ΔFosB: a molecular switch for long-term adaptation in the brain

McClung, Colleen A.; Ulery, Paula G.; Perrotti, Linda I.; Zachariou, Venetia; Berton, Olivier; Nestler, Eric J.

doi:10.1016/j.molbrainres.2004.05.014

Cited by 365 publications

(368 citation statements)

References 44 publications

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“…Here, we found that striatal ⌬FosB overexpression in these mice also increased progressive ratio responding for a food reinforcer and that these effects were reproduced by restricted viral-mediated overexpression of ⌬FosB in the NAc core in rat. Our data suggest that ⌬FosB may act as a transcriptional modulator of motivation for primary reinforcers, be they food, drugs, or perhaps exercise, an idea consistent with preliminary observations that striatal expression of ⌬FosB is increased after chronic wheel running or sucrose drinking (McClung et al, 2004). These data suggest that NAc overexpression of ⌬FosB can enhance the motivational impact of both natural and drug reinforcers.…”

Section: Discussionsupporting

confidence: 88%

ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation

Olausson¹,

Jentsch²,

Tronson³

et al. 2006

J. Neurosci.

101

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Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor ⌬FosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of ⌬FosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of ⌬FosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viralmediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(ϩ)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by ⌬FosB, and provide evidence that drug-induced alterations in gene expression via induction of ⌬FosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.

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Section: Discussionsupporting

confidence: 88%

ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation

Olausson¹,

Jentsch²,

Tronson³

et al. 2006

J. Neurosci.

101

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“…CREB is activated (phosphorylated) very rapidly after a single stimulus or acute drug treatment (Konradi et al, 1994). This can increase ΔFosB (Andersson et al, 2001), and with repeated stimuli (eg repeated morphine injections used in the present study), ΔFosB, an exquisitely stable protein, accumulates in brain tissue (McClung et al, 2004). The decreases in tissue pCREB may be a 'rebound' adaptation to its repeated elevation during treatment (see below for further discussion).…”

Section: Discussionmentioning

confidence: 73%

Changes in Accumbal and Pallidal pCREB and ΔFosB in Morphine-Sensitized Rats: Correlations with Receptor-Evoked Electrophysiological Measures in the Ventral Pallidum

McDaid

Dallimore

Mackie

et al. 2005

Neuropsychopharmacol

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Activation of μ-opioid receptors in the ventral pallidum (VP) is important for the induction of behavioral sensitization to morphine in rats. The present study was designed to ascertain if neurons within the VP demonstrate sensitization at a time when morphine-induced behavioral sensitization occurred (ie 3 or 14 days after five once-daily injections of 10 mg/kg i.p. morphine) in rats. Western blotting was used to evaluate transcription factors altered by opiates, CREB and ΔFosB. CREB levels did not change in the VP, but there was a significant decrease in levels of its active, phosphorylated form (pCREB) at both 3-and 14-days withdrawal. ΔFosB levels were elevated following a 3-day withdrawal, but returned to normal by 14 days. This profile also was obtained from nucleus accumbens tissue. In a separate group of similarly treated rats, in vivo electrophysiological recordings of VP neuronal responses to microiontophoretically applied ligands were carried out after 14-days withdrawal. The firing rate effects of local applications of morphine were diminished in rats withdrawn from i.p. morphine. Repeated i.p. morphine did not alter GABA-mediated suppression of firing, or the rate enhancing effects of the D1 dopamine receptor agonist SKF82958 or glutamate. However, VP neurons from rats withdrawn from repeated i.p. morphine showed a higher propensity to enter a state of depolarization inactivation to locally applied glutamate. Overall, these findings reveal that decreased pCREB in brain regions such as the VP accompanies persistent behavioral sensitization to morphine and that this biochemical alteration may influence the excitability of neurons in this brain region.

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“…Although acute administration of drugs of abuse can cause a rapid (within hours) activation of members of the Fos protein family, such as c-fos, FosB, Fra-1, and Fra-2 in the nucleus accumbens, other transcription factors, isoforms of DFosB, a highly stable form of FosB, have been shown to accumulate over longer periods of time (days) with repeated drug administration (Nestler, 2005). Animals with activated DFosB have exaggerated sensitivity to the rewarding effects of drugs of abuse, and DFosB may be a sustained molecular 'switch' that helps to initiate and maintain a state of addiction (McClung et al, 2004). Whether (and how) such transcription factors influence the function of the brain stress systems, such as CRF and those described above, remains to be determined.…”

Section: Molecular Targets For Neuroplasticity: Binge/intoxication Wmentioning

confidence: 99%

Erratum: Neurocircuitry of Addiction

Koob¹,

Volkow²

2010

Neuropsychopharmacol

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Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: 'binge/intoxication', 'withdrawal/negative affect', and 'preoccupation/anticipation' (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

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ΔFosB: a molecular switch for long-term adaptation in the brain

Cited by 365 publications

References 44 publications

ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation

ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation

Changes in Accumbal and Pallidal pCREB and ΔFosB in Morphine-Sensitized Rats: Correlations with Receptor-Evoked Electrophysiological Measures in the Ventral Pallidum

Erratum: Neurocircuitry of Addiction

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