1. 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 (30 pmol/injection/day) and NAC from days (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,
Reissner, KJ. et al. (2015). Addiction Bio.,
This research was funded by NIDA grant R00 DA and –S1 (CDG).