NeuropharmacologyInhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization
Section snippets
Generation and initial characterization of mice
All animal procedures were performed according to NIH guidelines on the ethical use of animals. Every effort was made to minimize the number of animals used and their suffering. Animals were housed three to five per cage on a 12-h light/dark cycle with free access to food and water. The TetOp-A-FOS mice have been previously described (Gerdes et al., 2006). These mice were produced and maintained on a FVB/N background. To produce A-FOS expression in the brain the TetOp-A-FOS line was crossed
Expression of A-FOS in the brain
To express A-FOS in the striatum we used the two-transgene tetracycline transactivator system. The TetOp-A-FOS line (Gerdes et al., 2006) that expresses A-FOS using the Tet-O promoter was crossed with a line using the NSE promoter to drive expression of tTA (NSE-tTA Line A) (Chen et al., 1998). Coronal brain sections were analyzed by in situ hybridization to confirmed the A-FOS mRNA expression patterns (Fig. 1). A-FOS expression was strong and homogenous throughout the striatum including the
Discussion
We expressed in the adult striatum A-FOS a novel AP-1 dominant negative. Expression does not affect baseline behavior or the initial behavioral response to cocaine. However, following repeated cocaine treatments, A-FOS animals displayed enhanced cocaine-induced hyperlocomotion compared with littermates. A-FOS had a similar affect on striatal gene expression, therefore no changes at baseline or 4 h following a single injection of cocaine, but producing significant effects on gene expression at
Acknowledgments
We would like to thank Eric Nestler for providing the NSE-tTA mice used in these experiments, and Shari Thomas for her technical support. We would also like to thank Mike Iadarola for his helpful comments on the manuscript. R.F.P. would also like to thank Alexei Morozov (Unit of Behavioral Genetics, National Institute of Mental Health, NIH) and Charles Gerfen (Laboratory of Systems Neuroscience, National Institute of Mental Health, NIH) for providing support for these studies.
References (64)
- et al.
Intra-accumbens protein kinase C inhibitor NPC 15437 blocks amphetamine-produced conditioned place preference in rats
Behav Brain Res
(2003) - et al.
Addiction, dopamine, and the molecular mechanisms of memory
Neuron
(2000) - et al.
Distribution of striatonigral and striatopallidal peptidergic neurons in both patch and matrix compartments: an in situ hybridization histochemistry and fluorescent retrograde tracing study
Brain Res
(1988) - et al.
Gene expression profile from the striatum of amphetamine-treated rats: a cDNA array and in situ hybridization histochemical study
Brain Res Gene Expr Patterns
(2002) - et al.
Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments
Neuron
(1994) - et al.
Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity
Brain Res Brain Res Rev
(1991) - et al.
A search for candidate genes for lipodystrophy, obesity and diabetes via gene expression analysis of A-ZIP/F-1 mice
Genomics
(2003) - et al.
Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal
Neuron
(1996) - et al.
Immediate-early genes: ten years on
Trends Neurosci
(1995) - et al.
A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity
Cell
(1991)
DNA binding activities of three murine Jun proteins: stimulation by Fos
Cell
Implications of protein kinase C in the nucleus accumbens in the development of sensitization to methamphetamine in rats
Neuroscience
A dominant negative to activation protein-1 (AP1) that abolishes DNA binding and inhibits oncogenesis
J Biol Chem
Cloning and characterization of guanine deaminase from mouse and rat brain
Neuroscience
Inducible, brain region-specific expression of a dominant negative mutant of c-Jun in transgenic mice decreases sensitivity to cocaine
Brain Res
Neurobehavioural mechanisms of reward and motivation
Curr Opin Neurobiol
Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res
Differential induction of Fos protein and a Fos-related antigen following acute and repeated cocaine administration
Brain Res Mol Brain Res
A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence
Drug Alcohol Depend
The effects of acute and repeated cocaine injections on protein kinase C activity and isoform levels in dopaminergic brain regions
Neuropharmacology
Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms
Am J Hum Genet
Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity
Neuron
Cocaine sensitization and reward are under the influence of circadian genes and rhythm
Proc Natl Acad Sci U S A
A genome-wide search for loci contributing to smoking and alcoholism
Genet Epidemiol
A complex program of striatal gene expression induced by dopaminergic stimulation
J Neurosci
A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence
Am J Med Genet A
Adenoviral delivery of A-FOS, an AP-1 dominant negative, selectively inhibits drug resistance in two human cancer cell lines
Cancer Gene Ther
Strain-dependent behavioural sensitization to amphetamine: role of environmental influences
Behav Pharmacol
Transgenic animals with inducible, targeted gene expression in brain
Mol Pharmacol
The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes
Genes Dev
Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine
J Neurosci
Cocaine differentially regulates activator protein-1 mRNA levels and DNA-binding complexes in the rat striatum and cerebellum
Mol Pharmacol
Cited by (0)
- 1
Present address: Laboratory of Systems Neuroscience, National Institute of Mental Health, NIH, Building 35, Room 3A1014, Bethesda, MD 20892, USA (R. F. Paletzki); Office of Provost, Massachusetts Hall, Harvard University, Cambridge, MA, USA (S. E. Hyman).