Previous work has implicated the transcription factor ΔFosB acting in the

Previous work has implicated the transcription factor ΔFosB acting in the nucleus accumbens in mediating the pro-rewarding effects of drugs of abuse such as cocaine as well as in mediating resilience to chronic social stress. overexpresses Δ2ΔFosB alone. Our results show that the mutant form of ΔFosB when overexpressed in the nucleus accumbens reproduces the enhancement of reward and of resilience seen with our earlier models with no effects seen for Δ2ΔFosB. Overexpression of full length FosB the other major product of the gene also has no effect. These findings confirm the unique role of ΔFosB in nucleus accumbens in controlling responses to drugs of abuse and stress. INTRODUCTION ΔFosB is encoded by the gene and shares homology with other Fos family transcription factors which include c-Fos FosB Fra1 and Fra2. All Fos family proteins are induced rapidly and transiently in specific brain regions after acute administration of many drugs of abuse [see Nestler 2008 These responses are seen most prominently in nucleus accumbens (NAc) and dorsal striatum which are important mediators of the rewarding and locomotor actions of the drugs. All of these Fos family proteins however are highly unstable and go back to basal amounts within hours of medication administration. On the other hand ΔFosB because of its uncommon balance in vitro and in vivo (Ulery et al. 2006 Carle et al. 2006 Ulery-Reynolds et al. 2009 accumulates exclusively inside the same human brain locations after repeated medication exposure (Wish et al. 1994 Hiroi et al. 1997 Perrotti et al. 2008 Newer studies have confirmed that chronic contact with certain types of tension also induces the deposition of ΔFosB in the NAc which such induction takes place preferentially in pets that are fairly resistant to the deleterious ramifications of the strain (i.e. resilient pets) (Perrotti et al. 2004 Vialou et al. 2010 2010 We’ve confirmed that overexpression of ΔFosB in the NAc either in inducible bitransgenic mice or by regional TH-302 viral-mediated gene transfer boosts an animal’s awareness to the satisfying and locomotor-activating effects of cocaine and other drugs of abuse (Kelz et al. 1999 Rabbit polyclonal to TDGF1. Colby et al. 2003 TH-302 Zachariou et al. 2006 Grueter et al. 2013 Robison et al. 2013 Such induction also boosts consumption of and motivation for natural rewards (Werme et al. 2002 Teegarden et al. 2007 Wallace et al. 2008 Hedges et al. 2009 Been et al. 2013 Pitchers et al. 2009 2013 increases brain stimulation reward in intra-cranial self-stimulation paradigms (Muschamps et al. 2012 and renders animals more resilient to several forms of chronic stress (Vialou et al. 2010 2010 Likewise mice that constitutively lack expression of full length FosB but show increased expression ΔFosB display reduced sensitivity to stress (Ohnishi et al. 2011 Together these findings support the view that ΔFosB acting in the NAc TH-302 boosts an animal’s state of reward mood and motivation. However a major caveat of these studies is usually that another TH-302 product of the gene termed Δ2ΔFosB is also expressed in all of these genetic mutant mice and viral vector systems leaving open the possible contribution of Δ2ΔFosB to the behavioral phenotypes observed. Δ2ΔFosB is usually translated from an alternative start codon located within the ΔmRNA transcript (Chen et al. 1997 This alternative translation leads to the formation of Δ2ΔFosB which lacks the 78 N-terminal aa of ΔFosB. In this study we examined the role of Δ2ΔFosB in drug abuse and stress models by overexpressing it or ΔFosB or FosB with AAV (adeno-associated virus) vectors; we used a mutant form of ΔmRNA that cannot undergo this alternative translation mechanism. Our results confirm that the pro-reward and pro-resilient actions seen in earlier studies are indeed mediated via ΔFosB and not by the two other protenproducts of the TH-302 gene full-length FosB or Δ2ΔFosB. METHODS Animals Prior to experimentation 9 to 11-week-old C57BL/6J male mice (The Jackson Laboratory Bar Harbor ME USA) were group housed at five per cage in a colony room set at constant temperature (23°C) on a 12 hr light/dark cycle (lights on at 7 AM) with ad libitum access to water and food. Some experiments used bitransgenic mice where overexpression of ΔFosB is certainly beneath the control of the tetracycline gene legislation system as referred to (Kelz et al. 1999 Mice had been applied to doxycycline (to keep gene expression away) or TH-302 away doxycycline which allows ΔFosB appearance. All protocols had been accepted by the Institutional Pet Care and Make use of Committee (IACUC) at Support Sinai. AAV vectors We utilized AAV2.