Molecular and circuit mechanisms regulating cocaine memory

Bender, Brooke N.; Torregrossa, Mary M.

doi:10.1007/s00018-020-03498-8

Cited by 34 publications

(19 citation statements)

References 212 publications

(380 reference statements)

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“…Learning and memory processes associate memories between cocaine’s reinforcing and rewarding effects and environmental stimuli, which then will trigger cocaine craving during abstinence. This vulnerability to relapse, even after a long period of abstinence, involves stable gene expression changes and epigenetic modifications, especially in the corticostriatolimbic circuitry (hippocampus, prefrontal cortex, NAc, dorsal striatum, and amygdala) [ 17 ]. Stress plays an important role in relapse since increases drug craving, involving mainly the HPA axis and corticotropin-releasing factor [ 18 ].…”

Section: Neurobiologymentioning

confidence: 99%

Molecular genetics of cocaine use disorders in humans

et al. 2021

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Drug addiction, one of the major health problems worldwide, is characterized by the loss of control in drug intake, craving, and withdrawal. At the individual level, drugs of abuse produce serious consequences on health and have a negative impact on the family environment and on interpersonal and work relationships. At a wider scale, they have significant socio-economic and public health consequences and they cause delinquency and citizen insecurity. Cocaine, a psychostimulant substance, is one of the most used illicit drugs, especially in America, Western Europe, and Australia. Cocaine use disorders (CUD) are complex multifactorial conditions driven by both genetic and environmental influences. Importantly, not all people who use cocaine develop CUD, and this is due, at least in part, to biological factors that are encoded in the genome of individuals. Acute and repeated use of cocaine induces epigenetic and gene expression changes responsible for the neuronal adaptations and the remodeling of brain circuits that lead to the transition from use to abuse or dependence. The purpose of this review is to delineate such factors, which should eventually help to understand the inter-individual variability in the susceptibility to cocaine addiction. Heritability estimates for CUD are high and genetic risk factors for cocaine addiction have been investigated by candidate gene association studies (CGAS) and genome-wide association studies (GWAS), reviewed here. Also, the high comorbidity that exists between CUD and several other psychiatric disorders is well known and includes phenotypes like schizophrenia, aggression, antisocial or risk-taking behaviors. Such comorbidities are associated with a worse lifetime trajectory, and here we report shared genetic factors that may contribute to them. Gene expression changes and epigenetic modifications induced by cocaine use and chronic abuse in humans are addressed by reviewing transcriptomic studies performed on neuronal cells and on postmortem brains. We report some genes which expression is altered by cocaine that also bear genetic risk variants for the disorder. Finally, we have a glance to the pharmacogenetics of CUD treatments, still in early stages. A better understanding of the genetic underpinnings of CUD will foster the search of effective treatments and help to move forward to personalized medicine.

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Section: Neurobiologymentioning

confidence: 99%

Molecular genetics of cocaine use disorders in humans

et al. 2021

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“…Acetylation and deacetylation of chromatin is another signaling pathway involved in regulating the formation of drug context-associated memories contributing to addiction-like behaviors (Rogge et al, 2013;Bender and Torregrossa, 2020;Campbell et al, 2021). These processes are regulated by two kinds of functionally similar enzymes.…”

Section: Function Of Epigenetic Mechanisms In Preventing Drug Relapsementioning

confidence: 99%

The Mechanisms and Boundary Conditions of Drug Memory Reconsolidation

Chen

et al. 2021

Front. Neurosci.

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Drug addiction can be seen as a disorder of maladaptive learning characterized by relapse. Therefore, disrupting drug-related memories could be an approach to improving therapies for addiction. Pioneering studies over the last two decades have revealed that consolidated memories are not static, but can be reconsolidated after retrieval, thereby providing candidate pathways for the treatment of addiction. The limbic–corticostriatal system is known to play a vital role in encoding the drug memory engram. Specific structures within this system contribute differently to the process of memory reconsolidation, making it a potential target for preventing relapse. In addition, as molecular processes are also active during memory reconsolidation, amnestic agents can be used to attenuate drug memory. In this review, we focus primarily on the brain structures involved in storing the drug memory engram, as well as the molecular processes involved in drug memory reconsolidation. Notably, we describe reports regarding boundary conditions constraining the therapeutic potential of memory reconsolidation. Furthermore, we discuss the principles that could be employed to modify stored memories. Finally, we emphasize the challenge of reconsolidation-based strategies, but end with an optimistic view on the development of reconsolidation theory for drug relapse prevention.

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“…Thus, relapse prevention is a particularly important goal for treatment. Long-lasting drug-associated memory formation is closely associated with the rewarding effects of the drug and drug exposure context (Bender and Torregrossa, 2020). Accumulating preclinical studies have also suggested that exposure to drug-associated contextual stimuli may reactivate drug-associated memories, evoke craving, and promote drug relapse in drug addicts (Farrell et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The Src-Kinase Fyn is Required for Cocaine-Associated Memory Through Regulation of Tau

Zhou

Chen

et al. 2022

Front. Pharmacol.

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Drug-associated context-induced relapse of cocaine-seeking behaviour requires the retrieval of drug-associated memory. Studies exploring the underlying neurobiological mechanism of drug memory formation will likely contribute to the development of treatments for drug addiction and the prevention of relapse. In our study, we applied a cocaine-conditioned place preference (CPP) paradigm and a self-administration paradigm (two drug-associated memory formation model) to confirm the hypothesis that the Src kinase Fyn critically regulates cocaine-associated memory formation in the hippocampus. For this experiment, we administered the Src kinase inhibitor PP2 into the bilateral hippocampus before cocaine-CPP and self-administration training, and the results showed that pharmacological manipulation of the Src kinase Fyn activity significantly attenuated the response to cocaine-paired cues in the cocaine-CPP and self-administration paradigms, indicating that hippocampal Fyn activity contributes to cocaine-associated memory formation. In addition, the regulation of cocaine-associated memory formation by Fyn depends on Tau expression, as restoring Tau to normal levels disrupted cocaine memory formation. Together, these results indicate that hippocampal Fyn activity plays a key role in the formation of cocaine-associated memory, which underlies cocaine-associated contextual stimulus-mediated regulation of cocaine-seeking behaviour, suggesting that Fyn represents a promising therapeutic target for weakening cocaine-related memory and treating cocaine addiction.

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Molecular and circuit mechanisms regulating cocaine memory

Cited by 34 publications

References 212 publications

Molecular genetics of cocaine use disorders in humans

Molecular genetics of cocaine use disorders in humans

The Mechanisms and Boundary Conditions of Drug Memory Reconsolidation

The Src-Kinase Fyn is Required for Cocaine-Associated Memory Through Regulation of Tau

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