Prolonged withdrawal following cocaine self-administration increases resistance to punishment in a cocaine binge

Gancarz‐Kausch, Amy M.; Adank, Danielle N.; Dietz, David M.

doi:10.1038/srep06876

Cited by 28 publications

(43 citation statements)

References 82 publications

(94 reference statements)

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“…1 ). This result is in agreement with the finding that prolonged withdrawal incubates craving for cocaine [40] and increases the resistance to punishment for cocaine seeking [42] . Considering our electrophysiological data from the 2-week withdrawn cocaine-CPP rats, which showed increased CPP, our results strongly suggest that the promoted cocaine-seeking behavior following prolonged withdrawal after repeated cocaine administrations may be associated with decreased GABAergic inhibitory synaptic transmission but not glutaminergic excitatory synaptic transmission at mPFC.…”

Section: Discussionsupporting

confidence: 92%

Cocaine Withdrawal Reduces Gamma-Aminobutyric Acid-Ergic Transmission and Gephyrin Expression at Medial Prefrontal Cortex in Cocaine-Conditioned Place-Preference Rats, Which Shows Increased Cocaine Seeking

Yang

He²,

Yan³

et al. 2016

Eur Addict Res

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Aims: Chronic cocaine abuse decreases the inhibitory synaptic transmission via unknown mechanisms, while pharmacologically augmenting gamma-aminobutyric acid-ergic (GABAergic) transmission attenuates cocaine craving. Here, we propose that prolonged cocaine withdrawal downregulates GABAergic transmission and its important regulator gephyrin in medial prefrontal cortex (mPFC), in cocaine-conditioned place-preference (CPP) rats. Methods: CPP test, patch clamp, and Western blot analysis are engaged to test this proposal. Results: Two-week cocaine withdrawal further increased CPP score, as compared to the 24-hour withdrawn group. The amplitude of GABAergic inhibitory postsynaptic currents (IPSCs) was decreased in 2-week-withdrawn mPFC neurons from cocaine-CPP rats, compared to that of saline-CPP rats. Two-week withdrawal did not alter the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) in mPFC in cocaine-CPP rats. Two-week withdrawal increased the ratio of EPSCs/IPSCs (E/I) in the same mPFC neuron in cocaine-CPP rats. In addition, Western blots showed 2-week cocaine-withdrawn down-regulated gephyrin at postsynaptic density (PSD) sites of mPFC. Conclusion: We found decreased GABAergic IPSCs and downregulated gephyrin in PSD at mPFC in 2-week cocaine-withdrawn rats that showed increased CPP, suggesting that an increased E/I ratio and neuron excitability in mPFC may associate with a cocaine-seeking tendency. Strategies aimed at GABAergic synapses in mPFC may therapeutically benefit to cocaine addiction treatment.

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Section: Discussionsupporting

confidence: 92%

Cocaine Withdrawal Reduces Gamma-Aminobutyric Acid-Ergic Transmission and Gephyrin Expression at Medial Prefrontal Cortex in Cocaine-Conditioned Place-Preference Rats, Which Shows Increased Cocaine Seeking

Yang

He²,

Yan³

et al. 2016

Eur Addict Res

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“…Rats were exposed to multiple within-session extinction sessions, during which the chambers were dark and responses were recorded but resulted in no programmed consequences. Extinction sessions were 1 h in duration, separated by 5 min, and were continued until responding levels fell to fewer than 20 responses per session (8–10 sessions) (23, 24). Animals were then allowed an additional 6 d of abstinence, followed by 1 h test of cue-induced reinstatement, during which active responses produced cues previously paired with drug delivery.…”

Section: Methodsmentioning

confidence: 99%

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

Wang

Martin

Mueller

et al. 2016

Biological Psychiatry

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Background Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that transcription factor SMAD3 is increased following seven days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here we examined the possible interaction of BRG1—also known as SMARCA4, an ATPase-containing chromatin remodeler—and SMAD3 in response to cocaine exposure. Methods The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using Western blotting, co-immunoprecipitation, and chromatin immunoprecipitation techniques, respectively, following withdrawal from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors following either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1. Results Following withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, while viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior. Conclusion BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity mediating cocaine seeking following a period of withdrawal.

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“…In addition, there may be links between incubation of craving and other behavioural characteristics related to addiction. Thus, rats predisposed to risky decision-making exhibit more robust incubation of cocaine craving 13 , whereas rats that have undergone incubation are less sensitive to punishment-induced suppression of cocaine-taking, indicating that cocaine-taking has become compulsive in these animals 14 . The incubation model mimics some common scenarios experienced by humans with addiction, and indeed the incubation of craving has been demonstrated in humans (BOX 1).…”

Section: Rodent Models Of Cue-induced Cravingmentioning

confidence: 99%

“…This has been exploited to produce a period of punishment-induced abstinence during which incubation of cue-induced methamphetamine seeking can be demonstrated 134 . Interestingly, after incubation of craving in a typical forced abstinence model, rats are less sensitive to punishment-induced suppression of cocaine-taking 14 .…”

Section: Rodent Models Of Cue-induced Cravingmentioning

confidence: 99%

Synaptic mechanisms underlying persistent cocaine craving

2016

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Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction.

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Prolonged withdrawal following cocaine self-administration increases resistance to punishment in a cocaine binge

Cited by 28 publications

References 82 publications

Cocaine Withdrawal Reduces Gamma-Aminobutyric Acid-Ergic Transmission and Gephyrin Expression at Medial Prefrontal Cortex in Cocaine-Conditioned Place-Preference Rats, Which Shows Increased Cocaine Seeking

Cocaine Withdrawal Reduces Gamma-Aminobutyric Acid-Ergic Transmission and Gephyrin Expression at Medial Prefrontal Cortex in Cocaine-Conditioned Place-Preference Rats, Which Shows Increased Cocaine Seeking

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

Synaptic mechanisms underlying persistent cocaine craving

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