FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects.
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 DeltaFosB 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.
Hiroi
N
N
Department of Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA.
Brown
J R
JR
Haile
C N
CN
Ye
H
H
Greenberg
M E
ME
Nestler
E J
EJ
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009042:Motivation; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics*; D011597:Psychomotor Performance / Q000187:drug effects*
D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine