An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: A pilot study

Mardikian, Pascale; LaRowe, Steven D.; Hedden, Sarra L.; Kalivas, Peter W.; Malcolm, Robert

doi:10.1016/j.pnpbp.2006.10.001

Cited by 161 publications

(131 citation statements)

References 21 publications

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“…The present data reveal that system x c Ϫ represents a novel target capable of preventing plasticity that underlies behaviors used to model aspects of addiction and are consistent with clinical studies indicating efficacy for N-acetylcysteine as an anticraving agent for cocaine addiction (Larowe et al, 2006;Mardikian et al, 2007). Aside from system x c Ϫ, numerous mechanisms may be capable of releasing glutamate into the extrasynaptic compartment including vesicular release from astrocytes (Bezzi et al, 2004;Zhang et al, 2004), nonvesicular release from astrocytic gap junction hemichannels (Ye et al, 2003), volume-sensitive organic anion channels (Strange et al, 1996;Basarsky et al, 1999), or hydrolysis of N-acetylaspartylglutamate (Blakely et al, 1988;Zhou et al, 2005).…”

Section: Discussionsupporting

confidence: 84%

“…It may seem paradoxical that targeting cystine-glutamate exchange, which increases nonvesicular glutamate, is effective in reducing cocaine-induced behaviors in rodents or drug craving and use in humans because these behaviors require increased glutamate signaling (Cornish and Kalivas, 2000;Baker et al, 2003;Di Ciano and Everitt, 2003;McFarland et al, 2003;Larowe et al, 2006;Mardikian et al, 2007). However, this may reflect the existence of multiple, functionally distinct pools of glutamate.…”

Section: Discussionmentioning

confidence: 99%

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RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Madayag¹,

Lobner²,

Kau³

et al. 2007

J. Neurosci.

203

242

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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.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Madayag¹,

Lobner²,

Kau³

et al. 2007

J. Neurosci.

203

242

View full text Add to dashboard Cite

show abstract

“…Other regimens, including ShA regimens that do not lead to CP-AMPAR accumulation, provide insight into strategies for decreasing addictive behavior under different conditions. The most striking example concerns the drug N-acetylcysteine, which reduces cocaine-related behaviors after non-contingent cocaine exposure and ShA cocaine self-administration and has shown promise in clinical trials (Mardikian et al, 2007;Amen et al, 2011;Olive et al, 2012).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Different Adaptations in AMPA Receptor Transmission in the Nucleus Accumbens after Short vs Long Access Cocaine Self-Administration Regimens

Purgianto

Scheyer

Loweth

et al. 2013

Neuropsychopharmacol

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Ca 2 þ -permeable AMPA receptors (CP-AMPARs) accumulate in the nucleus accumbens (NAc) after B1 month of withdrawal from a long-access cocaine self-administration regimen (6 h/d, 10d). This is functionally significant because CP-AMPARs mediate the 'incubated' cue-induced cocaine craving produced by this regimen. Our present goal was to determine if other commonly employed cocaine selfadministration regimens also elicit CP-AMPAR accumulation. We compared four regimens, named according to whether sessions were short-access (ShA, 2 h) or long-access (LgA, 6 h) and the total number of sessions: LgA/10d (already shown to elicit CP-AMPAR accumulation), ShA/11d, ShA/20-24d, and LgA/20-24d. In the latter regimens, rats began with 10 days of ShA and then entered a differential phase (10-14 days) in which ShA sessions either continued or switched to LgA. Controls self-administered saline. After 440 days of withdrawal, whole-cell patch-clamp recordings were performed in NAc core medium spiny neurons to assess the contribution of CP-AMPAR transmission, based on the magnitude of synaptic suppression elicited by bath application of the selective CP-AMPAR antagonist naspm (100 mM). Naspm produced a non-significant (B10%) attenuation of electrically evoked local excitatory postsynaptic current in the saline and ShA groups. By contrast, a significant naspm-induced synaptic attenuation (25-30%) was observed in both the LgA groups. Further analyses indicate that this emergence of CP-AMPAR transmission in the LgA groups is associated with increased baseline responsiveness of MSN to excitatory drive. Together with data on cocaine infusions in each group, our results show that CP-AMPAR accumulation and enhanced glutamate transmission is associated with longer sessions (6 h), rather than the number of sessions or cocaine infusions.

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“…It also represents an advance in "bench to bedside" translation, since daily administration of medication during extinction more closely models the treatment approaches used in clinical trials with human patients [8,9]. Compounds that impact cocaine seeking behaviors during extinction training in animal models may be candidate medications for promoting inhibition of drug-seeking behaviors in human addicts.…”

Section: Resultsmentioning

confidence: 99%

“…In clinical settings, however, medications are usually not administered on an acute basis, but rather as part of a chronic (i.e., daily) treatment regimen [8,9]. It is feasible that a drug that is found to be effective after acute administration may not be as effective if delivered chronically.…”

Section: Introductionmentioning

confidence: 99%

The Role of N-Acetylcysteine in Inhibiting Responding During Extinction in Rats Trained to Self-Administer Cocaine~!2009-12-01~!2010-02-08~!2010-04-09~!

LaRowe¹,

Kalivas²

2010

TOADDJ

Self Cite

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Previous work has found that N-acetylcysteine inhibits extinction responding in rats trained to self-administer heroin. The current study examined the ability of N-acetylcysteine to inhibit extinction responding in rats trained to self-administer cocaine. Rats were trained to selfadminister cocaine (0.39mg/kg) for 10 to 12 days and were pretreated with either N-acetylcysteine (60mg/kg) or saline beginning on the first day of extinction training and on each extinction training day thereafter. Results indicated that chronically administered N-acetylcysteine reduced lever pressing during extinction sessions. In addition to demonstrating the impact N-acetylcysteine has on lever pressing during extinction, the present study underscores the importance of using responding during extinction as a dependent measure in the development of medications for addictive behaviors.

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An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: A pilot study

Cited by 161 publications

References 21 publications

RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

RepeatedN-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Different Adaptations in AMPA Receptor Transmission in the Nucleus Accumbens after Short vs Long Access Cocaine Self-Administration Regimens

The Role of N-Acetylcysteine in Inhibiting Responding During Extinction in Rats Trained to Self-Administer Cocaine~!2009-12-01~!2010-02-08~!2010-04-09~!

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