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Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition.
Adv Pharmacol. 2020; 89:43-78.AP

Abstract

There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.

Authors+Show Affiliations

Department of Biology, Pennsylvania State University, University Park, PA, United States; Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA, United States; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States. Electronic address: BXL25@psu.edu.Department of Biology, Pennsylvania State University, University Park, PA, United States; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States.Department of Biology, Pennsylvania State University, University Park, PA, United States; Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32616214

Citation

Luscher, Bernhard, et al. "Antidepressant Mechanisms of Ketamine: Focus On GABAergic Inhibition." Advances in Pharmacology (San Diego, Calif.), vol. 89, 2020, pp. 43-78.
Luscher B, Feng M, Jefferson SJ. Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition. Adv Pharmacol. 2020;89:43-78.
Luscher, B., Feng, M., & Jefferson, S. J. (2020). Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition. Advances in Pharmacology (San Diego, Calif.), 89, 43-78. https://doi.org/10.1016/bs.apha.2020.03.002
Luscher B, Feng M, Jefferson SJ. Antidepressant Mechanisms of Ketamine: Focus On GABAergic Inhibition. Adv Pharmacol. 2020;89:43-78. PubMed PMID: 32616214.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition. AU - Luscher,Bernhard, AU - Feng,Mengyang, AU - Jefferson,Sarah J, Y1 - 2020/04/22/ PY - 2020/7/4/entrez KW - Excitation: Inhibition balance KW - Gephyrin KW - Interneurons KW - Major depressive disorder KW - Synaptic plasticity KW - Synaptogenesis KW - Synaptopathology KW - γ-aminobutyric acid SP - 43 EP - 78 JF - Advances in pharmacology (San Diego, Calif.) JO - Adv. Pharmacol. VL - 89 N2 - There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca2+ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine. SN - 1557-8925 UR - https://www.unboundmedicine.com/medline/citation/32616214/Antidepressant_mechanisms_of_ketamine:_Focus_on_GABAergic_inhibition L2 - https://linkinghub.elsevier.com/retrieve/pii/S1054-3589(20)30020-X DB - PRIME DP - Unbound Medicine ER -
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