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. Author manuscript; available in PMC: 2019 Jan 1.
Published in final edited form as: Biol Psychiatry. 2017 Jun 23;83(1):29–37. doi: 10.1016/j.biopsych.2017.06.017

Figure 6. Mechanisms underlying the rapid antidepressant actions of scopolamine: ACh-M1 receptor regulation of BDNF release and TrkB signaling.

Figure 6

Scopolamine or VU0255035 blockade of ACh-M1 receptors located on GABAergic interneurons results in disinhibition and a burst of glutamate that activates AMPA receptors. This leads to stimulation of voltage dependent calcium channels (VDCC) and influx of Ca2+ that activates BDNF release, which then stimulates TrkB signaling, including activation of the ERK1/2-mTORC1 pathway. This pathway controls the translation and synthesis of synaptic proteins (such as GluA1 and PSD95), which are required for the formation of new synapses, which is associated with the rapid antidepressant actions of scopolamine. Numbers indicate points in these pathways that were targeted by mutant and pharmacological approaches, including analysis of (1) BDNF Met knock in mice in which BDNF release is blocked or infusion of BDNF neutralizing antibody, (2) VDCC inhibitor, verapamil, (3) selective TrkB inhibitor, Ana-12, (4) AMPA receptor antagonist, CNQX, (5) blockade of neuronal firing, TTX, and (6) a neuronal silencing agent, the GABAA receptor agonist muscimol.