Inducible, brain region-specific expression of a dominant negative mutant of c-Jun in transgenic mice decreases sensitivity to cocaine.
Administration of cocaine induces the Fos family of transcription factors in the striatum, including the nucleus accumbens (NAc), a brain region important for the rewarding effects of addictive drugs. Several Fos proteins are induced acutely by cocaine, with stable isoforms of DeltaFosB predominating after chronic drug administration. However, it has been difficult to study the functional consequences of these Fos responses in vivo. Fos proteins heterodimerize with members of the Jun family to form active AP-1 transcription factor complexes. In the present study, we took advantage of this property and generated transgenic mice, using the tetracycline gene regulation system, that support the inducible, brain region-specific expression of a dominant negative mutant form of c-Jun (Deltac-Jun), which can antagonize the actions of Fos proteins. Expression of Deltac-Jun in the striatum and certain other brain regions of adult mice decreases their development of cocaine-induced conditioned place preference, suggesting reduced sensitivity to the rewarding effects of cocaine. In contrast, Deltac-Jun expression had no effect on cocaine-induced locomotor activity or sensitization. However, expression of Deltac-Jun in adult mice blocked the ability of chronic cocaine administration to induce three known targets for AP-1 in the NAc: the AMPA glutamate receptor subunit GluR2, the cyclin-dependent protein kinase Cdk5, and the transcription factor nuclear factor-kappaB (NFkappaB), without affecting several other proteins examined for comparison. Taken together, these results provide further support for an important role of AP-1-mediated transcription in some of the behavioral and molecular mechanisms underlying cocaine addiction.
Peakman
M-C
MC
Department of Exploratory Medicinal Sciences and CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Colby
C
C
Perrotti
L I
LI
Tekumalla
P
P
Carle
T
T
Ulery
P
P
Chao
J
J
Duman
C
C
Steffen
C
C
Monteggia
L
L
Allen
M R
MR
Stock
J L
JL
Duman
R S
RS
McNeish
J D
JD
Barrot
M
M
Self
D W
DW
Nestler
E J
EJ
Schaeffer
E
E
D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000502:physiology; D005799:Genes, Dominant / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D016716:PC12 Cells; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats
D016755:Proto-Oncogene Proteins c-jun; D003042:Cocaine