Naltrexone alters alcohol self-administration behaviors and hypothalamic-pituitary-adrenal axis activity in a sex-dependent manner in rats

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Background:The mu-opioid antagonist, naltrexone (NTX), is a FDA-approved treatment for alcohol use disorder (AUD); however, the data on whether it differentially affects males vs. females are mixed. NTX increases hypothalamic-pituitary-adrenal (HPA) axis activity that associates with subjective responses to alcohol and craving in individuals with AUD. The present study tested for sex differences in the ability of NTX to decrease appetitive and consummatory behaviors in rats in operant alcohol self-administration. Because the opioid system and HPA axis are sexually dimorphic, we examined NTX's effect on adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels.Methods:Male and female Sprague-Dawley rats (n's=6–8) were trained to lever press for alcohol (10% v/v) under a fixed-ratio 2 schedule of reinforcement. NTX doses (0, 0.1–10mg/kg) were assessed in tests conducted under a progressive ratio schedule of reinforcement. Separate groups of alcohol and water drinking rats (n's=8) were used to assess NTX's (10mg/kg) effects on HPA axis hormones.Results:NTX decreased consummatory behaviors for alcohol in a dose-related manner, but not appetitive behaviors in males. In females, NTX decreased appetitive behaviors for alcohol in a dose-dependent manner, but only decreased consummatory behaviors at the highest (10mg/kg) NTX dose. NTX increased ACTH levels in alcohol drinking females in diestrus, but not in other groups. However, NTX increased CORT levels for longer durations in alcohol drinking males relative to alcohol drinking females in diestrus.Conclusions:Our findings suggest that NTX selectively reduces consummatory behaviors for alcohol in males and appetitive behaviors in females, while also showing differential sex effects on HPA hormones.HIGHLIGHTSNTX dose-dependently decreased appetitive behaviors for alcohol in females.NTX dose-dependently decreased consummatory behaviors for alcohol in males.NTX increased CORT levels for a longer duration in males relative to females.

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