The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans

Abstract

Background The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement, and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affected the number of cigarettes smoked. Methods Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic mini-pumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex or amygdala. For the smoking-reduction study in humans, nicotine-dependent smokers were treated for four weeks with N-acetylcysteine (2400 mg/daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, CO measurements and logged daily cigarette and alcohol use. Results Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA, and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal. Conclusions These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are down-regulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

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.…”

N-Acetylcysteine as a Treatment for Addiction

“…Notably, inhibition of system xc-prevented the NAC-induced recovery of extracellular glutamate levels in this region, implicating the xc-system in the neurobiological mechanisms whereby NAC normalises cocaine-induced extracellular glutamate dysregulation (Baker et al, 2003a). Thus, NAC may induce a recovery of the downregulated xCT and GLT-1 function (Knackstedt et al, 2009;2010a). Indeed, the recovery of an altered GLT-1 function allows for increased transport of glutamate into the astrocyte while the recovery of altered system xcfunction by xCT recovery allows for increased export of glutamate back into the extrasynaptic space (see Figure 1).…”

“…In addition to protecting brain cells from the oxidative stress, GSH has been shown to enhance responsivity of NMDA receptors to glutamatergic stimulation (see Janáky et al, 1999), suggesting some direct modulation of glutamatergic signalling as a result of NAC administration. The role of GSH in addiction has yet to be determined, and thus far, the effects of NAC as a pharmacotherapy for drug dependence appear to be primarily mediated via its actions on system xc-and GLT-1 (Knackstedt et al, 2009;Knackstedt et al, 2010a). 3. N-acetylcysteine in animal models of self-administration, reinstatement, and relapse…”

“…This dysregulation of glutamate homeostasis as a result of drug withdrawal has been suggested to be caused by an overall downregulation of system xc-and is in fact mimicked by blocking system xc-in the NAc (Baker et al, 2003b). Indeed, following chronic cocaine or nicotine self-administration, there is reduced NAc expression of both xCT, the light chain and catalytic subunit of the system xc-antiporter heterodimers, and GLT-1 (Knackstedt et al, 2009;2010a), indicating these mechanisms are involved in the dysregulation of glutamate homeostasis and may impact the development and trajectory of addiction. Fig.…”

Emerging therapeutic targets for the treatment of nicotine addiction

“…Similarly, the novel dopamine D3 receptor antagonist GSK598809, currently being tested as a treatment for nicotine addiction, was shown to attenuate the rewarding and motivational effects of nicotine in rodents [20][21][22][23][24][25]. In an exciting recent study, Kalivas and colleagues demonstrated that N-acetylcysteine -a drug that promotes cystine-glutamate exchange -decreases signs of withdrawal in nicotine-dependent rats and reduces the number of cigarettes smoked by tobacco-dependent humans [26]. The drugs d-cycloserine (NMDA receptor partial agonist) and GW468816 (glycine-site NMDA receptor antagonist), also targeting glutamatergic transmission, are also being tested in human smokers for efficacy in facilitating smoking cessation and to reduce rates of relapse, respectively.…”