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.
Bibliographical noteFunding Information:
The authors thank Dr Peter Kalivas for use of equipment and morpholino experimental design. The authors thank Armani Del Franco, Joseph McCallum, Yeyoung Jun, Sandy Phan, Matt Miller, Jose Pi?a, Hanaa Ulangkaya, Vincent Carfagno, and Neringa Stankeviciute for their technical assistance. We also thank the laboratories of Dr M. Foster Olive and Dr Heather A. Bimonte-Nelson for providing equipment necessary for western blot experiments, as well as Dr Scott J. Russo for kindly gifting us the HSV-IKK vectors. We also thank Dr Jonna M. Leyrer-Jackson for providing helpful feedback on this manuscript. This work was supported by National Institutes of Health grants DA 036569 and -S1, DA044479, and DA045881 (to CDG).
© 2019 Society for the Study of Addiction