title: Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain.
abstract: Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Mao
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA.
authors.forename: Henry H
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA. wangjq@umkc.edu.|Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA. wangjq@umkc.edu.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D001552:Benzazepines; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C534628:SCH 23390; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Acetylcholine; Dopamine; ERK; Nucleus accumbens; Prefrontal cortex; SCH23390; Scopolamine; Striatum