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.
Woolley
Marie L
ML
Neurosciences CEDD, GlaxoSmithKline plc, New Frontiers Science Park, Harlow, Essex, England. marie.2.woolley-roberts@gsk.com
Carter
Helen J
HJ
Gartlon
Jane E
JE
Watson
Jeanette M
JM
Dawson
Lee A
LA
D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D043643:Receptor, Muscarinic M1 / Q000172:deficiency* / Q000235:genetics*; D043588:Receptor, Muscarinic M4 / Q000172:deficiency* / Q000235:genetics*; D013379:Substrate Specificity; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use
D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D013830:Thiadiazoles; C075257:xanomeline; D000661:Amphetamine