Archival ReportScopolamine Rapidly Increases Mammalian Target of Rapamycin Complex 1 Signaling, Synaptogenesis, and Antidepressant Behavioral Responses
Section snippets
Animals
Male Sprague–Dawley rats weighing 175 to 250 g were pair-housed and maintained in standard conditions with a 12-hour light–dark cycle and ad libitum access to food and water. Animal use and procedures were in accordance with the National Institutes of Health guidelines and approved by the Yale University Animal Care and Use Committees.
Drug Administration and Surgical Procedure
Animals received a single acute injection of vehicle, scopolamine (intraperitoneal [IP]) or the preferential M1 selective antagonist telenzepine (subcutaneous).
Muscarinic Receptor Antagonists Rapidly Increase mTORC1 Signaling
Based on previous studies demonstrating that the rapid-acting antidepressant effects of NMDA antagonists (i.e., ketamine) require mTORC1, we hypothesized that scopolamine would also increase mTORC1 signaling and related upstream signaling proteins ERK and Akt (19). A dose of 25 µg/kg was chosen based on preliminary studies indicating that low doses of scopolamine within this range increased mTORC1 signaling, whereas higher doses (100 µg/kg) had no effect (not shown). This is consistent with the
Discussion
The results demonstrate that administration of scopolamine, a muscarinic receptor antagonist with rapid antidepressant actions in humans, leads to fast activation of mTORC1 signaling and increased synaptogenesis in layer V pyramidal neurons of the medial PFC. These effects are similar to the synaptogenic actions of ketamine 10, 11, and together these findings indicate that mTORC1 signaling and synaptogenesis are key factors underlying the response to rapid acting antidepressants.
The results
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Authors BV and AN contributed equally to this work.