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

Abstract

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 to 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, i.p.) 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 to 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.

Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity

“…1) on a fixed ratio-1 (FR-1) schedule of reinforcement nicotine was delivered during a 5.9-s infusion after a lever press on a designated active lever. Concurrent with each infusion, cue lights located above the levers were illuminated and a tone (2900 Hz) was presented, followed by a 20-s timeout period during which additional lever presses were recorded by had no programmed consequences (Goenaga et al 2019;Powell et al 2019;Gipson et al 2013a, b). An inactive lever was present at all times and presses on this lever were recorded but produced no programmed consequences at any time during the experiment.…”

“…1b). Extinction criteria were the same as those used in prior studies (Powell et al 2019;Goenaga et al 2019), where active lever pressing was below 30 presses and was significantly reduced compared to session one of extinction training.…”

Administration of N-acetylcysteine Plus Acetylsalicylic Acid Markedly Inhibits Nicotine Reinstatement Following Chronic Oral Nicotine Intake in Female Rats

“…Administration of N -acetylcysteine combined with an appropriate psychotherapy has been shown to be clinically effective in the treatment of the tobacco use disorder ( Prado et al, 2015 ), while several preclinical studies have shown that N -acetylcysteine inhibits cue-induced nicotine reinstatement ( Ramirez-Nino et al, 2013 ; Powell et al, 2019 ; Goenaga et al, 2020 ; Moro et al, 2020 ; Namba et al, 2020 ). Noteworthily, such an effect of N -acetylcysteine was blocked by microinjection of a GLT-1 antisense morpholino into the nucleus accumbens ( Namba et al, 2020 ).…”

Efficacy of N‐acetylcysteine in the prevention of alcohol relapse‐like drinking: Study in long‐term ethanol‐experienced male rats

“…In fact, at present, it is unknown which the molecular fraction of the drug is, that correlates with its pharmacological effects (Samuni et al, 2013). Moreover, several papers have recently reported sex differences in the psycho‐pharmacological effects of NAC under different indications and experimental paradigms (Goenaga et al, 2020; Monte et al., 2020). Hence, following the pipeline to the clinical evaluation of its alcohol anti‐relapse effect, it would be highly recommended to previously elucidate its molecular mechanism of action, to determine plasma NAC levels that correlate with their pharmacological response as well as to evaluate different NAC treatment regimens and doses focusing on the sex and gender differences previously reported for this drug.…”