Amphetamine increases phosphorylation of extracellular signal-regulated kinase and transcription factors in the rat striatum via group I metabotropic glutamate receptors.
Amphetamine is an indirect dopamine receptor agonist and increases glutamate release in the striatum. Activation of group I metabotropic glutamate receptors (mGluRs) upregulates cAMP response element-binding protein (CREB) and Elk-1 phosphorylation via extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the striatum in vivo. In the present study the role of mGluRs in the regulation of ERK1/2 pathways leading to CREB and Elk-1 phosphorylation by amphetamine was investigated using immunohistochemistry and Western blot in the rat dorsal striatum. Acute administration of amphetamine (5 mg/kg, i.p.) caused increases in phosphorylated (p)CREB, pElk-1, and pERK1/2 immunoreactivity. Intrastriatal blockade of group I mGluRs with N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC; 25 nmol) significantly attenuated amphetamine-induced pCREB, pElk-1, pERK1/2, and Fos immunoreactivity in both medial and lateral areas of the striatum. Systemic injection of an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP; 10 mg/kg, i.p.), also blocked the amphetamine induction of these phosphoproteins. In contrast, intrastriatal blockade of group II/III mGluRs with (RS)-alpha-methylserine-o-phosphate monophenyl ester (MSOPPE; 25 nmol) did not affect amphetamine-induced increases in all the four markers. Similarly, intrastriatal dantrolene (2 or 20 nmol) that blocks intracellular Ca(2+) release from ryanodine-sensitive stores did not affect amphetamine effects. Injection of PHCCC, MPEP, MSOPPE, or dantrolene alone did not alter basal levels of the three phosphoproteins and Fos. These data suggest that acute amphetamine is able to facilitate the phosphorylation of CREB, Elk-1, and ERK1/2 signaling proteins and Fos gene expression via a group I mGluR-dependent mechanism in the dorsal striatum.
Choe
Eun Sang
ES
Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes St., M3-C15, Kansas City, MO 64108, USA.
Chung
Kyung Tae
KT
Mao
Limin
L
Wang
John Q
JQ
D000661:Amphetamine / Q000494:pharmacology*; D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D003620:Dantrolene / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D001578:Benzopyrans; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D018691:Excitatory Amino Acid Antagonists; D009125:Muscle Relaxants, Central; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D014157:Transcription Factors; C442477:alpha-methylserine-O-phosphate monophenyl ester; D050807:ets-Domain Protein Elk-1; D010768:Phosphoserine; C121465:6-methyl-2-(phenylethynyl)pyridine; D000661:Amphetamine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003620:Dantrolene