elevated plus maze and males exhibiting increased acoustic startle response. There were no effects of PSS on methamphetamine intake, but males exhibited greater intake and cued reinstatement. PSS-exposed females reinstated methamphetamine-seeking, but control-exposed females did not, in parallel with higher reinstatement-induced infralimbic cortex c-Fos expression. PSS males exhibited reduced prelimbic and infralimbic c-Fos relative to control-exposed males despite similar reinstatement behavior. To identify relationships between fear and anxiety-like behavior, cortical activation, and meth‑seeking, a principal components analysis was used. The analysis revealed that discrete behaviors exhibited during PSS exposure (locomotion and digging), together with select markers of anxiety (reduced startle response), predict methamphetamine intake and seeking. Altogether, these findings suggest that a specific set of stress-reactive and anxiety-like behaviors contribute to long-term resilience to drug-taking and seeking in a sex-specific manner.