TY - JOUR T1 - Subtype-Specific Inhibition of Nicotinic Acetylcholine Receptors by Choline: A Regulatory Pathway JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 268 LP - 275 DO - 10.1124/jpet.106.103135 VL - 318 IS - 1 AU - Manickavasagom Alkondon AU - Edson X. Albuquerque Y1 - 2006/07/01 UR - http://jpet.aspetjournals.org/content/318/1/268.abstract N2 - Choline is an essential nutrient and a precursor of neurotransmitter acetylcholine (ACh) and is produced at synapses during depolarization, upon hydrolysis of ACh via acetylcholinesterase, and under conditions of injury and trauma. Animal studies have shown that supplementation with choline during early development results in long-lasting improvement in memory in adults; however, the mechanisms underlying this effect are poorly defined. Previous studies revealed that choline interacts with type IA (α7*) nicotinic acetylcholine receptors (nAChRs) as a full agonist and as a desensitizing agent and is a weak agonist of type III (α3β4*) nAChRs. Because nAChRs play a role in learning and memory and are generally inhibited by agonists at low concentrations, we investigated in this study the inhibitory effects of choline on non-α7 nAChRs such as type II (α4β2*) and type III nAChRs. Using whole-cell patch-clamp recordings from neurons of rat hippocampal and dorsal striatal slices, we demonstrate that choline inhibited type III nAChR-mediated glutamate excitatory postsynaptic currents (EPSCs). Choline inhibited ACh-induced N-methyl-d-aspartate (NMDA) EPSCs in CA1 stratum radiatum (SR) interneurons of rat hippocampal slices with an IC50 of ∼15 μM. Choline did not inhibit NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in CA1 SR interneurons. Choline inhibited type II nAChRs in CA1 SR interneurons with an IC50 of ∼370 μM. The present results reveal an order of inhibitory potency for choline type III > type IA > type II nAChRs. It is concluded that brain nAChRs, but not glutamate receptors, are the primary targets for the regulatory actions of choline. The American Society for Pharmacology and Experimental Therapeutics ER -