Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53233, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2008; 27(51):13968-76. DOI: 10.1523/JNEUROSCI.2808-07.2007
Source: PubMed


Cocaine produces a persistent reduction in cystine-glutamate exchange via system x(c)- in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System x(c)- 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)- 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)- activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in [35S]cystine transport via system x(c)-, 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)- activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking.

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Available from: Matthew Hearing, Jan 23, 2014
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    • "NAC treatment during the extinction of cocaine self-administration restores accumbal glutamate homeostasis [23]. It also prevents the withdrawal-related decline in glial cystine-glutamate exchange and in extrasynaptic glutamate levels in the nucleus accumbens in a rat model of cocaine self-administration [8]. Caudate nucleus microdialysis studies in squirrel monkeys [18] and in vitro studies in rat striatal slices [24] revealed that NAC pretreatment counteracts cocaine-induced dopamine release, whereas it exerts opposing effects on amphetamine-induced DA release, depending on the dose employed, both in vivo and in vitro. "
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    ABSTRACT: A satisfactory pharmacological cure for addictions to psychostimulants has not yet been developed. Because of the well-known role of changes in the corticoaccumbal and corticostriatal glutamatergic system(s) in drug seeking and relapses in psychostimulant addiction, much hope is presently linked to the use of agents that restore glutamate homeostasis. In this regard, one of the most promising agents is N-acetyl cysteine, which has been shown to reverse some changes in neuroplasticity associated with psychostimulant addiction/dependence. In this study, we used the enhancement of locomotor activity and the induction of frequency-modulated 50-kHz ultrasonic vocalization (FM 50-kHz USV) to test the possible stimulant properties of N-acetyl cysteine itself in various experimental settings (acute and subchronic administration in amphetamine-naïve and amphetamine-pretreated rats) and the capacity of N-acetyl cysteine to attenuate both the rewarding effects of amphetamine and the behavioral sensitization to this stimulant in rats showing considerable differences in their susceptibility to the FM 50-kHz USV sensitization. Our data showed no stimulant properties of N-acetyl cysteine and no acute effect of the drug on the rewarding properties of amphetamine. Moreover, no effect of N-acetyl cysteine on the pre-existing sensitization of the FM 50-kHz USV and locomotor activity responses to amphetamine were observed, independent of the susceptibility of the rats to the FM 50-kHz USV sensitization. Hence, N-acetyl cysteine seems to be ineffective at reversing the neurobiological changes underlying the sensitization of these responses to amphetamine in rats. Copyright © 2014. Published by Elsevier B.V.
    Behavioural Brain Research 12/2014; 280. DOI:10.1016/j.bbr.2014.12.005 · 3.03 Impact Factor
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    • "Torregrossa et al. 2013); whether or not these processes offer a strategy to reduce cocaine relapse remains to be determined. Withdrawal from cocaine induces decrease in basal synaptic Glu levels (e.g., Wydra et al. 2013) and in mechanisms responsible for Glu clearance that is different in various brain structures (see Baker et al. 2002; Melendez et al. 2005; Cavelier and Attwell 2005, Madayag et al. 2007, Pendyam et al. 2009; Knackstedt et al. 2010). It is still unknown whether differences in Glu levels and region-dependent mechanisms maintaining the neurotransmitter level are responsible for the changes in receptor expression observed in the present paper following cocaine self-administration. "
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    ABSTRACT: In human addicts and in animal models, chronic cocaine use leads to numerous alterations in glutamatergic transmission, including its receptors. The present study focused on metabotropic glutamatergic receptors type 5 (mGluR5) and N-methyl-D-aspartate receptor subunits (NMDAR: GluN1, GluN2A, GluN2B) proteins during cocaine self-administration and after 10-day of extinction training in rats. To discriminate the contingent from the non-contingent cocaine delivery, we employed the "yoked"-triad control procedure. Protein expression in rat prefrontal cortex, nucleus accumbens, hippocampus, and dorsal striatum was determined. We also examined the Homer1b/c protein, a member of the postsynaptic density protein family that links NMDAR to mGluR5. Our results revealed that cocaine self-administration selectively increased GluN1 and GluN2A subunit in the rat hippocampus and dorsal striatum, respectively, while mGluR5 protein expression was similarly increased in the dorsal striatum of both experimental groups. Withdrawal from both contingent and non-contingent cocaine delivery induced parallel increases in prefrontal cortical GluN2A protein expression, hippocampal mGluR5, and GluN1 protein expression as well as in accumbal GluN1 subunit expression, while the mGluR5 expression was reduced in the prefrontal cortex. Extinction training in animals with a history of cocaine self-administration resulted in an elevation of the hippocampal GluN2A/GluN2B subunits and accumbal mGluR5, and in a 50 % decrease of mGluR5 protein expression in the dorsal striatum. The latter reduction was associated with Homer1b/1c protein level decrease. Our results showed that both contingent and non-contingent cocaine administration produces numerous, brain region specific, alterations in the mGluR5, NMDA, and Homer1b/1c protein expression which are dependent on the modality of cocaine administration.
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    • "These data suggest that there is a reduction in post-synaptic responsiveness in the PFC, possibly mediated by decreased glutamate or dopamine input. Indeed, there are studies indicating that cocaine induces reductions in glutamatergic tone [35], [36]. However, using the Golgi method, we observed an increase in the number of thin dendritic spines on basal dendrites of pyramidal neurons, which suggests an increase in excitatory input in the PFC to remaining neurites. "
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    ABSTRACT: Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.
    PLoS ONE 07/2014; 9(7):e102524. DOI:10.1371/journal.pone.0102524 · 3.23 Impact Factor
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