N‐acetylcysteine yields sex‐specific efficacy for cue‐induced reinstatement of nicotine seeking

• Published in: Addiction biology Vol. 25; no. 1; pp. e12711 - n/a
• Main Authors: Goenaga, Julianna, Powell, Gregory L., Leyrer‐Jackson, Jonna M., Piña, Jose, Phan, Sandy, Prakapenka, Alesia V., Koebele, Stephanie V., Namba, Mark D., McClure, Erin A., Bimonte‐Nelson, Heather A., Gipson, Cassandra D.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2020
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Animal models; Animals; Craving - drug effects; Cues; Disease Models, Animal; Drug therapy; Drug-Seeking Behavior - drug effects; Estrous Cycle; Estrus cycle; Extinction behavior; Extinction, Psychological; Female; Females; Free Radical Scavengers - pharmacology; Gender differences; Glutamatergic transmission; Male; Menstrual cycle; Nicotine; N‐acetylcysteine; Rats; Rats, Sprague-Dawley; Reinstatement; Rodents; Sex; Sex differences; Sex Factors; smoking; Substance Withdrawal Syndrome - physiopathology; Tobacco Use Disorder - drug therapy; Tobacco Use Disorder - physiopathology; nicotine; estrous cycle; sex differences; smoking; N-acetylcysteine
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12711

Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N‐Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex‐specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue‐induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle–dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex‐specific effect of NAC. Furthermore, for females, both vehicle‐ and NAC‐treated groups significantly reinstated nicotine‐seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers. N‐acetylcysteine (NAC) is a Food and Drug Administration (FDA)‐approved pharmacotherapy used in the treatment of substance use disorders. We examined how sex differences impact preclinical NAC treatment prior to reinstatement of cued nicotine‐seeking behavior, as many studies fail to assess sex differences in the treatment of nicotine use disorder. NAC reduced nicotine seeking in male rats but did not reduce nicotine seeking in females regardless of estrous cycle phase. Our findings indicate that NAC treatment has sex‐specific efficacy, which may impact testing during clinical trials.