title: M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine.
abstract: Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2 (-/-) mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: J M
authors.initials: JM
authors.lastname: Witkin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Overshiner
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: J T
authors.initials: JT
authors.lastname: Catlow
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: G N
authors.initials: GN
authors.lastname: Wishart
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: D A
authors.initials: DA
authors.lastname: Schober
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: B A
authors.initials: BA
authors.lastname: Heinz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Nikolayev
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: V V
authors.initials: VV
authors.lastname: Tolstikov
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: W H
authors.initials: WH
authors.lastname: Anderson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: R E
authors.initials: RE
authors.lastname: Higgs
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: M-S
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom felder_christian@lilly.com jwitkin@lilly.com.
authors.forename: C C
authors.initials: CC
authors.lastname: Felder
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology*; D013550:Swimming / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D012601:Scopolamine