c-Fos facilitates the acquisition and extinction of cocaine-induced persistent changes.
Development of drug addiction involves persistent neurobiological changes. The dopamine D1 receptor is involved in mediating cocaine-induced neuroadaptation, yet the underlying intracellular mechanisms remain unclear. We examined a potential role of the immediate early gene Fos, which is robustly and rapidly induced by cocaine via D1 receptors, in mediating cocaine-induced persistent neurobiological changes by creating and analyzing a mouse in which Fos is primarily disrupted in D1 receptor-expressing neurons in the brain. We show that the expression levels of several transcription factors, neurotransmitter receptors, and intracellular signaling molecules induced by repeated cocaine administration are altered in Fos-deficient brains. Dendritic remodeling of medium spiny neurons induced by repeated exposure to cocaine is blunted in the mutant mice. The mutant mice exhibit attenuated behavioral sensitization after repeated exposure to cocaine and more persistent memory of cocaine-induced conditioned place preference. Our findings indicate that c-Fos produced in D1 receptor-expressing neurons integrates mechanisms to facilitate both the acquisition and extinction of cocaine-induced persistent changes.
Zhang
Jianhua
J
Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Zhang
Lu
L
Jiao
Hongyuan
H
Zhang
Qi
Q
Zhang
Dongsheng
D
Lou
Danwen
D
Katz
Jonathan L
JL
Xu
Ming
M
D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003042:Cocaine; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000096:biosynthesis
D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D003042:Cocaine