β-Arrestin–biased β-adrenergic signaling promotes extinction learning of cocaine reward memory

Bing, Huang; Li, Youxing; Cheng, Deqin; He, Guanhong; Liu, Xing; Ma, Lan

doi:10.1126/scisignal.aam5402

Cited by 27 publications

(24 citation statements)

References 51 publications

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“…However, different subregions of the mPFC in rodents are highly specialized and individually receive distinct inputs and exert top-down control over behaviors through varied outputs. For instance, the prelimbic PFC (PL) promotes drug-induced memory (Ma et al , 2014) whereas the infralimbic PFC (IL) is believed to attenuate the original memory and promote extinction of drug reward memory (Augur et al , 2016; Huang et al , 2018; Otis et al , 2014).…”

Section: Resultsmentioning

confidence: 99%

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

et al. 2018

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Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior.

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Section: Resultsmentioning

confidence: 99%

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

et al. 2018

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“…For factor loadings, see Table S7. As documented in multiple species, including mice [17,33], lever responding in our paradigm decreased with successive extinction sessions in a manner that was best fit by a two-phase model: rapidly at first (i.e., sessions 1-4) and then more slowly (i.e., sessions [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. At the time mice met final extinction criterion, active lever responding was not only reduced, but active vs. inactive lever discrimination was lost for cocaine and it was significantly reduced for remifentanil.…”

Section: Discussionmentioning

confidence: 99%

“…A two-phase extinction model is supported further by the shape of the total presses vs. extinction session number best-fit curve and by prior observations in support of the early- and late-stage extinction phases as biologically distinct. For example, loss of β-arrestin2 in the infralimbic prefrontal cortex affects extinction responding only in its early stages (i.e., sessions 1-4), and not in subsequent sessions [17]. Another noteworthy observation is that the number of sessions required to reach final extinction criteria in the cocaine-administered mice was almost entirely unrelated to the extent of self-administration during the maintenance stage, suggesting that the rate of extinction learning is independent of the degree of cocaine consumption.…”

Section: Discussionmentioning

confidence: 99%

“…Advances in materials, surgical techniques, and operant protocols have, however, recently led to unprecedented success in mouse self-administration approaches. While studies utilizing genetic techniques and evaluating genetically modified mice are becoming more prevalent [14][15][16][17][18][19][20], self-administration in mice continues to be plagued by a low rate of study completion (e.g., 20-30% of trained mice), limited data collection (e.g., evaluation of a single drug dose on a single delivery schedule), and abbreviated study length [16,21,22].…”

Section: Introductionmentioning

confidence: 99%

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Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

Slosky

Pires

Bai

et al. 2020

Preprint

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A major impediment to identifying the molecular substrates of addiction and developing effective therapeutics has been the lack of animal models that both recapitulate clinical disease presentation and are amenable to genetic manipulation. Intravenous self-administration is the “gold standard” for modeling cocaine and opioid addiction-associated behaviors in animals, but technical limitations have precluded its widespread use in mice, the mammalian species for which the most genetic tools are available. Here, we describe the establishment and demonstrate the utility of multi-stage cocaine and remifentanil paradigms that overcome classic challenges in murine intravenous self-administration. We evaluated self-administration acquisition, maintenance, extinction, and cue-induced reinstatement of drug seeking longitudinally in large cohorts of mice with indwelling catheters. In short daily sessions, mice without prior operant conditioning engaged in drug-associated lever responding that was fixed ratio- and dose-dependent, extinguished by the withholding of drugs, and reinstated by the reintroduction of paired cues. Multivariate statistics, to which this type of longitudinal data is well-suited, revealed that patterns of cocaine and remifentanil taking were similar while those of cocaine and remifentanil seeking were distinct. Individual performance in both drug paradigms was a function of two latent variables we termed incentive motivation and discriminative control. These latent variables identified drug class-specific self-administration phenotypes and were differentially predicted by a priori novelty- and drug-induced locomotor activity in the open field. Application of this behavioral and statistical analysis approach to genetically engineered mice will facilitate the identification of the cell types and neural circuits driving addictive behaviors and their underlying constructs.

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“…Importantly, propranolol facilitated extinction of fear in rabbits (162). However, a recent study has reported that direct injections of propranolol in the infralimbic PFC attenuated extinction learning of cocaine-induced CPP via inhibition of ERK-signaling pathway (111) ( Table 1 ; Figure 2 ). In fact, the study also reported that overexpression of β-arrestin 2 in the infralimbic PFC promoted extinction of cocaine-induced CPP.…”

Section: Pharmacological Targets To Treat Psychostimulant-induced Cogmentioning

confidence: 99%

Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits

D’Souza

2019

Front. Psychiatry

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Addiction to psychostimulants like cocaine, methamphetamine, and nicotine poses a continuing medical and social challenge both in the United States and all over the world. Despite a desire to quit drug use, return to drug use after a period of abstinence is a common problem among individuals dependent on psychostimulants. Recovery for psychostimulant drug-dependent individuals is particularly challenging because psychostimulant drugs induce significant changes in brain regions associated with cognitive functions leading to cognitive deficits. These cognitive deficits include impairments in learning/memory, poor decision making, and impaired control of behavioral output. Importantly, these drug-induced cognitive deficits often impact adherence to addiction treatment programs and predispose abstinent addicts to drug use relapse. Additionally, these cognitive deficits impact effective social and professional rehabilitation of abstinent addicts. The goal of this paper is to review neural substrates based on animal studies that could be pharmacologically targeted to reverse psychostimulant-induced cognitive deficits such as impulsivity and impairment in learning and memory. Further, the review will discuss neural substrates that could be used to facilitate extinction learning and thus reduce emotional and behavioral responses to drug-associated cues. Moreover, the review will discuss some non-pharmacological approaches that could be used either alone or in combination with pharmacological compounds to treat the above-mentioned cognitive deficits. Psychostimulant addiction treatment, which includes treatment for cognitive deficits, will help promote abstinence and allow for better rehabilitation and integration of abstinent individuals into society.

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β-Arrestin–biased β-adrenergic signaling promotes extinction learning of cocaine reward memory

Cited by 27 publications

References 51 publications

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits

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