The Effect of N-Acetylcysteine in the Nucleus Accumbens on Neurotransmission and Relapse to Cocaine

Abstract

Background Relapse to cocaine-seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine-seeking and depotentiate PFC-NAcore synapses. Here we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors (mGluRs) mGluR2/3 and mGluR5. Methods Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, prior to inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures. Results NAC microinjection into the NAcore inhibited the reinstatement of cocaine-seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in a mGluR2/3-dependent manner, while high doses of NAC increased amplitude in a mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine-seeking by NAC was potentiated. Conclusions The effect of NAC on relapse to cocaine-seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…In contrast, NAC does decrease the rewarding effects of smoking a first cigarette after a period of abstinence but does not reduce the craving to smoke (Schmaal et al, 2011). Moreover, data from human magnetic resonance spectroscopy studies confirm that as in preclinical studies (Kupchik et al, 2012), NAC normalized levels of extracellular glutamate in the NAcore of cocaine-dependent individuals and, reassuringly, had no effect in control subjects (Schmaal et al, 2012).…”

“…In addition, mGluR2/3 appears to be under tonic activation in control conditions. Microdialysis experiments show that infusion of the mGluR2/3 antagonist LY341495 (2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-Dalanine) increased baseline levels of glutamate Moussawi and Kalivas, 2010), whereas the same antagonist caused an increase in evoked EPSC amplitude Kupchik et al, 2012; although see Moran et al, 2005).…”

“…After cocaine self-administration and extinction, the same protocol no longer induces LTD. This may be a result of a change in the baseline activity of the mGluR2/3; whereas mGluR2/3 is tonically activated in naïve or yoked-saline rats Kupchik et al, 2012), the tonic activation is removed after extinction of cocaine self-administration , presumably because of a reduction in extracellular glutamate levels Kalivas, 2009). Normalization of extracellular glutamate levels using N-acetylcysteine (NAC) restores the ability to electrically induce LTD in the NAc and this is blocked by mGluR2/3 antagonists .…”

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

“…As depicted in Fig. 1, nonvesicular glutamate release by system x c Ϫ , which is highly expressed by astrocytes, regulates synaptic activity by stimulating extrasynaptic receptors (Pow, 2001;Baker et al, 2002;Moran et al, 2005;Kupchik et al, 2012). The potential for system x c Ϫ to contribute to multiple aspects of neuronal function and plasticity is evident from the finding that increased cystine-glutamate exchange influences the capacity of some cells to undergo long-term potentiation and longterm depression (Moussawi et al, 2009.…”

The Cardioprotective Role of Naca in the Prevention of Doxorubicin and Trastuzumab Mediated Cardiac Dysfunction

“…101 The clinical use of NAC as a cardioprotective agent has been evaluated in DOX mediated cardiac dysfunction. 15 NAC has failed to show any beneficial properties in DOX mediated cardiac dysfunction.…”