Abstract:
BACKGROUND AND PURPOSE: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. EXPERIMENTAL APPROACH: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. KEY RESULTS: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. CONCLUSIONS AND IMPLICATIONS: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.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Timmermann DB,Sandager-Nielsen K,Dyhring T,Smith M,Jacobsen AM,Nielsen EØ,Grunnet M,Christensen JK,Peters D,Kohlhaas K,Olsen GM,Ahring PKdoi
10.1111/j.1476-5381.2012.01989.xsubject
Has Abstractpub_date
2012-09-01 00:00:00pages
164-82issue
1eissn
0007-1188issn
1476-5381journal_volume
167pub_type
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journal_title:British journal of pharmacology
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