Inhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization.
We have expressed A-FOS, an inhibitor of activator protein-1 (AP-1) DNA binding, in adult mouse striatal neurons. We observed normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral response to cocaine. We analyzed mRNA from the striatum before and 4 and 24 h after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 h following cocaine treatment relative to controls. However, 24 h after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. Fifty-six genes are down-regulated while 28 genes are up-regulated including previously identified candidates for addiction including brain-derived neurotrophic factor and period homolog 1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared with human genome scans of addiction to identify potential genes in humans that are involved in addiction.
Paletzki
R F
RF
Laboratory of Molecular Pathophysiology, National Institute of Neurological Disorders and Stroke, NIH, Building 36, Room 4C-24, Bethesda, MD 20892, USA.
Myakishev
M V
MV
Polesskaya
O
O
Orosz
A
A
Hyman
S E
SE
Vinson
C
C
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D002874:Chromosome Mapping / Q000379:methods; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis / Q000379:methods; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051818:Replication Protein C / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D051818:Replication Protein C; D010751:Phosphopyruvate Hydratase; D003042:Cocaine