Timmermann_2012_Br.J.Pharmacol_167_164

BACKGROUND AND PURPOSE: Positive allosteric modulation of alpha4beta2 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 (alpha4)(3) (beta2)(2) nACh receptors in electrophysiology paradigms. (alpha2)(3) (beta2)(2) , (alpha2)(3) (beta4)(2) and (alpha4)(3) (beta4)(2) were modulated to comparable extents, but no effects were detected at alpha3-containing or any 2alpha : 3beta stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHbetaE-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 (alpha4)(3) (beta2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that alpha4beta2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.