The Role of Cell Adhesion Molecule Genes Regulating Neuroplasticity in Addiction

Muskiewicz, Dawn E.; Uhl, George R.; Hall, F. Scott

doi:10.1155/2018/9803764

Cited by 26 publications

(20 citation statements)

References 163 publications

(195 reference statements)

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“…Many drugs of abuse, including opioids, induce synaptic plasticity, suggesting that this type of neuroadaptation may be a common mechanism underlying the development of substance use disorders ( 29 – 31 ). Moreover, polymorphisms in genes associated with synaptic plasticity have been associated with vulnerability to drug addiction ( 32 , 33 ). Our data indicate that coordinated expression of genes implicated in synaptic plasticity may predispose pairs of brain regions to increased FOS correlation networks induced by opiate dependence.…”

Section: Discussionmentioning

confidence: 99%

Gene coexpression patterns predict opiate-induced brain-state transitions

Brynildsen

Mace

Cornblath

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.

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Section: Discussionmentioning

confidence: 99%

Gene coexpression patterns predict opiate-induced brain-state transitions

Brynildsen

Mace

Cornblath

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the aim of the present study was not to investigate the molecular and cellular mechanisms by which NCAM deficiency leads to enhanced behavioral responses to cocaine, several mechanisms can be brought forward based on previous studies. It has been suggested that cell adhesion molecules, such as SynCAM 1 37 or NrCAM, 38 regulate addiction liability because of their pivotal role in synaptic plasticity 39 . Similarly, NCAM had long been known to affect synaptic plasticity and ablated NCAM impairs hippocampal long‐term potentiation 18 .…”

Section: Discussionmentioning

confidence: 99%

Hyperfunction of the stress response system and novelty‐induced hyperactivity correlate with enhanced cocaine‐induced conditioned place preference in NCAM‐deficient mice

et al. 2020

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Several studies in humans and rodents suggest an association between impulsivity and activity of the stress response on the one hand and addiction vulnerability on the other. The neural cell adhesion molecule (NCAM) has been related to several neuropsychiatric disorders in humans. Constitutively NCAM‐deficient (−/−) mice display enhanced novelty‐induced behavior and hyperfunction of the hypothalamic‐pituitary‐adrenal axis. Here we hypothesize that NCAM deficiency causes an altered response to cocaine. Cocaine‐induced behaviors of NCAM−/− mice and wild‐type (+/+) littermates were analyzed in the conditioned place preference (CPP) test. c‐fos mRNA levels were investigated by quantitative polymerase chain reaction (qPCR) to measure neural activation after exposure to the cocaine‐associated context. NCAM−/− mice showed an elevated cocaine‐induced sensitization, enhanced CPP, impaired extinction, and potentiated cocaine‐induced hyperlocomotion and CPP after extinction. NCAM−/− showed no potentiated CPP as compared with NCAM+/+ littermates when a natural rewarding stimulus (ie, an unfamiliar female) was used, suggesting that the behavioral alterations of NCAM−/− mice observed in the CPP test are specific to the effects of cocaine. Activation of the prefrontal cortex and nucleus accumbens induced by the cocaine‐associated context was enhanced in NCAM−/− compared with NCAM+/+ mice. Finally, cocaine‐induced behavior correlated positively with novelty‐induced behavior and plasma corticosterone levels in NCAM−/− mice and negatively with NCAM mRNA levels in the hippocampus and nucleus accumbens in wild‐type mice. Our findings indicate that NCAM deficiency affects cocaine‐induced CPP in mice and support the view that hyperfunction of the stress response system and reactivity to novelty predict the behavioral responses to cocaine.

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“…In particular, genetically modified mice were widely used for this purpose. These studies have been widely reviewed [Charbogne et al, 2014;Uhl et al, 2014;Muskiewicz et al, 2018], so only a few points will be made on this topic here. GWAS for drug dependence nominated many novel genes for potential involvement in drug dependence phenotypes.…”

Section: Confirming That the Results Of Gwas Studies Are Not Just False Positivesmentioning

confidence: 99%

“…Although the prominence of cell adhesion molecule genes among those identified in GWAS studies was ini-tially surprising, this was reconsidered in the light of the importance of learning mechanisms in drug dependence [Uhl, 2004]. Clearly the importance of neuroplasticity and learning mechanisms in drug dependence [for a review, see Robbins et al, 2008;Badiani and Robinson, 2004] is consistent with a role of cell adhesion molecules in drug dependence mechanisms [Muskiewicz et al, 2018]. These learning mechanisms include both the development of positive reinforcement early in the course of drug dependence and negative reinforcement later in in the course of drug dependence.…”

Section: Gwas: Leaving a Priori Considerations Behindmentioning

confidence: 99%

The Streetlight Effect: Reappraising the Study of Addiction in Light of the Findings of Genome-wide Association Studies

2020

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Drug dependence has long been thought to have a genetic component. Research seeking to identify the genetic basis of addiction has gone through important transitions over its history, in part based upon the emergence of new technologies, but also as the result of changing perspectives. Early research approaches were largely dictated by available technology, with technological advancements having highly transformative effects on genetic research, but the limitations of technology also affected modes of thinking about the genetic causes of disease. This review explores these transitions in thinking about the genetic causes of addiction in terms of the “streetlight effect,” which is a type of observational bias whereby people search for something only where it is easiest to search. In this way, the genes that were initially studied in the field of addiction genetics were chosen because they were the most “obvious,” and formed current understanding of the biological mechanisms underlying the actions of drugs of abuse and drug dependence. The problem with this emphasis is that prior to the genomic era the vast majority of genes and proteins had yet to be identified, much less studied. This review considers how these initial choices, as well as subsequent choices that were also driven by technological limitations, shaped the study of the genetic basis of drug dependence. While genome-wide approaches overcame the initial biases regarding which genes to choose to study inherent in candidate gene studies and other approaches, genome-wide approaches necessitated other assumptions. These included additive genetic causation and limited allelic heterogeneity, which both appear to be incorrect. Thus, the next stage of advancement in this field must overcome these shortcomings through approaches that allow the examination of complex interactive effects, both gene × gene and gene × environment interactions. Techniques for these sorts of studies have recently been developed and represent the next step in our understanding of the genetic basis of drug dependence.

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The Role of Cell Adhesion Molecule Genes Regulating Neuroplasticity in Addiction

Cited by 26 publications

References 163 publications

Gene coexpression patterns predict opiate-induced brain-state transitions

Gene coexpression patterns predict opiate-induced brain-state transitions

Hyperfunction of the stress response system and novelty‐induced hyperactivity correlate with enhanced cocaine‐induced conditioned place preference in NCAM‐deficient mice

The Streetlight Effect: Reappraising the Study of Addiction in Light of the Findings of Genome-wide Association Studies

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