Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors
| Autor: | D B, Timmermann, K, Sandager-Nielsen, T, Dyhring, M, Smith, A-M, Jacobsen, E Ø, Nielsen, M, Grunnet, J K, Christensen, D, Peters, K, Kohlhaas, G M, Olsen, P K, Ahring |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Nicotine Oxadiazoles Pyridines Recognition Psychology Motor Activity Receptors Nicotinic Research Papers Cell Line Rats Rats Sprague-Dawley Mice Protein Subunits Xenopus laevis Cognition HEK293 Cells Allosteric Regulation Cell Line Tumor Oocytes Animals Humans Female Nicotinic Agonists Rats Wistar Maze Learning |
| Zdroj: | British journal of pharmacology. 167(1) |
| ISSN: | 1476-5381 |
| Popis: | Positive allosteric modulation of α4β2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively.Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+) imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats.NS9283 was shown to increase agonist-evoked response amplitude of (α4)(3) (β2)(2) nACh receptors in electrophysiology paradigms. (α2)(3) (β2)(2) , (α2)(3) (β4)(2) and (α4)(3) (β4)(2) were modulated to comparable extents, but no effects were detected at α3-containing or any 2α : 3β stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHβE-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors.These results provide compelling evidence that positive allosteric modulators acting at the (α4)(3) (β2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that α4β2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment. |
| Databáze: | OpenAIRE |
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