Protein kinase A mediates scopolamine-induced mTOR activation and an antidepressant response.

BACKGROUND: Clinical reports have shown that scopolamine produces a rapid (3-4 d) and potent anti-depressive response without severe adverse effects. Animal experiments have proven that scopolamine induces mTOR pathway activation in an AMPAR dependent manner. The present study aimed to determine the role of PKA in scopolamine-induced potentiation of AMPAR, as well as in mTOR pathway activation and rapid antidepressant effects.

METHODS: We utilized electrophysiological recording, Western blotting, and behavior tests to examine the effects of scopolamine, the selective M2 cholinergic receptor antagonist methoctramine, and H89, a PKA specific inhibitor on AMPAR potentiation, mTOR pathway activation, and behavioral responses in a rat depression model of learned helplessness.

RESULTS: Scopolamine (1μM) rapidly increased AMPAR-fEPSP amplitudes and membrane GluA1 expression in CA1 region of hippocampal slices, both of which were abolished by H89. Moreover, scopolamine promoted AMPAR phosphorylation on GluA1 ser845, a PKA site involved in GluA1 membrane insertion. H89 disrupted both GluA1 ser845 phosphorylation and mTOR activation, as well as the antidepressant effects of scopolamine as determined via forced swim test. Additionally, methoctramine mimicked the effects of scopolamine on phosphorylation and counter-depressive action in a PKA-dependent manner.

LIMITATIONS: Only one test was used to evaluate depressive behavior, and gene knock-out rats were not yet utilized to refine our hypotheses.

CONCLUSION: Our findings revealed that PKA pathway is necessary for scopolamine-induced synaptic plasticity and mTOR pathway activation, and indicated that a potential M2-PKA mechanism underlies scopolamine's antidepressant effects. Such findings suggest that GluA1 ser845 phosphorylation may be a trigger event for scopolamine's actions, and that PKA may represent a novel target for the treatment of depressive symptoms.