Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine.
Acute exposure to cocaine transiently induces several Fos family transcription factors in the nucleus accumbens, a region of the brain that is important for addiction. In contrast, chronic exposure to cocaine does not induce these proteins, but instead causes the persistent expression of highly stable isoforms of deltaFosB. deltaFosB is also induced in the nucleus accumbens by repeated exposure to other drugs of abuse, including amphetamine, morphine, nicotine and phencyclidine. The sustained accumulation of deltaFosB in the nucleus accumbens indicates that this transcription factor may mediate some of the persistent neural and behavioural plasticity that accompanies chronic drug exposure. Using transgenic mice in which deltaFosB can be induced in adults in the subset of nucleus accumbens neurons in which cocaine induces the protein, we show that deltaFosB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of deltaFosB appear to be mediated partly by induction of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole) glutamate receptor subunit GluR2 in the nucleus accumbens. These results support a model in which deltaFosB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction.
Kelz
M B
MB
Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Chen
J
J
Carlezon
W A
WA
Whisler
K
K
Gilden
L
L
Beckmann
A M
AM
Steffen
C
C
Zhang
Y J
YJ
Marotti
L
L
Self
D W
DW
Tkatch
T
T
Baranauskas
G
G
Surmeier
D J
DJ
Neve
R L
RL
Duman
R S
RS
Picciotto
M R
MR
Nestler
E J
EJ
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018091:Receptors, AMPA / Q000235:genetics / Q000502:physiology; D018139:Simplexvirus / Q000235:genetics
D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D003042:Cocaine; C104722:glutamate receptor ionotropic, AMPA 2