FOSB MUTANT MICE - LOSS OF CHRONIC COCAINE INDUCTION OF FOS-RELATED PROTEINS AND HEIGHTENED SENSITIVITY TO COCAINE PSYCHOMOTOR AND REWARDING EFFECTS

Chronic exposure to cocaine leads to prominent, long-lasting changes i n behavior that characterize a state of addiction. The striatum, inclu ding the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-rel ated proteins of 35-37 kDa are induced in the striatum by chronic coca ine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using fosB mutant mic e. 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 l ocomotor activation in response to initial cocaine exposures as well a s robust conditioned place preference to a lower dose of cocaine, comp ared with wild-type littermates. These results establish the long-last ing Fos-related proteins as products of the fosB gene (specifically De lta FosB isoforms) and suggest that transcriptional regulation by fosB gene products plays a critical role in cocaine-induced behavioral res ponses, This finding demonstrates that a Fos family member protein pla ys a functional role in behavioral responses to drugs of abuse and imp licates fosB gene products as important determinants of cocaine abuse.