title: Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors.
abstract: Clinical studies demonstrate that scopolamine, a non-selective muscarinic acetylcholine receptor (mAchR) antagonist, produces rapid therapeutic effects in depressed patients, and preclinical studies report that the actions of scopolamine require glutamate receptor activation and the mechanistic target of rapamycin complex 1 (mTORC1). The present study extends these findings to determine the role of the medial prefrontal cortex (mPFC) and specific muscarinic acetylcholine receptor (M-AchR) subtypes in the actions of scopolamine. The administration of scopolamine increases the activity marker Fos in the mPFC, including the infralimbic (IL) and prelimbic (PrL) subregions. Microinfusions of scopolamine into either the IL or the PrL produced significant antidepressant responses in the forced swim test, and neuronal silencing of IL or PrL blocked the antidepressant effects of systemic scopolamine. The results also demonstrate that the systemic administration of a selective M1-AChR antagonist, VU0255035, produced an antidepressant response and stimulated mTORC1 signaling in the PFC, similar to the actions of scopolamine. Finally, we used a chronic unpredictable stress model as a more rigorous test of rapid antidepressant actions and found that a single dose of scopolamine or VU0255035 blocked the anhedonic response caused by CUS, an effect that requires the chronic administration of typical antidepressants. Taken together, these findings indicate that mPFC is a critical mediator of the behavioral actions of scopolamine and identify the M1-AChR as a therapeutic target for the development of novel and selective rapid-acting antidepressants.
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA; Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 64, Catania, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Navarria
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wohleb
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Voleti
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dutheil
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Lepack
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fuchikami
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Becker
authors.affiliation: Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 64, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06520, USA. Electronic address: ronald.duman@yale.edu.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D059445:Anhedonia / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002908:Chronic Disease; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008845:Microinjections; D046912:Multiprotein Complexes / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D000928:Antidepressive Agents; D019422:Dietary Sucrose; D046912:Multiprotein Complexes; D018727:Muscarinic Antagonists; C542801:N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide; D016760:Proto-Oncogene Proteins c-fos; D043643:Receptor, Muscarinic M1; D013449:Sulfonamides; D013830:Thiadiazoles; D012601:Scopolamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Anhedonia; Depression; Glutamate; Neuronal silencing; Stress