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The Journal of Neuroscience, April 15, 2000, 20(8):2783-2791

UB-165: A Novel Nicotinic Agonist with Subtype Selectivity Implicates the 42* Subtype in the Modulation of Dopamine Release from Rat Striatal Synaptosomes

Christopher G. V. Sharples¹, Sergio Kaiser¹, Lev Soliakov¹, Michael J. Marks², Allan C. Collins², Mark Washburn³, Emma Wright⁴, James A. Spencer⁴, Timothy Gallagher⁴, Paul Whiteaker², and Susan Wonnacott¹

¹ Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom, ² Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, ³ SIBIA Neurosciences Inc., La Jolla, California 92037-4641, and ⁴ School of Chemistry, University of Bristol, Bristol BS8 1TS United Kingdom

Presynaptic nicotinic acetylcholine receptors (nAChRs) on striatal synaptosomes stimulate dopamine release. Partial inhibition by the 32-selective -conotoxin-MII indicates heterogeneity of presynaptic nAChRs on dopamine terminals. We have used this -conotoxin and UB-165, a novel hybrid of epibatidine and anatoxin-a, to address the hypothesis that the -conotoxin-MII-insensitive subtype is composed of 4 and 2 subunits. UB-165 shows intermediate potency, compared with the parent molecules, at 42* and 3-containing binding sites, and resembles epibatidine in its high discrimination of these sites over 7-type and muscle binding sites. (±)-Epibatidine, (±)-anatoxin-a, and (±)-UB-165 stimulated [³H]-dopamine release from striatal synaptosomes with EC₅₀ values of 2.4, 134, and 88 nM, and relative efficacies of 1:0.4:0.2, respectively. -Conotoxin-MII inhibited release evoked by these agonists by 48, 56, and 88%, respectively, suggesting that (±)-UB-165 is a very poor agonist at the -conotoxin-MII-insensitive nAChR subtype. In assays of ⁸⁶Rb⁺ efflux from thalamic synaptosomes, a model of an 42* nAChR response, (±)-UB-165 was a very weak partial agonist; the low efficacy of (±)-UB-165 at 42 nAChR was confirmed in Xenopus oocytes expressing various combinations of human nAChR subunits. In contrast, (±)-UB-165 and (±)-anatoxin-a were similarly efficacious and similarly sensitive to -conotoxin-MII in increasing intracellular Ca²⁺ in SH-SY5Y cells, a functional assay for native 3-containing nAChR. These data support the involvement of 42* nAChR in the presynaptic modulation of striatal dopamine release and illustrate the utility of exploiting a novel partial agonist, together with a selective antagonist, to dissect the functional roles of nAChR subtypes in the brain.

Key words: neuronal nicotinic acetylcholine receptor; presynaptic nicotinic modulation; dopamine release; rat striatal synaptosomes; Xenopus oocytes; SH-SY5Y cells; -conotoxin

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2082783-09$05.00/0

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