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Review
, 98 (20), 11042-6

DeltaFosB: A Sustained Molecular Switch for Addiction

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Review

DeltaFosB: A Sustained Molecular Switch for Addiction

E J Nestler et al. Proc Natl Acad Sci U S A.

Abstract

The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor DeltaFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. DeltaFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of DeltaFosB occurs after compulsive running, which suggests that DeltaFosB may accumulate in response to many types of compulsive behaviors. Importantly, DeltaFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, DeltaFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either DeltaFosB or a dominant negative inhibitor of the protein provide direct evidence that DeltaFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that DeltaFosB functions as a type of sustained "molecular switch" that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.

Figures

Figure 1
Figure 1
Scheme showing the gradual accumulation of ΔFosB versus the rapid and transient induction of other Fos family proteins in response to drugs of abuse. (A) The autoradiogram illustrates the differential induction of these various proteins by acute stimulation (1–2 hr after a single drug exposure) versus chronic stimulation (1 day after repeated drug exposure). (B) Several waves of Fos-like proteins [comprised of c-Fos (52- to 58-kDa isoforms), FosB (46- to 50-kDa isoforms), ΔFosB (33-kDa isoform), and Fra1 or Fra2 (40 kDa)] are induced in nucleus accumbens and dorsal striatal neurons by acute administration of a drug of abuse. Also induced are biochemically modified isoforms of ΔFosB (35–37 kDa); they, too, are induced (although at low levels) after acute drug administration, but persist in brain for long periods because of their stability. (C) With repeated (e.g., twice daily) drug administration, each acute stimulus induces a low level of the stable ΔFosB isoforms, which is indicated by the lower set of overlapping lines that indicate ΔFosB induced by each acute stimulus. The result is a gradual increase in the total levels of ΔFosB with repeated stimuli during a course of chronic treatment, which is indicated by the increasing stepped line in the graph.
Figure 2
Figure 2
The AMPA glutamate receptor subunit, GluR2, is a putative target for ΔFosB. Shown is how ΔFosB-mediated induction of GluR2 may alter the physiological responsiveness of nucleus accumbens neurons and lead to sensitized responses to drugs of abuse. According to this scheme, drugs of abuse produce their acute reinforcing effects via inhibition of nucleus accumbens neurons. With repeated exposure, the drugs induce ΔFosB, which regulates numerous target genes, including GluR2. This increases the proportion of AMPA receptors (AMPA-R) on nucleus accumbens neurons that contain the GluR2 subunit, which causes reduced overall AMPA current and reduced Ca2+ current. This reduced excitability could render the neurons more sensitive to the acute inhibitory effects of the drugs and thereby to the drugs' reinforcing effects.
Figure 3
Figure 3
Dynorphin is a putative target for ΔFosB. Shown is a ventral tegmental area (VTA) dopamine (DA) neuron innervating a class of nucleus accumbens (NAc) GABAergic projection neuron that expresses dynorphin (DYN). Dynorphin serves a feedback mechanism in this circuit: dynorphin, released from terminals of the NAc neurons, acts on κ opioid receptors located on nerve terminals and cell bodies of the DA neurons to inhibit their functioning. ΔFosB, by inhibiting dynorphin expression, may down-regulate this feedback loop and enhance the rewarding properties of drugs of abuse. Not shown is the reciprocal effect of CREB on this system: CREB enhances dynorphin expression and thereby attenuates the rewarding properties of drugs of abuse (4). GABA, γ-aminobutyric acid; DR, dopamine receptor; OR, opioid receptor.
Figure 4
Figure 4
Regulation of dendritic structure by drugs of abuse. Shown is the expansion of a neuron's dendritic tree after chronic exposure to a drug of abuse, as has been observed with cocaine in the nucleus accumbens and prefrontal cortex (41). The areas of magnification show an increase in dendritic spines, which is postulated to occur in conjunction with activated nerve terminals. This increase in dendritic spine density may be mediated via ΔFosB and the consequent induction of Cdk5 (see text). Such alterations in dendritic structure, which are similar to those observed in some learning models (e.g., long-term potentiation), could mediate long-lived sensitized responses to drugs of abuse or environmental cues. [Reproduced with permission from ref. (Copyright 2001, Macmillian Magazines Ltd.)].

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