Sex Differences in μ-Opioid Receptor Regulation of the Rat Locus Coeruleus and Their Cognitive Consequences

Stress-related neuropsychiatric pathologies are more prevalent in females compared with males. An important component of the stress response is activation of the locus coeruleus (LC)–norepinephrine system. Because LC activation is tempered by endogenous opioid release during stress, the magnitude of opioid regulation of the LC could determine stress vulnerability. Here we report convergent evidence for decreased μ-opioid receptor (MOR) function in the female rat LC. The selective MOR agonist, DAMGO (10 pg), completely inhibited LC discharge of male but not female rats and DAMGO (30 pg) produced no further inhibition of female LC neurons. Consistent with a decreased maximum DAMGO response, MOR protein and mRNA expression were decreased in female compared with male LC. These molecular and cellular sex differences were associated with sexually distinct effects of LC-MOR activation on cognitive processing in an operant strategy-shifting task. Although DAMGO (10 pg intra-LC) increased the number of trials to reach criterion for both sexes, it increased the duration to complete the task and the total number of errors selectively in males. Specifically, DAMGO increased premature responses, regressive errors, and random errors in males and perseverative errors in females. The sexually distinct cognitive consequences of activating LC-MOR may contribute to sex differences in opioid abuse patterns and may guide sex-specific therapies. Finally, given evidence that endogenous opioids restrain stress-induced LC activation and promote recovery of activity to pre-stress levels, decreased MOR function in the female LC could contribute to LC-NE overactivity that underlies the hyperarousal symptoms of stress-related psychiatric diseases.