Lasting reduction of nicotine‐seeking behavior by chronic N‐acetylcysteine during experimental cue‐exposure therapy

Abstract

Nicotine‐associated cues can trigger reinstatement in humans as well as in animal models of drug addiction. To date, no behavioral intervention or pharmacological treatment has been effective in preventing relapse in the long term. A large body of evidence indicates that N‐acetylcysteine (N‐AC) blunts the activation of glutamatergic (GLUergic) neurons in the nucleus accumbens (Nacc) associated with reinstatement. We evaluated the effect of an experimental cue exposure therapy (eCET) alone or in combination with N‐AC to verify whether restoring GLU homeostasis enhances extinction of nicotine‐associated cues. Rats were trained to associate discriminative stimuli with intravenous nicotine or saline self‐administration. Reinforced response was followed by cue signals. After rats met the self‐administration criteria, the lasting anti‐relapse activity of i.p. N‐AC or vehicle was assessed in three different experimental conditions after 14 days of treatment: treatment + eCET; treatment + lever‐presses extinction (LP‐EXT); and treatment + abstinence. N‐AC 100 mg/kg, but not 60 mg/kg, induced anti‐relapse activity that persisted 50 days after treatment only when paired with either LP‐EXT or eCET with the greater activity found in the latter condition. To identify potential mechanisms for behavioral results, separate groups of rats that received either N‐AC or vehicle + eCET were killed at different time points for Nacc Western‐blot analysis. Seven days after treatment, chronic N‐AC restored the expression of proteins crucial for GLU homeostasis, while at 50 days, it increased the expression of type II metabotropic GLU receptors. These results suggest that N‐AC treatment in combination with eCET may offer a novel strategy to prevent relapse in nicotine addiction.

Potential of Glial Cell Modulators in the Management of Substance Use Disorders

“…In mice, NAC decreased nicotine's rewarding effects [354]. In rats, NAC also reduced nicotine self-administration and cue-induced reinstatement of nicotine seeking [355,356], reduced nicotine withdrawal [357], and enhanced extinction of nicotine-associated cues [358]. Like some studies above, Powell and Colleagues (2019) found that NAC decreased extinction responding and reduced reinstatement of nicotine seeking.…”

Differential Effects of Nicotine, Alcohol, and Coexposure on Neuroimmune-Related Protein and Gene Expression in Corticolimbic Brain Regions of Rats

“…This decision was made in order to have the greatest control over exposure/dosage. However, the predominant source of nicotine use is still traditional tobacco which can have very different effects on neuroimmune activation and inflammation compared to nicotine alone. , Moreover, the anti-inflammatory compound N -acetylcysteine decreases nicotine self-administration and nicotine-seeking behavior. − Taken together, these studies show chronic nicotine exposure may regionally counteract unique proinflammatory effects of alcohol in blood plasma and the AcbC (broadly, particularly in females) while also influencing other corticolimbic brain regions (mPFC-PL, TLR3/STAT3 in males) relevant to drug seeking and taking behaviors. These findings give further insight into the role that sex and the neuroimmune system play in modulating neurobiology in nicotine and alcohol co-abuse.…”

N-acetylcysteine in substance use disorder: a lesson from preclinical and clinical research

“…Furthermore, NAC blocked mouse behaviors associated with nicotine somatic withdrawal signs, but not anxiety developed during nicotine withdrawal [36]. Other proofs that NAC may have high clinical utility in NUD were provided in reports showing the drug reducing efficacy in models assessing nicotine seeking and reinstatement behaviors [35,[38][39][40][41][42] (Table 1). Of note, subchronic NAC administration (< 4 days) was found as ineffective in reducing cue-induced reinstatement and in restoring nicotine-evoked disruption in dendritic spine morphology and glutamatergic transcripts in the accumbal core region [42].…”

“…Of note, subchronic NAC administration (< 4 days) was found as ineffective in reducing cue-induced reinstatement and in restoring nicotine-evoked disruption in dendritic spine morphology and glutamatergic transcripts in the accumbal core region [ 42 ]. In other molecular and neurochemical assays combined with behavioral evaluations, it was found that NAC effectively reversed a drop in the accumbal x c − system and GLT-1, seen 7 or 50 days after cue-induced reinstatement, respectively [ 39 , 40 ]. The latter paper even reports the anti-relapse activity of NAC with cue exposure therapy that persisted 50 days after drug treatment, supporting the idea of adopting a combined strategy for treating NUD.…”