title: Further Evaluation of Mechanisms Associated with the Antidepressantlike Signature of Scopolamine in Mice.
abstract: BACKGROUND
  Conventional antidepressants lack efficacy for many patients (treatmentresistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action.
  
  
  METHODS
  Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature with ketamine or scopolamine when studied under the forced-swim test.
  
  
  RESULTS
  The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (AZD8055) also attenuated the antidepressant- like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant- like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action.
  
  
  CONCLUSIONS
  Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Martin
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Schober
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nikolayev
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Tolstikov
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Wesley H
authors.initials: WH
authors.lastname: Anderson
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Higgs
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Laksmanan
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: John T
authors.initials: JT
authors.lastname: Catlow
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Neuroscience Discovery Research, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285-0510, United States.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.affiliation: Neuroscience Discovery Research, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285-0510, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015283:Citalopram / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D055442:Metabolome / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D009025:Morpholines; D011810:Quinoxalines; D043643:Receptor, Muscarinic M1; D018091:Receptors, AMPA; D012601:Scopolamine; D017367:Selective Serotonin Reuptake Inhibitors; D058570:TOR Serine-Threonine Kinases; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546843:mTOR protein, mouse
keywords: Antidepressant; ketamine; metabolomics; mice; scopolamine; α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic
  acid