Elsevier

Biological Psychiatry

Volume 74, Issue 10, 15 November 2013, Pages 742-749
Biological Psychiatry

Archival Report
Scopolamine Rapidly Increases Mammalian Target of Rapamycin Complex 1 Signaling, Synaptogenesis, and Antidepressant Behavioral Responses

https://doi.org/10.1016/j.biopsych.2013.04.025Get rights and content

Background

Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of N-methyl-D-aspartate receptor antagonists.

Methods

The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and two-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and glutamate receptor inhibitors.

Results

The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist.

Conclusions

Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to N-methyl-D-aspartate receptor antagonists. These findings provide novel targets for safer and more efficacious rapid-acting antidepressant agents.

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.

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