title: Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice.
abstract: Xanomeline is an M(1)/M(4) preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimer's disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. H.Shannon@Lilly.com
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: K
authors.initials: K
authors.lastname: Rasmussen
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: J C
authors.initials: JC
authors.lastname: Hart
authors.forename: S C
authors.initials: SC
authors.lastname: Peters
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: L
authors.initials: L
authors.lastname: Jeppesen
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
authors.forename: A
authors.initials: A
authors.lastname: Fink-Jensen
mesh_terms: D000544:Alzheimer Disease / Q000523:psychology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000502:physiology; D018679:Cholinergic Agonists / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004594:Electrophysiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology; D011618:Psychotic Disorders / Q000188:drug therapy / Q000209:etiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000187:drug effects*; D012559:Schizophrenia / Q000150:complications; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D018679:Cholinergic Agonists; D018721:Muscarinic Agonists; D011725:Pyridines; D011950:Receptors, Cholinergic; D013830:Thiadiazoles; C075257:xanomeline; D004298:Dopamine