Rapid Communication: 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 M4 muscarinic acetylcholine receptor (M4 mAChR KO) and partially attenuated in mice lacking M1 muscarinic acetylcholine receptor (M1 mAChR KO). Collectively, these data suggest that the efficacy exhibited by xanomeline in the mouse amphetamine-induced hyperactivity model, is mediated predominantly by M4 muscarinic acetylcholine receptors, and that M1 muscarinic acetylcholine receptors may play a more minor role. This supports the hypothesis that activation of M4, and to a lesser extent M1 muscarinic acetylcholine receptors, may represent a potential target for the treatment of psychosis seen in schizophrenia.