title: Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors.
abstract: Dopamine and acetylcholine are two principal transmitters in the striatum and are usually balanced to modulate local neural activity and to maintain striatal homeostasis. This study investigates the role of dopamine and muscarinic acetylcholine receptors in the regulation of a central signaling protein, i.e., the mitogen-activated protein kinase (MAPK). We focus on the synaptic pool of MAPKs because of the fact that these kinases reside in peripheral synaptic structures in addition to their somatic locations. We show that a systemic injection of dopamine D1 receptor (D1R) agonist SKF81297 enhances phosphorylation of extracellular signal-regulated kinases (ERKs), a prototypic subclass of MAPKs, in the adult rat striatum. Similar results were observed in another dopamine-responsive region, the medial prefrontal cortex (mPFC). The dopamine D2 receptor agonist quinpirole had no such effects. Pretreatment with a positive allosteric modulator (PAM) of muscarinic acetylcholine M4 receptors (M4Rs), VU0152100, attenuated the D1R agonist-stimulated ERK phosphorylation in the two regions, whereas the PAM itself did not alter basal ERK phosphorylation. All drug treatments had no effect on phosphorylation of c-Jun N-terminal kinases (JNKs), another MAPK subclass, in the striatum and mPFC. These results demonstrate that dopamine and acetylcholine are integrated to control synaptic ERK but not JNK activation in striatal and mPFC neurons in vivo. Activation of M4Rs exerts an inhibitory effect on the D1R-mediated upregulation of synaptic ERK phosphorylation.
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Bing
authors.initials: B
authors.lastname: Xue
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
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, Kansas City, Missouri.
authors.forename: Dao-Zhong
authors.initials: DZ
authors.lastname: Jin
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018678:Cholinergic Agents; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D011976:Receptors, Muscarinic; D048370:MAP Kinase Kinase 2; D004298:Dopamine
keywords: D1 dopamine receptor; M4 receptor; RRID:AB_10693936; RRID:AB_10695746; RRID:AB_2140557; RRID:AB_331646; RRID:AB_476693; RRID:nif-0000-30467; basal ganglia; c-Jun N-terminal kinase; extracellular signal-regulated kinase; stress-activated protein kinase