mGluR2/3 mediates short‐term control of nicotine‐seeking by acute systemic N‐acetylcysteine

Abstract

Chronic self-administration of nicotine induces maladaptive changes in the cortico-accumbal glutamate (Glu) network. Consequently, re-exposure to nicotine-associated cues raises extracellular Glu in the nucleus accumbens reinstating drug-seeking. Restoring basal concentrations of extracellular Glu, thereby increasing tonic activation of the presynaptic group II metabotropic Glu receptors (mGluR2/3) with N-acetylcysteine (N-AC), might offer a valid therapeutic approach for maintaining smoking abstinence. Although N-AC modulates nicotine-seeking behavior by drug-associated stimuli in abstinent rats, it is still unclear whether it occurs through activation of mGluR2/3. Male Wistar rats were trained to associate discriminative stimuli (S s) with the availability of intravenous nicotine (0.03 mg/kg/65 µl/2-second/infusion) or oral saccharin (100 µl of 50 mg/l) self-administration versus non-reward. Reinforced response was followed by a cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent lever press extinction, without reinforcers, S s and CSs. Re-exposure to nicotine or saccharin S /CS , but not non-reward S /CS , revived responding on the previously reinforced lever. Acute N-AC, 100 but not 60 or 30 mg/kg i.p., reduced cue-induced nicotine-seeking. N-AC 100 mg/kg did not modify cue-induced saccharin-seeking behavior or influenced locomotor activity. Blocking mGluR2/3 with the selective antagonist LY341495, 1 mg/kg i.p., completely prevented the antirelapse activity of N-AC. The finding that N-AC prevents cue-induced nicotine-seeking by stimulating mGluR2/3 might indicate a therapeutic opportunity for acute cue-controlled nicotine-seeking. Future studies could evaluate the persistent effects of chronic N-AC in promoting enduring suppression of nicotine-cue conditioned responding.

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

“…The interactive effect of pre-session menthol administration as an occasion setter and discrete nicotine-conditioned cue is consistent with results that were obtained in rats that were trained to self-administer other drugs of abuse (e.g., cocaine and alcohol) or natural rewards (e.g., Cervo et al, 2013; Katner et al, 1999; Moro et al, 2016; Weiss et al, 2001). It could be postulated that pre-session menthol administration produced an interoceptive state (an occasion setter) that signaled the availability of nicotine reward and brought the rats into contact with the lever while the response-contingent presentation of the cue then served as conditioned reinforcement to support responding on the lever.…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…Experiments in rats evaluating the effects of mGlu 2/3 activation on reinstatement of drug seeking by cues previously associated with drug self-administration show that mGlu 2/3 activation attenuates reinstated seeking of cocaine (Lu et al, 2007; Cannella et al, 2013), methamphetamine (Kufahl et al, 2013), alcohol (Zhao et al, 2006) and nicotine (Liechti et al, 2007; Moro et al, 2016). LY379268 also reduces context-induced reinstatement of heroin seeking (Bossert et al, 2004) and drug priming-induced reinstatement of methamphetamine seeking (Kufahl et al, 2013).…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…However, strategies aimed at increasing extracellular glutamate levels in the brain during nicotine withdrawal have produced mixed effects on nicotine-seeking behavior. For example, systemic administration of N-acetylcysteine, a cystine pro-drug that increases the activity of the xCT resulting in increased extracellular glutamate levels, has been shown to attenuate [87] or have no effect [88] on the reinstatement of nicotine seeking. With regard to the clinical literature, N-acetylcysteine does not produce a therapeutically robust response in human smokers.…”

“…Moreover, nicotine self-administration is associated with decreased mGlu2/3 receptor expression in the NAc shell [93]. Additional changes in the cysteine/glutamate exchange and glial glutamate exchange systems, important regulators of glutamate release, have also been observed after nicotine exposure [84, 86, 88]. For instance, acute activation of the cystine/glutamate exchange (xCT) system with N-acetylcysteine attenuates cue-induced nicotine reinstatement [87], effects that are mediated by mGluR 2/3 [88], although results describing the effective dose of N-acetylcysteine to suppress reinstatement are mixed.…”

“…Additional changes in the cysteine/glutamate exchange and glial glutamate exchange systems, important regulators of glutamate release, have also been observed after nicotine exposure [84, 86, 88]. For instance, acute activation of the cystine/glutamate exchange (xCT) system with N-acetylcysteine attenuates cue-induced nicotine reinstatement [87], effects that are mediated by mGluR 2/3 [88], although results describing the effective dose of N-acetylcysteine to suppress reinstatement are mixed. Importantly, N-acetylcysteine has been shown to reduce daily cigarettes smoked in smokers [86], especially if combined with varenicline [89].…”