Molecular mechanisms of drug addiction

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Abstract

Regulation of gene expression is one mechanism by which drugs of abuse can induce relatively long-lasting changes in the brain to cause a state of addiction. Here, we focus on two transcription factors, CREB (cAMP response element binding protein) and ΔFosB, which contribute to drug-induced changes in gene expression. Both are activated in the nucleus accumbens, a major brain reward region, but mediate different aspects of the addicted state. CREB mediates a form of tolerance and dependence, which dampens an individual’s sensitivity to subsequent drug exposure and contributes to a negative emotional state during early phases of withdrawal. In contrast, ΔFosB mediates a state of relatively prolonged sensitization to drug exposure and may contribute to the increased drive and motivation for drug, which is a core symptom of addictive disorders. A major goal of current research is to identify the many target genes through which CREB and ΔFosB mediate these behavioral states. In addition, future work needs to understand how CREB and ΔFosB, acting in concert with numerous other drug-induced molecular changes in nucleus accumbens and many other brain regions, interact with one another to produce the complex behavioral phenotype that defines addiction.

Introduction

Drug addiction is defined today solely on the basis of behavioral abnormalities, for example, loss of control over drug intake and compulsive drug taking despite horrendous adverse consequences. These behavioral abnormalities develop gradually and progressively during a course of repeated exposure to a drug of abuse, and can persist for months or years after discontinuation of drug use. As a result, drug addiction can be considered a form of drug-induced neural plasticity (Nestler et al., 1993). The stability of the behavioral abnormalities that define addiction suggests a role for gene expression in this process. According to this view, repeated exposure to a drug of abuse alters the amounts, and even the types, of genes expressed in specific brain regions. Such altered expression of genes then mediates altered function of individual neurons and the larger neural circuits within which the neurons operate. Ultimately, such neural circuit changes underlie the behavioral abnormalities seen in drug addicts (Nestler et al., 1993, Nestler, 2001a, Hyman and Malenka, 2001).

There are many mechanisms by which repeated exposure to a drug of abuse could alter gene expression in the brain. These include altered rates of transcription of genes, altered processing of primary RNA transcripts into mature mRNAs, altered translation of these mRNAs into proteins, altered processing of proteins, and altered trafficking of mature proteins to their intracellular sites of action (see Nestler et al., 2001a). Of all these mechanisms, the best understood, and the one which has received most study to date, is the regulation of gene transcription. According to this scheme, illustrated in Fig. 1, drug perturbation of synaptic transmission causes changes in numerous intracellular signaling pathways, which eventually signal to the cell nucleus, where specific proteins, called transcription factors, are altered. Transcription factors bind to short sequences of DNA located in the regulatory regions of genes and thereby control the rate of gene transcription. Over the past decade, drugs of abuse have been shown to alter many types of transcription factors in a variety of brain regions (see O’Donovan et al., 1999, Berke and Hyman, 2000, Nestler, 2001a, Mackler et al., 2003).

This review focuses on two transcription factors, CREB (cAMP response element binding protein) and ΔFosB, which our laboratory has investigated. It is important to state at the outset that these particular proteins represent just a small part of the overall plasti city that drugs of abuse induce in the brain. Nevertheless, consideration of these proteins serves as an illustration of how reductionistic changes (alterations in a single transcription factor in a particular neuronal cell type in the brain) can be related to something as complex as the behavioral phenotype of addiction.

Section snippets

Role of CREB in drug addiction

CREB and related proteins were described originally as transcription factors that mediate effects of the cAMP second messenger pathway on gene expression (Shaywitz and Greenberg, 1999, Mayr and Montminy, 2001). This occurs via the phosphorylation of CREB on a single serine residue, Ser133, by protein kinase A (a protein kinase activated by cAMP). Once phosphorylated, CREB dimers, bound to specific CRE (cAMP response element) sites on target genes, can interact with the basal transcriptional

Role of ΔFosB in drug addiction

ΔFosB is a member of the Fos family of transcription factors. These proteins dimerize with a Jun family member to form activator protein-1 (AP-1) transcription factor complexes, which bind to AP-1 sites present within the regulatory regions of certain genes (Morgan and Curran, 1995). Acute administration of most types of drugs of abuse causes the rapid and transient induction of several Fos and Jun proteins in the nucleus accumbens and dorsal striatum (see Graybiel et al., 1990, Young et al.,

Conclusions

This review focuses on two transcription factors, CREB and ΔFosB, as targets for drugs of abuse. Both are induced in nucleus accumbens, among other brain regions, but seem to function very differently even in that one region (Fig. 5). Chronic exposure to drugs of abuse causes the activation of CREB in this region, but this activation dissipates within a few days of coming off the drug. In contrast, ΔFosB persists in brain for up to two months, meaning that it mediates a much more long-lived

Acknowledgements

Preparation of this review was supported by grants from the National Institute on Drug Abuse. This review is based, with permission, on Nestler, E.J., 2003. Molecular mechanisms of drug addiction. In: D.S. Charney (Ed.), Molecular Neurobiology for the Clinician. American Psychiatric Press, pp. 107–121.

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