Together, these early findings suggest that ∆FosB, in addition to increasing sensitivity to drugs of abuse, produces qualitative changes in behavior that promote drug-seeking behavior. Thus, ∆FosB may function as a sustained “molecular switch” that helps initiate and then maintain crucial aspects of the addicted state. An important question under current investigation is whether ∆FosB accumulation during drug exposure promotes drug-seeking behavior after extended withdrawal periods, even after ∆FosB levels have normalized (see below).

Adult mice that overexpress ∆FosB selectively within the nucleus accumbens and dorsal striatum also exhibit greater compulsive running compared with control littermates.^† These observations raise the interesting possibility that ∆FosB accumulation within these neurons serves a more general role in the formation and maintenance of habit memories and compulsive behaviors, perhaps by reinforcing the efficacy of neural circuits in which those neurons function.

∆FosB accumulates in certain brain regions outside the nucleus accumbens and dorsal striatum after chronic exposure to cocaine. Prominent among these regions are the amygdala and medial prefrontal cortex (15). A major goal of current research is to understand the contributions of ∆FosB induction in these regions to the addiction phenotype.

Earlier work on fosB knockout mice revealed that these animals fail to develop sensitization to the locomotor effects of cocaine, which is consistent with the findings of the ∆FosB-overexpressing mice mentioned above (22). However, the fosB mutants showed enhanced sensitivity to cocaine’s acute effects, which is inconsistent with these other findings. Interpretation of findings with the fosB mutants, though, is complicated by the fact that these animals lack not only ∆FosB, but full-length FosB as well. Moreover, the mutants lack both proteins throughout the brain and from the earliest stages of development. Indeed, more recent work supports conclusions from the ∆FosB overexpressing mice: inducible overexpression of a truncated mutant of c-Jun, which acts as a dominant negative antagonist of ∆FosB, selectively in nucleus accumbens and dorsal striatum shows reduced sensitivity to the rewarding effects of cocaine.^¶ These findings emphasize the caution that must be used in interpreting results from mice with constitutive mutations and illustrate the importance of mice with inducible and cell type-specific mutations in studies of plasticity in the adult brain.

Because ∆FosB is a transcription factor, presumably the protein causes behavioral plasticity through alterations in the expression of other genes. ∆FosB is generated by alternative splicing of the fosB gene and lacks a portion of the C-terminal transactivation domain present in full-length FosB. As a result, it was originally proposed that ∆FosB functions as a transcriptional represser (29). However, work in cell culture has demonstrated clearly that ∆FosB can either induce or repress AP-1-mediated transcription depending on the particular AP-1 site used (21, 29–31). Full-length FosB exerts the same effects as ∆FosB on certain promoter fragments, but different effects on others. Further work is needed to understand the mechanisms underlying these varied actions of ∆FosB and FosB.

Our group has used two approaches to identify target genes for ∆FosB. One is the candidate gene approach. We initially considered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors as putative targets, given the important role of glutamatergic transmission in the nucleus accumbens. Work to date has indicated that one particular AMPA glutamate receptor subunit, GluR2, may be a bona fide target for ∆FosB (Fig. 2). GluR2 expression, but not the expression of other AMPA receptor subunits, is increased in nucleus accumbens (but not dorsal striatum) upon overexpression of ∆FosB (28), and expression of a dominant negative

mutant attenuates the ability of cocaine to induce the protein.^¶ In addition, the promoter of the GluR2 gene contains a consensus AP-1 site that binds ∆FosB (28). Overexpression of GluR2 in the nucleus accumbens, by use of viral-mediated gene transfer, increases an animal’s sensitivity to the rewarding effects of cocaine, thereby mimicking part of the phenotype seen in the ∆FosB-expressing mice (28). Induction of GluR2 could account for the reduced electrophysiological sensitivity of nucleus accumbens neurons to AMPA receptor agonists after chronic cocaine administration (32), because AMPA receptors containing GluR2 show reduced overall conductance and reduced Ca²⁺ permeability. Reduced responsiveness of these neurons to excitatory inputs may then enhance responses to a drug of abuse. However, the ways in which dopaminergic and glutamatergic signals in nucleus accumbens regulate addictive behavior remain unknown; this will require a neural circuit level of understanding, which is not yet available.

Another putative target for ∆FosB is the gene encoding dynorphin. As stated earlier, dynorphin is expressed in the subset of nucleus accumbens medium spiny neurons that show induction of ∆FosB. Dynorphin appears to function in an intercellular feedback loop: its release inhibits the dopaminergic neurons that innervate the medium spiny neurons, via K opioid receptors present on dopaminergic nerve terminals in the nucleus accumbens and also on cell bodies and dendrites in the ventral tegmental area (Fig. 3) (33–35). This idea is consistent with the ability of a K receptor agonist, upon administration into either of these two brain regions, to decrease drug reward (35). Recent work has indicated that ∆FosB decreases the expression of dynorphin,^|| which could contribute to the enhancement of reward mechanisms seen with ∆FosB induction. Interestingly, another drug-regulated transcription factor, CREB (cAMP response element binding protein) (2, 3), exerts the opposite

Front Matter (R1-R5)

1 Introduction (10994-10995)

2 Neural Roles for Heme Oxygenase: Contrasts to Nitric Oxide Synthase (10996-11002)

3 Presynaptic Kainate Receptors at Hippocampal Mossy Fiber Synapses (11003-11008)

4 Retrograde Signaling at Central Synapses (11009-11015)

5 Controlling Potassium Channel Activities: Interplay Between the Membrane and Intracellular Factors (11016-11023)

6 Calcium Regulation of Neuronal Gene Expression (11024-11031)

7 Sensory Experience and Sensory Activity Regulate Chemosensory Receptor Gene Expression in Caenorhabditis Elegans (11032-11038)

8 Presenilin, Notch, and the Genesis and Treatment of Alzheimer's Disease (11039-11041)

9 FosB: A Sustained Molecular Switch for Addiction (11042-11046)

10 Glutabatergic Modulation of Hyperactivity in Mice Lacking the Dopamine Transporter (11047-11054)

11 Zinc Induces a Src Family Kinase-Medicated Up-Regulation of NMDA Receptor Activity and Excitotoxicity (11055-11061)

12 Regulation of Cyclin-Dependent Kinase 5 and Casein Kinase 1 by Metabotropic Glutamate Receptors (11062-11068)