Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors

Neurobiol Dis. 2015 Oct;82:254-261. doi: 10.1016/j.nbd.2015.06.012. Epub 2015 Jun 21.

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.

Keywords: Anhedonia; Depression; Glutamate; Neuronal silencing; Stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anhedonia / drug effects
  • Anhedonia / physiology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Chronic Disease
  • Dietary Sucrose
  • Disease Models, Animal
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Microinjections
  • Multiprotein Complexes / metabolism
  • Muscarinic Antagonists / pharmacology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1 / antagonists & inhibitors
  • Receptor, Muscarinic M1 / metabolism*
  • Scopolamine / pharmacology*
  • Signal Transduction / drug effects
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Thiadiazoles / pharmacology
  • Time Factors
  • Tissue Culture Techniques

Substances

  • Antidepressive Agents
  • Dietary Sucrose
  • Multiprotein Complexes
  • Muscarinic Antagonists
  • N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide
  • Proto-Oncogene Proteins c-fos
  • Receptor, Muscarinic M1
  • Sulfonamides
  • Thiadiazoles
  • Scopolamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1