Overexpression of ΔFosB is associated with attenuated cocaine-induced suppression of saccharin intake in mice.

ΔFosB is a member of the Fos family of transcription factors that has received a great deal of attention as a possible molecular switch for the long-term neuronal plasticity observed in drug addiction (McClung et al., 2004; Nestler, Barrot, & Self, 2001; Nestler, Kelz, & Chen, 1999). ΔFosB can homodimerize (Jorissen et al., 2007) or heterodimerize with JunD (and to a lesser extent, JunB; Hiroi et al., 1998; Perez-Otano, Mandelzys, & Morgan, 1998) to form activator protein-1 complexes (Chen et al., 1995; Curran & Franza, 1988; Nestler et al., 2001). Activator protein-1, then, binds at the activator protein-1 consensus site (TGAC/GTCA) to promote or inhibit transcription of various genes including, but not limited to, dynorphin, the AMPA glutamate receptor subunit GluR2, cyclin-dependent kinase 5, and nuclear factor kappa B (Chen, Kelz, Hope, Nakabeppu, & Nestler, 1997; Dobrazanski et al., 1991; Nakabeppu & Nathans, 1991; Yen, Wisdom, Tratner, & Verma, 1991). In the nucleus accumbens, elevation of ΔFosB inhibits transcription of dynorphin (McClung et al., 2004, but see Andersson, Westin, & Cenci, 2003) but promotes transcription of GluR2 (Kelz & Nestler, 2000), cyclin-dependent kinase 5 (McClung & Nestler, 2003), and nuclear factor kappa B (Ang et al., 2001). Manipulation of many of these genes (and/or their products) has been found to influence sensitivity to drugs of abuse. For example, overexpression of GluR2 using viral-mediated gene transfer in rats, or blockade of dynorphin by the κ-receptor antagonist nor-BNI in mice, increases the rewarding effects of cocaine and morphine, respectively (Kelz et al., 1999; Zachariou et al., 2006). A number of factors can elevate ΔFosB in the brain, and the elevation can be region specific. Chronic stress, antipsychotic drugs, and drugs of abuse all elevate ΔFosB in the dorsal (caudate–putamen) and ventral striatum (Atkins et al., 1999; Perrotti et al., 2004, 2008). In the ventral striatum (i.e., nucleus accumbens), however, each of these factors differentially elevates ΔFosB in specific cell types. For example, chronic stress elevates ΔFosB in the dynorphin +/substance P+ and enkephalin+ subsets of medium spiny dopamine neurons in the ventral striatum (Perrotti et al., 2004). Antipsychotic drugs elevate ΔFosB in the enkephalin+ dopamine neurons in the ventral striatum (Atkins et al., 1999; Hiroi & Graybiel, 1996), and drugs of abuse elevate ΔFosB in the dynorphin+/substance P+ dopamine neurons in the ventral striatum (Moratalla, Elibol, Vallejo, & Graybiel, 1996; Nye, Hope, Kelz, Iadarola, & Nestler, 1995; Perrotti et al., 2008). It is this latter pattern of ΔFosB expression in the dorsal striatum and in the dynorphin+/substance P+ dopamine neurons in the nucleus accumbens that we refer to as “striatal” expression in this article (unless otherwise noted) because it is this pattern of expression that is most relevant to natural rewards, drugs of abuse, and addiction (Colby, Whisler, Steffen, Nestler, & Self, 2003; McClung et al., 2004; Olausson et al., 2006; Werme et al., 2002), and it is this pattern of expression found in the transgenic mice used in our studies (Kelz et al., 1999). Interestingly, the elevation of ΔFosB by drugs of abuse requires chronic rather than acute exposure (McClung et al., 2004; Nye et al., 1995; Nye & Nestler, 1996). Thus, although acute exposure to drugs rapidly increases many Fos family proteins in the striatum, such as c-Fos and FosB (Daunais & McGinty, 1994; B. Hope, Kosofsky, Hyman, & Nestler, 1992; Persico, Schindler, O’Hara, Brannock, & Uhl, 1993; Sheng & Greenberg, 1990), there is only a very small increase in ΔFosB (Nestler, 2001a; Nestler et al., 1999). However, once generated, ΔFosB is relatively stable and has an in vivo half-life of more than 1 week compared with 10–12 hr for other Fos proteins (Chen et al., 1997). This stability allows for the slow accumulation of ΔFosB with chronic exposure to drug. Other Fos proteins, in comparison, demonstrate a desensitized response over time (Hope et al., 1992, 1994; Moratalla et al., 1996; Nye et al., 1995). Chronic drug exposure, then, allows ΔFosB to reach levels at which it can affect gene expression and become behaviorally relevant. There is a growing body of literature demonstrating that elevation of ΔFosB increases the perceived reward value of drugs of abuse. For example, preference for drug-associated locations, modeled by conditioned place preference, is increased in mice with elevated ΔFosB in the striatum (Kelz et al., 1999). Acquisition and maintenance of drug-taking behavior, as well as motivation to get drug, are similarly increased in mice with elevated ΔFosB (Colby et al., 2003). Although progress has been made in understanding the effects of ΔFosB in numerous aspects of drug addiction, one area that has not been investigated is the effect of ΔFosB on drug-induced devaluation of natural rewards. In humans, this phenomenon is manifested in reduced motivation for work, friends, family, and monetary gain (e.g., Goldstein et al., 2006, 2008; Jones, Casswell, & Zhang, 1995; Nair et al., 1997; Santolaria-Fernandez et al., 1995). Our data suggest that this devastating consequence of addiction in humans can be modeled in rodents using the reward comparison paradigm (Grigson & Twining, 2002). In this paradigm, access to an otherwise palatable saccharin cue is followed by access to a drug of abuse, such as morphine or cocaine. Under these circumstances, rats and mice come to avoid intake of the taste cue in anticipation of the administration of the drug (Grigson, 1997; Grigson & Twining, 2002; Risinger & Boyce, 2002). According to the reward comparison hypothesis, intake of a natural reward cue is avoided after pairings with a drug of abuse, at least initially (see Wheeler et al., 2008), because the value of the gustatory stimulus pales in comparison to the potent rewarding properties of the drug (Grigson, 1997). This view differs from the long-standing conditioned taste aversion (CTA) account of the data—that is, the view differs from the suggestion that rats avoid intake of the taste cue because it predicts aversive drug properties (Nachman, Lester, & Le Magnen, 1970; Riley & Tuck, 1985). If the reward comparison hypothesis is correct, any condition or circumstance that augments the perceived value of the drug reward should augment avoidance of the lesser saccharin cue. In accordance, drug-sensitive Lewis rats exhibit greater avoidance of a saccharin cue after saccharin–cocaine pairings than do less sensitive Fischer rats (Grigson & Freet, 2000). Sprague–Dawley rats also exhibit greater avoidance of a taste cue paired with cocaine or sucrose after a history of chronic morphine treatment (Grigson, Wheeler, Wheeler, & Ballard, 2001). Interestingly, both drug-naive Lewis rats and Sprague–Dawley rats with a history of chronic morphine treatment have elevated ΔFosB in the nucleus accumbens (Haile, Hiroi, Nestler, & Kosten, 2001; Nye & Nestler, 1996). Experiment 1 more directly examines the role of ΔFosB in drug-induced suppression of conditioned stimulus (CS) intake by evaluating cocaine-induced suppression of intake of a saccharin cue in mice that overexpress this transcription factor in the striatum.