ΔFosB In Nucleus Accumbens Research Articles

Post-weaning social isolation increases the incentive value of nicotine-related contexts and decreases the accumulation of ΔFosB in nucleus accumbens in adolescent rats

Adolescent social conditions profoundly affect vulnerability to drug abuse. Preclinical studies have shown that preventing social interactions during adolescence increases the rewarding effects of drugs like alcohol, cocaine, or amphetamines, however, little data exist regarding the impact of social isolation on nicotine effects. The current study evaluated the effects of differential rearing conditions during adolescence (isolation or group rearing) on (1) conditioned place preference induced by low nicotine doses (0.1 or 0.3 mg/kg) and (2) sensitization to the locomotor effects of nicotine after sub-chronic administration (3) and accumulation of ΔFosB in nucleus accumbens (NAc). Results showed that nicotine induced place preference in isolated and grouped rats, but the effect was more persistent for the rats reared in isolation. Isolated reared rats also exhibited lower levels of ΔFosB accumulation in NAc. No differences were found in the behavioral sensitization to nicotine effects between rearing conditions. The results suggest that isolation engenders a more robust incentive value of nicotine-related contexts. This effect could be related to the basal expression of ΔFosB: lower levels of this transcription factor seem to impair the motivation of isolated reared rats and increase their vulnerability to the effects of drugs like nicotine.

Fosb Induction in Nucleus Accumbens by Cocaine Is Regulated by E2F3a.

The transcription factor ΔFosB has been proposed as a molecular switch for the transition from casual, volitional drug use into a chronically addicted state, but the upstream regulatory mechanisms governing ΔFosB expression are incompletely understood. In this study, we find a novel regulatory role for the transcription factor E2F3, recently implicated in transcriptional regulation by cocaine, in controlling ΔFosB induction in the mouse nucleus accumbens (NAc) following cocaine administration. We find that an E2F consensus sequence 500 bp upstream of the Fosb transcription start site is enriched for E2F3 specifically over other E2F isoforms. We further conclude that ΔFosB expression is regulated specifically by E2F3a, not E2F3b, that E2f3a expression is specific to D1 receptor-expressing medium spiny neurons, and that E2F3a overexpression in NAc recapitulates the induction of Fosb and ΔFosb mRNA expression observed after chronic cocaine exposure. E2F3a knockdown in NAc does not abolish ΔFosb induction by cocaine, a result consistent with previously published data showing that singular knockdown of upstream regulators of ΔFosB is insufficient to block cocaine-induced expression. Finally, to elucidate potential combinatorial epigenetic mechanisms involved in E2F3a’s regulation of Fosb, we explore H3K4me3 enrichment at the Fosb promoter and find that it is not enhanced by E2F3a overexpression, suggesting that it may instead be a pre-existing permissive mark allowing for E2F3a to interact with Fosb. Together, these findings support a role for E2F3a as a novel, upstream regulator of the addiction-mediating transcription factor ΔFosB in NAc.

Repeated cannabinoid administration induces ΔFosB and sensitizes mu opioid receptor activity in the nucleus accumbens

CB1 cannabinoid receptors (CB1Rs) mediate the central effects of Δ9‐tetrahydrocannabinol (THC), the main psychoactive constituent in marijuana. CB1Rs and endocannabinoids are expressed in striatum and regulate reward, motivation and motor activity. We reported that inducible transgenic expression of ΔFosB in D1/dynorphin medium spiny striatal neurons enhanced mu opioid receptor (MOR) signaling in the nucleus accumbens (NAc) and enhanced rewarding effects of morphine, without affecting MOR expression. Moreover, repeated THC administration induces the transcription factor ΔFosB in the NAc, but inducible transgenic expression of ΔFosB did not enhance CB1R signaling in this region. Here we show that repeated THC administration induced ΔFosB in both NAc and dorsal striatum. Interestingly, repeated THC administration also enhanced MOR‐mediated G‐protein activation in the NAc, whereas CB1R‐mediated G‐protein activity was not increased. Neither THC nor inducible transgenic expression of ΔFosB altered MOR‐mediated G‐protein activity in dorsal striatum. Finally, inducible transgenic expression of ΔcJun, a dominant negative inhibitor of ΔFosB‐mediated transcription, blocked THC‐induced enhancement of MOR‐mediated G‐protein activity in NAc. These results suggest that sensitization of MOR activity by repeated THC could be mediated by ΔFosB. Support: R01‐ DA014277 and R01‐DA030404 from NIDA

Serum Response Factor and cAMP Response Element Binding Protein Are Both Required for Cocaine Induction of ΔFosB

The molecular mechanism underlying induction by cocaine of ΔFosB, a transcription factor important for addiction, remains unknown. Here, we demonstrate a necessary role for two transcription factors, cAMP response element binding protein (CREB) and serum response factor (SRF), in mediating this induction within the mouse nucleus accumbens (NAc), a key brain reward region. CREB and SRF are both activated in NAc by cocaine and bind to the fosB gene promoter. Using viral-mediated Cre recombinase expression in the NAc of single- or double-floxed mice, we show that deletion of both transcription factors from this brain region completely blocks cocaine induction of ΔFosB in NAc, whereas deletion of either factor alone has no effect. Furthermore, deletion of both SRF and CREB from NAc renders animals less sensitive to the rewarding effects of moderate doses of cocaine when tested in the conditioned place preference (CPP) procedure and also blocks locomotor sensitization to higher doses of cocaine. Deletion of CREB alone has the opposite effect and enhances both cocaine CPP and locomotor sensitization. In contrast to ΔFosB induction by cocaine, ΔFosB induction in NAc by chronic social stress, which we have shown previously requires activation of SRF, is unaffected by the deletion of CREB alone. These surprising findings demonstrate the involvement of distinct transcriptional mechanisms in mediating ΔFosB induction within this same brain region by cocaine versus stress. Our results also establish a complex mode of regulation of ΔFosB induction in response to cocaine, which requires the concerted activities of both SRF and CREB.