Delta FosB: A novel molecular switch regulating long-term signaling in brain and susceptibility to cocaine

Previous research has demonstrated a temporal and spatial correlation in the nucleus accumbens (NAc), between the appearance of post-translationally modified isoforms of delta FosB (ΔFosB), formerly known as chronic FRAs, and long-lasting biochemical, electrophysiological, and behavioral changes in rats given chronic cocaine. Because ΔFosB and its variants are transcription factors and because they have the capability to alter patterns of gene expression, they are ideal candidates to mediate some of these long-term changes. Endogenous levels of ΔFosB and its variants are low in drug-naive animals. Hence, these proteins are ideally suited for study with inducible gene overexpression systems such as the tetracycline regulated system. By selectively activating the ΔFosB intracellular pathway in vivo, in the absence of an exogenous extracellular stimulus (such as chronic cocaine), it is possible to discern which of the phenotypic components of the drug addicted state are due to activation of ΔFosB In this thesis, I report that the accumulation of ΔFosB in the nucleus accumbens is sufficient to cause a state of behavioral dependence similar to that seen with prior cocaine exposure. Mice that express ΔFosB show increased sensitivity to the locomotor activating and rewarding properties of cocaine. Moreover, these animals have increased levels of GluR2 in the nucleus accumbens Finally, it is demonstrated that this latter biochemical adaptation, by itself, can account for the increased vulnerability to cocaine.