WO03/062224 is an in vivo selective agonist at nicotinic ß4 receptors

Pharmacological agents that increase cholinergic transmission have considerable use in cognitive disorders and evidence from both human and animal studies suggests that nicotinic acetylcholine receptors (nAChRs) represent an attractive target for treating certain neurological disorders. This investigation aimed to provide an in vivo verification of the in vitro data on WO03/062224, an agonist selective at ß4 subunit-containing nicotinic receptors. The effects of WO03/062224 were tested on wildtype and ß4 nAChR null mice on two behavioural paradigms; locomotor behaviour and instrumental responding for food on a second order schedule. Separate groups of wildtype and ß4 nAChR subunit knockout mice were tested in each paradigm with instrumental responding and forward locomotion being measured. WO03/062224 had a greater effect in the wildtype mice than the ß4 knockout mice in both locomotor activity (unconditioned behaviour) and instrumental responding (conditioned behaviour). In wildtype mice WO03/062224 caused a significant initial depression in locomotor activity followed by a significant increase in activity. The ß4 knockout mice displayed no significant drug-induced alterations in locomotor activity at any time point. In wildtype mice WO03/062224 caused a significant depression in instrumental responding throughout the session at both 3 mg/kg and 10 mg/kg. The ß4 knockout mice only displayed a reduction in initial responding at 10 mg/kg. The present study demonstrated that the effects of WO03/062224 at 3 mg/kg on locomotor activity and instrumental responding are likely occurring through a ß4 nicotinic mechanism. This investigation has shown that at an appropriate dose WO03/062224 is a suitable in vivo probe for the contribution of ß4-containing nAChRs to behaviour and suggests that their involvement is greater than previously recognised.