Sustained extracellular signal-regulated kinase 1/2 phosphorylation in neonate 6-hydroxydopamine-lesioned rats after repeated D1-dopamine receptor agonist administration: implications for NMDA receptor involvement.
Extracellular signal-regulated kinase (ERK) 1/2, a well known regulator of gene expression, is likely to contribute to signaling events underlying enduring neural adaptations. Phosphorylated (phospho)-ERK was examined immunohistochemically after both single and repeated (i.e., sensitizing) doses of the partial D1-dopamine (DA) receptor agonist SKF-38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benazepine HCl) to adult rats lesioned as neonates (neonate lesioned) with 6-hydroxydopamine. Remarkably, prolonged phospho-ERK accumulated primarily in layers II-III of medial prefrontal cortex (MPC), where it declined gradually yet remained significantly elevated for at least 36 d after repeated doses of SKF-38393. Sustained (> or =7 d) phospho-ERK was observed for shorter periods in various other cortical regions but was not detectable in striatum or nucleus accumbens. At 36 d, an additional injection of SKF-38393 to sensitized rats restored phospho-ERK to maximal levels only in MPC when examined 7 d later. Phosphorylated cAMP response element-binding protein (CREB), examined 7 d after the sensitizing regimen, was observed exclusively in MPC, where it was abundant throughout all layers. Systemic injections of SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile), an inhibitor of the upstream ERK activator mitogen ERK kinase, attenuated both ERK and CREB phosphorylation in layers II-III of MPC. Pretreatment with the D1 antagonist SCH-23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-OL maleate) inhibited the prolonged increase in MPC phospho-ERK, whereas the 5-HT2 receptor antagonist ketanserin (3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione tartrate) was ineffective. Competitive and noncompetitive NMDA receptor antagonists also blocked sustained ERK phosphorylation. Collectively, the present results demonstrate coupling of D1 and NMDA receptor function reflected in sustained activation of the ERK signaling pathway in MPC of SKF-38393-sensitized neonate-lesioned rats. Ultimately, long-lasting phosphorylation of ERK and CREB in MPC may play a pivotal role in any permanent adaptive change(s) in these animals.
Papadeas
Sophia T
ST
Neurobiology Curriculum, Department of Psychiatry and University of North Carolina Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7178, USA.
Blake
Bonita L
BL
Knapp
Darin J
DJ
Breese
George R
GR
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000607:Aminoacetonitrile / Q000031:analogs & derivatives; D000818:Animals; D000831:Animals, Newborn; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists
D001552:Benzazepines; D017362:Cyclic AMP Response Element-Binding Protein; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D011480:Protease Inhibitors; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C424127:SL 327; D058830:Serotonin 5-HT2 Receptor Antagonists; D000607:Aminoacetonitrile; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D007650:Ketanserin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3