Extracellular signal-regulated mitogen-activated protein kinase inhibitors decrease amphetamine-induced behavior and neuropeptide gene expression in the striatum.
The aim of this study was to determine whether inhibition of the extracellular-regulated kinase signaling pathway decreases acute amphetamine-induced behavioral activity and neuropeptide gene expression in the rat striatum. Western blotting revealed that extracellular-regulated kinase1/2 phosphorylation was highly induced in the rat striatum 15 min after an acute amphetamine (2.5 mg/kg, i.p.) injection without altering the total amount of extracellular-regulated kinase protein. In a separate experiment, the systemic injection of SL327, a selective inhibitor of extracellular regulated kinase kinase that crosses the blood-brain barrier, 1 h prior to amphetamine administration decreased amphetamine-induced vertical and horizontal activity. Quantitative in situ hybridization histochemistry showed that SL327 abolished the high levels of preproenkephalin and preprodynorphin mRNA induced by amphetamine in the striatum with no alteration of their basal levels. In another set of experiments, the hyperlocomotor activity induced by amphetamine was reduced by pretreatment with intra-striatal infusion of U0126. U0126 also blocked the amphetamine-induced increases in phospho-extracellular-regulated kinase and preproenkephalin and preprodynorphin gene expression in the striatum. These data indicate that activation of the extracellular-regulated kinase cascade contributes to the behavioral effects and changes in striatal neuropeptide gene expression induced by acute amphetamine.
Shi
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Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 403, Charleston, SC 29425, USA.
McGinty
J F
JF
D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000661:Amphetamine / Q000009:adverse effects*; D019969:Amphetamine-Related Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004399:Dynorphins / Q000235:genetics; D004745:Enkephalins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002070:Butadienes; D004745:Enkephalins; D004791:Enzyme Inhibitors; D009479:Neuropeptides; D009570:Nitriles; D011498:Protein Precursors; D012333:RNA, Messenger; C424127:SL 327; C113580:U 0126; C036448:pre-prodynorphin; D000607:Aminoacetonitrile; D004399:Dynorphins; C033660:preproenkephalin; D000661:Amphetamine; D048049:Extracellular Signal-Regulated MAP Kinases