Fos B mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine’s psychomotor and rewarding effects

Abstract

Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-related proteins of 35-37 kDa are induced in the striatum by chronic cocaine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using fosB mutant mice. The striatum of these mice completely lacked basal levels of the 35-to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration. This deficiency was associated with enhanced behavioral responses to cocaine: fosB mutant mice showed exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related proteins as products of the fosB gene (specifically ⌬FosB isoforms) and suggest that transcriptional regulation by fosB gene products plays a critical role in cocaine-induced behavioral responses. This finding demonstrates that a Fos family member protein plays a functional role in behavioral responses to drugs of abuse and implicates fosB gene products as important determinants of cocaine abuse.

Effects of Cocaine on c-Fos and NGFI-B mRNA Expression in Transgenic Mice Underexpressing Glucocorticoid Receptors

“…This ceiling effect could in part be because of the dose used and the fact that COC was administered in the animal home cages. It has been shown that COC at a dose of 10-20 mg/kg dose would be inclined to give rise to stereotyped behaviors (Hiroi et al, 1997). Such behaviors, like sniffing and rearing, would have been difficult to detect with the telemetric system used.…”

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims

“…18 In humans, the functional activity of the NAc is associated with the subjective effects of cocaine 6 and with craving for cocaine. 7,8,19 In addition to the cocaine-induced NAc plasticity, studies in rodent models indicate persistent or even permanent biochemical alterations in regions associated with the mesolimbic dopamine pathway including upregulation of the cyclic AMP (cAMP) pathway, [20][21][22][23][24][25][26] activator protein 1 family members [27][28][29][30][31][32] as well as glutamate, dopamine, gaminobutyric acid (GABA) and opiate receptors, growth factors, cytoskeletal elements and cell metabolism. [33][34][35][36][37][38][39][40][41] Genomic analyses in human post-mortem tissue of cocaine overdose (COD) victims have confirmed the findings of studies employing rodent models and have revealed novel mechanisms of drug-induced neuronal and non-neuronal dysregulation in human post-mortem brain tissue.…”

Time course of striatal ΔFosB‐like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment

“…DFosB encodes for stable transcription factors of 33, 35 and 37 kDa (Chen et al, 1997), which are induced in a region-specific manner in the brain as a response to various chronic perturbations (Hope et al, 1994;Doucet et al, 1996;Hiroi et al, 1997). In a rat model of Parkinson's disease, DFosB-like immunoreactivity provides a cellular marker to map neuronal systems that become activated by chronic, dyskinesiogenic treatment with L-DOPA .…”