Adolescent stress avoidance influences cue-induced heroin seeking and chaperonin gene expression in the dorsal striatum of adult female rats.

Females remain underrepresented in opioid use disorder (OUD) research, particularly regarding dorsal striatal neuroadaptations. Chaperonins seem to play a role in opioid-induced neural plasticity, yet their contribution to OUD-related changes in the dorsal striatum (DS) remains poorly understood. Given known sex differences in opioid sensitivity, it is important to determine how chaperonin expression contributes to OUD-related adaptations in females. To investigate how stressor controllability during adolescence influences heroin self-administration (SA) and responses to drug-paired cues in adult female rats, focusing on differential gene expression of chaperonins in the DS. Female rats were exposed to stress avoidance training during adolescence. These rats underwent, in adulthood, heroin SA followed by cue-induced seeking tests after early and prolonged abstinence. Heroin intake during SA was similar between stress-avoiding and stress-naïve females ( = 8/group,  = .89). However, stress-avoiding females exhibited reduced drug-seeking behavior in response to drug cues at 14 days of abstinence compared to controls ( < .05; d = 0.99), suggesting a protective effect of stressor controllability. qPCR showed that the gene expression of Hspa5, a heat shock protein, was elevated in the dorsolateral striatum (DLS) of stress-avoiding females ( < .05; Cohen d > 1.0). Hspb1 gene expression was upregulated in the dorsomedial striatum (DMS) of stress-avoiding females ( < .05; d > 1.0). These findings suggest that chaperonin dysregulation links opioid exposure and stress avoidance conditions. Increased Hspa5 in the DLS and Hspb1 in the DMS may contribute to the observed behavioral differences supporting further preclinical investigation with clinical implications for stress and OUD.