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Fig. 3. Dynorphin is a putative target for ∆FosB. Shown is a ventral tegmental area (VIA) 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 ĸ opioid receptors located on nerve terminals and cell bodies of the DA neurons to inhibit their functioning. ∆FosB, 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. effect: it induces dynorphin expression in the nucleus accumbens and reduces the rewarding properties of cocaine and morphine (4).** Because drug-induced activation of CREB dissipates rapidly after drug administration, such reciprocal regulation of dynorphin by CREB and ∆FosB could explain the reciprocal behavioral changes that occur during early and late phases of withdrawal, with negative emotional symptoms and reduced drug sensitivity predominating during early phases of withdrawal, and sensitization to the rewarding and incentive motivational effects of drugs predominating at later time points. The second approach used to identify target genes for ∆FosB involves DNA microarray analysis. Inducible overexpression of ∆FosB increases or decreases the expression of numerous genes in the nucleus accumbens (36). Although considerable work is now needed to validate each of these genes as physiologic targets of ∆FosB and to understand their contribution to the addiction phenotype, one important target appears to be Cdk5 (cyclin-dependent kinase-5). Thus, Cdk5 was initially identified as ∆FosB-regulated by use of microarrays, and later shown to be induced in nucleus accumbens and dorsal striatum after chronic cocaine administration (37). ∆FosB activates the cdk5 gene via an AP-1 site present within the gene’s promoter (36). Together, these data support a scheme wherein cocaine induces Cdk5 expression in these brain regions via ∆FosB. Induction of Cdk5 appears to alter dopaminergic signaling at least in part via increased phosphorylation of DARPP-32 (37), which is converted from an inhibitor of protein phosphatase-1 to an inhibitor of protein kinase A upon its phosphorylation by Cdk5 (26). Role of ∆FosB in Mediating “Permanent” Plasticity to Drugs of AbuseAlthough the ∆FosB signal is relatively long-lived, it is not permanent. ∆FosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal, even though certain behavioral abnormalities persist for much longer periods of time. Therefore, ∆FosB per se would not appear to be able to mediate these semipermanent behavioral abnormalities. 
Fig. 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 ∆FosB 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. 3 (Copyright 2001, Macmillian Magazines Ltd.)]. The difficulty in finding the molecular adaptations that underlie the extremely stable behavioral changes associated with addiction is analogous to the challenges faced in the learning and memory field. Although there are elegant cellular and molecular models of learning and memory, it has not to date been possible to identify molecular and cellular adaptations that are sufficiently long-lived to account for highly stable behavioral memories. Indeed, ∆FosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn’t involve lesions) as well. Two proposals have evolved, both in the addiction and learning and memory fields, to account for this discrepancy. One possibility is that more transient changes in gene expression, such as those mediated via ∆FosB or other transcription factors (e.g., CREB), may mediate more long-lived changes in neuronal morphology and synaptic structure. For example, an increase in the density of dendritic spines (particularly an increase in two-headed spines) accompanies the increased efficacy of glutamatergic synapses at hippocampal pyramidal neurons during long-term potentiation (38–40), and parallels the enhanced behavioral sensitivity to cocaine mediated at the level of medium spiny neurons of the nucleus accumbens (41). It is not known whether such structural changes are sufficiently long-lived to account for highly stable changes in behavior, although the latter persist for at least 1 month of drug withdrawal. Recent evidence raises the possibility that ∆FosB, and its induction of Cdk5, is one mediator of drug-induced changes in synaptic structure in the nucleus accumbens (Fig. 4).†† Thus, infusion of a Cdk5 inhibitor into the nucleus accumbens prevents the ability of repeated cocaine exposure to increase dendritic spine density in this region. This is consistent with the view that Cdk5, which is enriched in brain, regulates neural structure and growth (see refs. 36 and 37). It is possible, although by no means proven, that such changes in neuronal morphology may outlast the ∆FosB signal itself.
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