N-Acetylcysteine reverses cocaine-induced metaplasticity

Moussawi, Khaled; Pacchioni, Alejandra M.; Moran, Megan M.; Olive, M. Foster; Gass, Justin T.; Lavín, Antonieta; Kalivas, Peter W.

doi:10.1038/nn.2250

Cited by 366 publications

(431 citation statements)

References 51 publications

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“…Glutamatergic synaptic transmission to dopamine neurons is a key site of plasticity [32][33][34][35][36][37][38][39][40] , and both stress and cocaine directly target NMDARs, which in turn can modulate AMPAR-mediated synaptic transmission 11 . Studies of the effects of acute stress on glutamatergic transmission have shown that such stress enhances synaptic strength by increasing AMPAR trafficking or AMPARmediated excitatory transmission in various brain regions, including midbrain dopaminergic neurons, the prefrontal cortex and the NAc shell [41][42][43][44] .…”

Section: Discussionmentioning

confidence: 99%

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

et al. 2013

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Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.

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Section: Discussionmentioning

confidence: 99%

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

et al. 2013

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“…drug-induced behaviors such as sensitization, CPP, and reinstated drug-seeking (Achat-Mendes et al, 2007;Moussawi et al, 2009;Muriach et al, 2010;Numa et al, 2008).…”

Section: Potential Role Of Cocaine-induced Protein S-glutathionylationmentioning

confidence: 99%

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

Uys

Knackstedt

Hurt

et al. 2011

Neuropsychopharmacol

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Impaired glutamate homeostasis in the nucleus accumbens has been linked to cocaine relapse in animal models, and results in part from cocaine-induced downregulation of the cystine-glutamate exchanger. In addition to regulating extracellular glutamate, the uptake of cystine by the exchanger is a rate-limiting step in the synthesis of glutathione (GSH). GSH is critical for balancing cellular redox in response to oxidative stress. Cocaine administration induces oxidative stress, and we first determined if downregulated cystineglutamate exchange alters redox homeostasis in rats withdrawn from daily cocaine injections and then challenged with acute cocaine. Among the daily cocaine-induced changes in redox homeostasis were an increase in protein S-glutathionylation and a decrease in expression of GSH-S-transferase pi (GSTpi). To mimic reduced GSTpi, a genetic mouse model of GSTpi deletion or pharmacological inhibition of GSTpi by administering ketoprofen during daily cocaine administration was used. The capacity of cocaine to induce conditioned place preference or locomotor sensitization was augmented, indicating that reducing GSTpi may contribute to cocaineinduced behavioral neuroplasticity. Conversely, an acute cocaine challenge after withdrawal from daily cocaine elicited a marked increase in accumbens GSTpi, and the expression of behavioral sensitization to a cocaine challenge injection was inhibited by ketoprofen pretreatment; supporting a protective effect by the acute cocaine-induced rise in GSTpi. Together, these data indicate that cocaineinduced oxidative stress induces changes in GSTpi that contribute to cocaine-induced behavioral plasticity.

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“…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).…”

Section: Molecular Targets For Neuroplasticity: Binge/intoxication Wmentioning

confidence: 99%

Erratum: Neurocircuitry of Addiction

Koob¹,

Volkow²

2010

Neuropsychopharmacol

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Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: 'binge/intoxication', 'withdrawal/negative affect', and 'preoccupation/anticipation' (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

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N-Acetylcysteine reverses cocaine-induced metaplasticity

Cited by 366 publications

References 51 publications

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

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

Erratum: Neurocircuitry of Addiction

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