title: Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses.
abstract: Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550; and.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550; and Department of Neurophysiology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550; and rmiledi@uci.edu ksumikaw@uci.edu.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Miledi
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550; and rmiledi@uci.edu ksumikaw@uci.edu.
authors.forename: Katumi
authors.initials: K
authors.lastname: Sumikawa
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007189:Indans / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013388:Succinimides / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D018721:Muscarinic Agonists; C121001:NR2B NMDA receptor; D018722:Nicotinic Agonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013388:Succinimides; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; D009538:Nicotine; D000077265:Donepezil
keywords: donepezil; hippocampus; m1 muscarinic receptor
references.citation: Neuron. 2004 Sep 30;44(1):5-21
references.pmid: 15450156
references.citation: Neuropharmacology. 2013 Apr;67:272-83
references.pmid: 23206502
references.citation: Psychopharmacology (Berl). 1984;84(4):572-3
references.pmid: 6441959
references.citation: Ann N Y Acad Sci. 1991;621:90-7
references.pmid: 1859104
references.citation: Eur J Neurosci. 2002 Feb;15(3):498-506
references.pmid: 11876777
references.citation: Eur J Neurosci. 2007 May;25(9):2666-81
references.pmid: 17466021
references.citation: Mol Neurobiol. 2008 Aug;38(1):101-21
references.pmid: 18690555
references.citation: J Pharmacol Exp Ther. 1988 Jan;244(1):213-7
references.pmid: 3335998
references.citation: Neuron. 2001 Jul 19;31(1):131-41
references.pmid: 11498056
references.citation: Brain Res. 1999 Oct 30;846(1):137-43
references.pmid: 10536221
references.citation: Life Sci. 1997;60(13-14):1145-52
references.pmid: 9121359
references.citation: J Neurochem. 1994 Apr;62(4):1345-51
references.pmid: 8133265
references.citation: J Neurosci. 2009 Jan 28;29(4):918-29
references.pmid: 19176801
references.citation: Neurology. 2001 Aug 14;57(3):489-95
references.pmid: 11502918
references.citation: Nat Med. 2011 Apr;17(4):470-8
references.pmid: 21441918
references.citation: Neuroscience. 1991;44(1):137-47
references.pmid: 1770993
references.citation: Eur J Neurosci. 2005 Aug;22(4):845-60
references.pmid: 16115208
references.citation: J Pharmacol Exp Ther. 1995 Apr;273(1):273-9
references.pmid: 7714776
references.citation: Brain Res. 2002 Jul 19;944(1-2):82-9
references.pmid: 12106668
references.citation: Eur J Neurosci. 2006 Nov;24(10):2903-16
references.pmid: 17156213
references.citation: Eur J Neurosci. 2004 Sep;20(5):1267-75
references.pmid: 15341598
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: Eur J Pharmacol. 1987 Jul 2;139(1):79-89
references.pmid: 3653242
references.citation: J Neurosci. 2002 Oct 1;22(19):8379-90
references.pmid: 12351712
references.citation: ScientificWorldJournal. 2012;2012:267120
references.pmid: 22654580
references.citation: J Biol Chem. 2011 Mar 4;286(9):7558-66
references.pmid: 21190942
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11465-70
references.pmid: 9736760
references.citation: J Neurosci. 1995 Feb;15(2):1455-62
references.pmid: 7869110
references.citation: J Neurosci. 2005 Nov 30;25(48):11194-200
references.pmid: 16319319
references.citation: J Neurosci. 1995 May;15(5 Pt 2):4077-92
references.pmid: 7751967
references.citation: Neurosci Lett. 2005 Dec 9;389(3):163-8
references.pmid: 16112453
references.citation: Brain Res. 1992 Feb 14;572(1-2):281-5
references.pmid: 1611524
references.citation: Neuropharmacology. 1999 Apr;38(4):579-86
references.pmid: 10221761
references.citation: Br J Pharmacol. 1999 Mar;126(5):1246-52
references.pmid: 10205015
references.citation: Annu Rev Neurosci. 2000;23:649-711
references.pmid: 10845078
references.citation: Neurobiol Aging. 2006 Sep;27(9):1216-23
references.pmid: 16129514
references.citation: Eur J Neurosci. 2006 Dec;24(11):3271-84
references.pmid: 17156388
references.citation: Eur J Neurosci. 2006 Apr;23(7):1819-28
references.pmid: 16623839
references.citation: Neuroscience. 2000;99(1):17-23
references.pmid: 10924948
references.citation: Nature. 1999 Sep 2;401(6748):63-9
references.pmid: 10485705
references.citation: Neurotherapeutics. 2008 Jul;5(3):433-42
references.pmid: 18625455
references.citation: Brain Res. 2002 Aug 9;946(1):148-52
references.pmid: 12133604
references.citation: Br J Pharmacol. 1999 Jul;127(6):1486-94
references.pmid: 10455300
references.citation: Biol Psychiatry. 2001 Feb 1;49(3):258-67
references.pmid: 11230877
references.citation: Int J Geriatr Psychiatry. 2003 Apr;18(4):292-7
references.pmid: 12673604
references.citation: Nat Rev Neurosci. 2004 Apr;5(4):317-28
references.pmid: 15034556