Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-08, Vol.111 (34), p.12538-12543
• Main Authors: Ishibashi, Masaru, Yamazaki, Yoshihiko, Miledi, Ricardo, Sumikawa, Katumi
• Format: Article
• Language: English
• Subjects: Agonists; Animals; Biological Sciences; Brain; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - physiology; Cholinergic agents; Cholinergic receptors; Cholinergics; Cholinesterase Inhibitors - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Hippocampus; Indans - pharmacology; Learning; Long-Term Potentiation - drug effects; Memory; Muscarinic Agonists - pharmacology; Muscarinic receptors; Neurochemistry; Neurons; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Pharmacology; Piperidines - pharmacology; Pyramidal cells; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1 - agonists; Receptors; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - metabolism; Signal Transduction - drug effects; Stimulants; Succinimides - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1408805111

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.