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

  • Bhavya Voleti
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Andrea Navarria
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Rong-Jian Liu
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Mounira Banasr
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Nanxin Li
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Rose Terwilliger
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Gerard Sanacora
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Tore Eid
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • George Aghajanian
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Ronald S. Duman
    Correspondence
    Address correspondence to Ronald S. Duman, Ph.D., 34 Park Street, New Haven, CT 06520
    Affiliations
    Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry, Neurobiology, and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut
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      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.

      Key Words

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      Linked Article

      • Scopolamine and Ketamine: Evidence of Convergence?
        Biological PsychiatryVol. 74Issue 10
        • Preview
          Recent findings have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the muscarinic acetylcholine receptor antagonist scopolamine have rapid antidepressant effects in depressed individuals (1–3). Patients resistant to other treatments reported alleviation of core major depression symptoms following infusion of low-dose ketamine or scopolamine, with effects lingering for longer than 2 weeks in some patients. The rapid efficacy of these compounds is in striking contrast to traditional antidepressants, which target the monoamine system and exert mood-elevating effects only after repeated administration (typically several weeks to months).
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