Accumbens neuroimmune signaling and dysregulation of astrocytic glutamate transport underlie conditioned nicotine‐seeking behavior

Abstract

Nicotine self‐administration is associated with decreased expression of the glial glutamate transporter (GLT‐1) and the cystine‐glutamate exchange protein xCT within the nucleus accumbens core (NAcore). N‐acetylcysteine (NAC) has been shown to restore these proteins in a rodent model of drug addiction and relapse. However, the specific molecular mechanisms driving its inhibitory effects on cue‐induced nicotine reinstatement are unknown. Here, we confirm that extinction of nicotine‐seeking behavior is associated with impaired NAcore GLT‐1 function and expression and demonstrates that reinstatement of nicotine seeking rapidly enhances membrane fraction GLT‐1 expression. Extinction and cue‐induced reinstatement of nicotine seeking was also associated with increased tumor necrosis factor alpha (TNFα) and decreased glial fibrillary acidic protein (GFAP) expression in the NAcore. NAC treatment (100 mg/kg/day, i.p., for 5 d) inhibited cue‐induced nicotine seeking and suppressed AMPA to NMDA current ratios, suggesting that NAC reduces NAcore postsynaptic excitability. In separate experiments, rats received NAC and an antisense vivo‐morpholino to selectively suppress GLT‐1 expression in the NAcore during extinction and were subsequently tested for cue‐induced reinstatement of nicotine seeking. NAC treatment rescued NAcore GLT‐1 expression and attenuated cue‐induced nicotine seeking, which was blocked by GLT‐1 antisense. NAC also reduced TNFα expression in the NAcore. Viral manipulation of the NF‐κB pathway, which is downstream of TNFα, revealed that cue‐induced nicotine seeking is regulated by NF‐κB pathway signaling in the NAcore independent of GLT‐1 expression. Ultimately, these results are the first to show that immunomodulatory mechanisms may regulate known nicotine‐induced alterations in glutamatergic plasticity that mediate cue‐induced nicotine‐seeking behavior.

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

“…In mice, microglial morphology changes in striatal tissues have been reported following chronic treatment with nicotine and undergoing withdrawn, which were associated with the release of pro-inflammatory cytokines and increase in ROS ( Adeluyi et al, 2019 ; Saravia et al, 2019 ). Increased TNFα levels have been reported in the nucleus accumbens of rats during cue-induced nicotine seeking ( Namba et al, 2020 ), and an increased TNFα gene expression has also been described in the prefrontal cortex of nicotine- and cigarette smoke-exposed rats ( Lau et al, 2012 ). It is well established that through the activation and nuclear translocation of the transcription factor NF-κB, TNFα induces the synthesis of various pro-inflammatory cytokines, including IL-6 ( Shimizu et al, 1990 ; Kunsch and Rosen, 1993 ; Ping et al, 1996 ).…”

“…Recent studies suggest a likely role of astrocytes and microglia in nicotine addiction. Cue-induced reinstatement of nicotine self-administration and chronic nicotine exposure in rats is associated with increased tumor necrosis factor-alpha (TNFα) levels in the prefrontal cortex and nucleus accumbens ( Royal et al, 2018 ; Namba et al, 2020 ). Consistent with the above, studies in the authors’ laboratory showed that both chronic nicotine intake and nicotine-conditioned place preference were associated with changes in markers of glial inflammation, including an increased length and thickness of astrocytic processes and increased microglial density (cell number/area) in the rat hippocampus ( Quintanilla et al, 2018 , 2019 ).…”

“…The above findings suggest that both antioxidants and anti-inflammatory agents, via the restoration of normal glutamate homeostasis, would reduce the cue-induced reinstatement of nicotine-seeking behavior. N -acetylcysteine, an antioxidant and a prodrug in the generation of cysteine, has been reported to inhibit cue-induced nicotine seeking, an effect that was accompanied by normalization of the reduced GLT-1 expression induced by nicotine self-administration in the nucleus accumbens ( Namba et al, 2020 ). The finding that N -acetylcysteine also activates the xCT cystine/glutamate transporter ( Baker et al, 2003 ; Knackstedt et al, 2009 ; Alasmari et al, 2017 ) suggests that N -acetylcysteine could normalize the nicotine-induced overflow of glutamate seen in the nucleus accumbens during cue-induced nicotine reinstatement ( Gipson et al, 2013 ), both by increasing the xCT cystine-glutamate transporter levels and importantly by increasing cystine levels a substrate for the antiporter, thus activating the inhibitory presynaptic metabotropic mGlu2/3 receptor.…”

Accumbens Cholinergic Interneurons Mediate Cue-Induced Nicotine Seeking and Associated Glutamatergic Plasticity

“…and xylazine (8 mg/kg, i.m.) and underwent surgical implantation of intravenous jugular catheters as well as stereotaxically implanted guide cannulae targeting the NAcore as previously described ( Leyrer-Jackson et al, 2020 ; Namba et al, 2020 ). Intravenous jugular catheters (made from polyurethane tubing; BTPU-040; Instech) were inserted 2.5–3 cm into the right jugular vein and were threaded subcutaneously to the posterior side of the animal where it was connected to an indwelling back port (Instech).…”

Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

“…and xylazine (8 mg/kg, i.m.) and underwent surgical implantation of intravenous jugular catheters as well as stereotaxically implanted guide cannulae targeting the NAcore as previously described [30,31].…”