Conclusions & Future Directions N-acetylcysteine (NAC) Inhibits Cue-Induced Nicotine Seeking Through a GLT-1 Dependent Mechanism Mark D Namba1, Gregory Powell1,2, Julianna Goenaga1, Armani Del Franco2, Joseph McCallum2, Cassandra D Gipson1 1Department of Psychology, Arizona State University, 2School of Life Science, Arizona State University Results Rationale 2. 1. Dysregulation of glutamatergic signaling is a neuroadaptation induced by drugs of abuse. The glial glutamate transporter 1 (GLT-1) is down-regulated following chronic exposure to nicotine1. NAC inhibits cue-induced cocaine seeking in a GLT-1-dependent manner2. However, the mechanisms through which it inhibits cue-induced nicotine seeking is unknown. NAC may also inhibit drug seeking through modulation of neuroinflammatory signaling. Does chronic NAC inhibit cue-induced nicotine reinstatement by restoring GLT-1? Methods & Materials Figure 2. Cue-induced nicotine reinstatement. NAC significantly attenuated active lever pressing relative to saline controls. This effect was blocked by administration of GLT-1 antisense vivo-morpholino. *P < 0.05, comparing each treatment group to the CTRL-NAC group Figure 1. Nicotine self-administration and extinction training. Following self-administration, rats were placed into extinction training and received vivo-morpholino between days 10 and 12, followed by NAC (100 mg/kg, i.p.) or saline injections between days 12 and 16. 3A. 3B. Conclusions & Future Directions NAC inhibits cue-induced nicotine reinstatement through a GLT-1 dependent mechanism. NAC increased GLT-1 expression in the NAcore. NAC decreased cue-induced reinstatement Inhibition of GLT-1 expression in the NAcore with an antisense vivo-morpholino blocked the restoration of GLT-1 via NAC and prevented NAC from attenuating reinstatement. NAC might decrease inflammatory signaling by inhibiting IKK expression, which may inhibit NF-κB signaling. Future studies will utilize an HSV to induce a dominant negative mutant or constitutively active form of IKK in order to examine its effects on drug-induced neurobehavioral plasticity. Male Sprague-Dawley rats were trained to self administer nicotine (0.02 mg/kg/infusion) on an FR-1 schedule. Following self-administration, rats entered extinction, where they received GLT-1 vivo-morpholino from days 10-12 (30 pmol/injection/day) and NAC from days 12-16 (100 mg/kg/day, i.p.). Rats were tested for cue-induced reinstatement and immediately sacrificed for nucleus accumbens core (NAcore) tissue collection for western blot analysis. References Figure 3. Protein expression in the NAcore. (A) GLT-1 expression in the nucleus accumbens core (NAcore) across treatment groups. NAC significantly increased GLT-1 protein expression as compared to saline controls. Additionally, GLT-1 antisense vivo-morpholino suppressed GLT-1 levels in NAC-treated rats. (B) Although a trend, NAC appeared to decrease NAcore IKK expression relative to saline controls, suggesting a role of neuroinflammatory signaling in NAC’s therapeutic efficacy. *P < 0.05, comparing each treatment group to the CTRL-NAC group Gipson, CD. et al. (2013) Proc. Natl. Acad. Sci. USA, 110. 9124-9129. Reissner, KJ. et al. (2015). Addiction Bio., 20. 316-323. This research was funded by NIDA grant R00 DA036569 and –S1 (CDG).