title: Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline.
abstract: Disturbances in central dopaminergic neurotransmission are believed to be centrally involved in the pathogenesis of schizophrenia. Central dopaminergic and cholinergic systems interact and the cholinergic muscarinic agonist xanomeline has shown antipsychotic effects in clinical studies. Preclinical studies indicate that the M(4) muscarinic cholinergic receptor subtype (mAChR) modulates the activity of the dopaminergic system and that this specific mAChR subtype is involved in mediating the antipsychotic-like effects of xanomeline. A specific neuronal subpopulation that expresses M(4) mAChRs together with D(1) dopamine receptors seems to be especially important in modulating dopamine-dependent behaviors. Using mutant mice that lack the M(4) mAChR only in D(1) dopamine receptor-expressing cells (D1-M4-KO), we investigated the role of this neuronal population in the antipsychotic-like effects of xanomeline in amphetamine-induced hyperactivity and apomorphine-induced climbing. Interestingly, the antipsychotic-like effects of xanomeline in the two models were almost completely abolished in D1-M4-KO mice, suggesting that M(4) mAChRs colocalized with D(1) dopamine receptors are centrally involved in mediating the antipsychotic-like effects of xanomeline. This is consistent with the hypothesis that activation of the M(4) mAChR represents a potential target for the future medical treatment of psychosis.
authors.affiliation: Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Dencker
authors.forename: Gitta
authors.initials: G
authors.lastname: Wörtwein
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.forename: Jongrye
authors.initials: J
authors.lastname: Jeon
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomsen
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Sager
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.forename: David P D
authors.initials: DP
authors.lastname: Woldbye
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Anders
authors.initials: A
authors.lastname: Fink-Jensen
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D000697:Central Nervous System Stimulants; D018721:Muscarinic Agonists; D011725:Pyridines; D043588:Receptor, Muscarinic M4; D013830:Thiadiazoles; C075257:xanomeline; D000661:Amphetamine