Abstract
Aims:Cigarette smoking is a leading cause of preventable death, and addiction to nicotine produces long-lasting, stable changes in brain synaptic physiology thatmight contribute to thevulnerability to relapse. Existing smoking cessation treatments are insufficient as relapse rates remain high. Thus, we examined the ability of Nacetylcysteine (NAC), an antioxidant, to inhibit relapse, restore glial glutamateuptake, and inhibit relapse-associatedsynapticplasticity in the nucleus accumbens core. Methods: We examined the ability of NAC to reduce reinstatement of cue-induced nicotine seeking in a preclinical model nicotine relapse. NAC (30mg/kg, i.p.) was given chronically for 5 days duringwithdrawalwith extinction training fromnicotine selfadministration (0.02mg/kg/infusion for 10days). Following the last injection, animals were either sacrificed for sodiumdependent (via the glial glutamate transporter, GLT-1) or independent (via the cystine-glutamate exchanger) glutamate uptake, or animals were given a 15min cue-induced reinstatement session and sacrificed for dendritic spine or electrophysiological analysis. Results: NAC given chronically during withdrawal with extinction training from nicotine self-administration inhibited both cue-induced nicotine seeking and relapse-associated rapid, transient synaptic plasticity in the nucleus accumbens core measured via dendritic spine head diameter and AMPA/NMDA ratios in medium spiny neurons. In addition, we found reduced sodiumdependentglial glutamateuptake (viaGLT-1) followingwithdrawal from nicotine self-administration, and NAC restored nucleus accumbenscoreglutamateuptake innicotine-withdrawnrats compared to drug-naive controls. Conclusions: These results show that NACmay be an important pharmacotherapeutic avenue in restoring glutamate homeostasis and in reducing nicotine relapse vulnerability. Financial support: NIH grants K99 DA036569 (CDG) and DA015369 (PWK).
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