Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice

The muscarinic acetylcholine receptor (mAChR) agonist, xanomeline, attenuates amphetamine-induced activity in WT mice. This effect is abolished in mice lacking the M-4 muscarinic acetylcholine receptor (M-4 mAChR KO) and partially attenuated in mice lacking M-1 muscarinic acetylcholine receptor (M-1 mAChR KO). Collectively, these data suggest that the efficacy exhibited by xanomeline in the mouse amphetamine-induced hyperactivity model, is mediated predominantly by M-4 muscarinic acetylcholine receptors, and that M-1 muscarinic acetylcholine receptors may play a more minor role. This supports the hypothesis that activation of M-4, and to a lesser extent M-1 muscarinic acetylcholine receptors, may represent a potential target for the treatment of psychosis seen in schizophrenia. (C) 2009 Elsevier B.V. All rights reserved.