Targeting the Reconsolidation of Licit Drug Memories to Prevent Relapse: Focus on Alcohol and Nicotine

Barak, Segev; Goltseker, Koral

doi:10.3390/ijms22084090

Cited by 10 publications

(8 citation statements)

References 110 publications

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“…Thus, memories have been suggested to be reactivated upon their retrieval, leading to a process of a temporary destabilization followed by restabilization, termed reconsolidation [7][8][9] . Indeed, recent studies in animal models and humans have shown that pharmacological and behavioral interventions during reconsolidation immediately following memory retrieval can attenuate relapse to alcohol drinking and seeking [3][4][5][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

Aronovici,

Prilutski,

Urshansky

et al. 2023

Preprint

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Alcohol-associated memories play an important role in relapse in alcohol use disorder. Disrupting these memories, which become labile upon retrieval, through interference with their reconsolidation process, could reduce relapse. Memories are thought to be encoded within specific patterns of sparsely distributed neurons, called neuronal ensembles. Here, we explored the role of neuronal ensembles in alcohol-memory reconsolidation and relapse and characterized their transcriptional signature. Upon retrieving alcohol-related memories, we observed increased neuronal activation in the nucleus accumbens (NAc). We established the causal role of these NAc ensembles in alcohol-memory reconsolidation using the Daun02 method with the Fos-LacZ transgenic rat, which expresses β-galactosidase (β-gal) under the Fos promoter, allowing the selective ablation of activated neurons. Selective inactivation of the active NAc neuronal ensemble produced a long-lasting attenuation of relapse. Through fluorescence-activated cell sorting (FACS) and RNA sequencing, we found a unique transcriptional fingerprint in activated Fos-positive neuronal ensembles in NAc following alcohol memory retrieval (vs. no retrieval controls) that was not present in the Fos-negative neurons. Our findings underscore the critical role of NAc neuronal ensembles in alcohol-associated memory reconsolidation. These neurons have a unique transcriptional profile that can provide novel targets for reducing alcohol relapse.

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Section: Introductionmentioning

confidence: 99%

“…Relapse is often caused by cue-induced craving, where an alcohol-associated cue evokes strong craving and relapse even after protracted abstinence. Therefore, disruption of the memory for the cue-alcohol association is expected to reduce or even prevent relapse [3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

Aronovici,

Prilutski,

Urshansky

et al. 2023

Preprint

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“…A promising approach for the disruption of maladaptive memories is to target the process of memory reconsolidation 10,13,14 . Thus, it is believed that reactivation of stable memories via their retrieval initiates a 5-6-hour window, during which the memories become flexible and labile, before their re-stabilization, in the process of “memory reconsolidation” 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Involvement of FKBP5, but not of stress, in alcohol memory reconsolidation

Rahamim,

Aronovici,

Liran

et al. 2023

Preprint

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Relapse is a fundamental challenge in drug addiction, often evoked by exposure to drug-associated cues. Upon retrieval, memories become temporarily labile before re-stabilizing in a process termed reconsolidation. Therefore, targeting the reconsolidation process offers a therapeutic approach for relapse prevention via the disruption of the drug-cue memories. We recently demonstrated that retrieval of contextual alcohol memories increased the expression of the mRNA encoding for FK506 binding protein 51 (FKBP51), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we explored the role of the HPA axis, and FKBP5/FKBP51 in particular, in the reconsolidation of alcohol memories. We found that the FKBP51 inhibitor SAFit2 given before alcohol-memory retrieval using contextual cues prevented the extinction of alcohol place preference behavior in female mice, suggesting that this protein may play a role in cognitive flexibility in a sex-dependent manner. Conversely, the retrieval of alcohol memories using an odor-taste cue did not affectFkbp5expression in rats with a history of chronic alcohol consumption, suggesting that FKBP5 may play a differential role in different alcohol-associated memories. In addition, we provide evidence for HPA axis activation following alcohol memory retrieval, by showing that exposure to an alcohol-associated context led to elevated corticosterone secretion. However, we found that the reconsolidation process was unaffected by HPA axis-related manipulations, namely stress exposure, and administration of corticosterone or the glucocorticoid receptors inhibitor, mifepristone. Our results suggest that although FKBP5 can affect cognitive flexibility, and thereby impact the reconsolidation of alcohol memories, this effect is not likely mediated by HPA axis-related mechanisms.

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“…Exposure to environmental cues or contexts associated with drug elicits craving and relapse, which is the core primary clinical problem in drug addicts (Childress et al, 1999 ; Crombag et al, 2008 ; Chen et al, 2021b ). To address the persistent propensity for relapse, an increasing number of studies suggest that disrupting drug-associated memory, which maintains conditioned reinforcing properties through various manipulations, is a promising strategy to prevent relapse (Milton and Everitt, 2010 ; Jian et al, 2014 ; Barak and Goltseker, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Extracellular signal-regulated kinase in the basolateral amygdala is required for reconsolidation of heroin-associated memory

Zhang³

et al. 2022

Front. Mol. Neurosci.

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Reconsolidation of heroin-associated memory is an independent memory process that occurs following retrieval, which is essential for the sustained capacity of an associative drug stimulus to precipitate heroin-seeking. Extracellular signal-regulated kinase (ERK) in the basolateral amygdala (BLA) mediates the reconsolidation of drug memory. In the present study, we utilized a rat model of drug craving and relapse to verify the hypothesis that the reconsolidation of heroin-associated memory requires ERK in an instrumental heroin-seeking behavior, focusing on the BLA brain region, which is crucial for synaptic plasticity and memory processes. We found that bilateral intra-BLA infusions of U0126 (1 μg/0.5 μl), an ERK inhibitor, immediately after retrieving heroin-associated memory significantly reduced cue-induced and drug-induced reinstatement and spontaneous recovery of heroin-seeking compared to the vehicle. Furthermore, this inhibitory effect was related to the characteristic of reconsolidation. Conversely, no effect was observed on the heroin-seeking behavior when the intra-BLA infusion of U0126 was administered 6 h after the heroin-associated memory retrieval or without memory retrieval. Together, these data suggest that disrupting the reconsolidation of heroin-associated memory via an ERK inhibitor may serve as a promising option for treating relapse in opiate addicts.

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Targeting the Reconsolidation of Licit Drug Memories to Prevent Relapse: Focus on Alcohol and Nicotine

Cited by 10 publications

References 110 publications

Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

Involvement of FKBP5, but not of stress, in alcohol memory reconsolidation

Extracellular signal-regulated kinase in the basolateral amygdala is required for reconsolidation of heroin-associated memory

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