RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Abstract

Cocaine produces a persistent reduction in cystine-glutamate exchange via system x c Ϫ in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System x c Ϫ influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens, which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system x c Ϫ activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered before daily cocaine to determine the impact of increased cystine-glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered before cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2-3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered before daily cocaine also prevented the persistent reduction in system x c Ϫ activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in [35 S]cystine transport via system x c Ϫ, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least 3 weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system x c Ϫ activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking.

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

“…Preclinical studies have shown that chronic self-administration of cocaine disrupts synaptic communication between the PFC and the striatum and results in decreased basal levels of non-synaptic, extracellular glutamate in the NAcc. 11,[62][63][64][65] Reduced extracellular glutamate tone in the NAcc core has in turn been associated with downregulation of mGluR5 expression and function in rats, [12][13][14][15][16][17] resulting in disrupted synaptic plasticity, which is assumed to contribute to the persisting nature of addiction. 9 It has been proposed, that the observed down-regulation of mGluR5s and Homer1b/c, post-synaptic scaffolding proteins influencing mGluR5 trafficking and signal transduction, after chronic cocaine administration may constitute a compensatory mechanism, as mGluR5 antagonists attenuate drug-seeking behaviors.…”

Erratum: Neurocircuitry of Addiction

“…Here, repeated administration of cocaine blunts cystine-glutamate exchange, leading to reduced basal and increased cocaine-induced glutamate in the nucleus accumbens that persists for at least 3 weeks after the last cocaine treatment (Baker et al, 2003). Most compelling is the observation that treatment with N-acetylcysteine, by activating cystine-glutamate exchange, prevented cocaineinduced escalation and behavioral sensitization, restored the ability to induce LTP and long-term depression in the nucleus accumbens, and blunted reinstatement in animals and conditioned reactivity to drug cues in humans (Moussawi et al, 2009;LaRowe et al, 2007;Madayag et al, 2007).…”

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

“…In addition, astrocytes are able to exchange glutamate for cystine (cyteine disulfide) through the cystine-glutamate exchanger, system Xc-, which allows cystine to be used for astrocytic GSH synthesis (O 'Connor et al, 1995). Cystineglutamate exchange (Xc-) is downregulated by daily cocaine or nicotine administration, and the ensuing decrease in release of non-synaptic glutamate via system Xc-contributes to relapse vulnerability in animal models of addiction (Baker et al, 2003;Knackstedt et al, 2009;Madayag et al, 2007). Although research has focused on system Xc-mediated release of glutamate, it is possible that by downregulating system Xc-daily cocaine may also affect cellular redox via decreasing substrate for de novo GSH synthesis.…”