Abstract
The relative contribution of α4β2, α7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the α7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to α7 nAChR in rat brain membranes (Ki = 62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)3 receptors (Ki = 60 nM). ABBF was a potent agonist at the recombinant rat and human α7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT3 receptor and α3β4, α4β2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3–1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the α7 nAChR antagonist methyllycaconitine at 10 μg, indicating that it is mediated by α7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3–1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3–30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that selective α7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118976.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; MLA, methyllycaconitine; 5-HT, 5-hydroxytryptamine; ABBF, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide; HEK, human embryonic kidney; D, drug; V, vehicle; ANOVA, analysis of variance; LSD, least significant difference; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); A-85380, 3-(2(S)-azetidinylmethoxy) pyridine; AR-R 17779, (–)-spiro[1-azabicyclo[2.2.2]octane-3,5′-oxazolidin-2′-one; GTS-21 (DMXB), 3-[2,4-dimethoxybenzylidene]anabaseine; GR65630, 3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone; SSR180711, 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester; PHA-543,613, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide.
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↵1 Current affiliation: Lilly Research Centre, Windlesham, United Kingdom.
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↵2 Current affiliation: Grünenthal GmbH, Aachen, Germany.
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↵3 Current affiliation: Merz GmbH, Frankfurt, Germany.
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↵4 Current affiliation: Department of Pharmacology, University of Iowa City, Iowa City, Iowa.
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↵5 Current affiliation: Animal Sciences Group, Wageningen University and Research Center, Lelystad, The Netherlands.
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↵6 Current affiliation: Schwarz BioSciences GmbH, Monheim, Germany.
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↵7 Current affiliation: EnVivo Pharmaceuticals, Watertown, Massachusetts.
- Received December 21, 2006.
- Accepted February 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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