Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: Direct inhibition and disinhibition.

Miller, Oliver H; Moran, Jacqueline T; Hall, Benjamin J

Miller, Oliver H; Moran, Jacqueline T; Hall, Benjamin J.

Afiliación

Miller OH; Neuroscience Program, Tulane University, School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA. Electronic address: omiller1@tulane.edu.
Moran JT; Neuroscience Program, Tulane University, School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA. Electronic address: jmoran4@tulane.edu.
Hall BJ; Neuroscience Program, Tulane University, School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA. Electronic address: benjamin.hall@roche.com.

Neuropharmacology ; 100: 17-26, 2016 Jan.

Article en En | MEDLINE | ID: mdl-26211972

RESUMEN

A single, low dose of ketamine evokes antidepressant actions in depressed patients and in patients with treatment-resistant depression (TRD). Unlike classic antidepressants, which regulate monoamine neurotransmitter systems, ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) family of glutamate receptors. The effectiveness of NMDAR antagonists in TRD unveils a new set of targets for therapeutic intervention in major depressive disorder (MDD) and TRD. However, a better understanding of the cellular mechanisms underlying these effects is required for guiding future therapeutic strategies, in order to minimize side effects and prolong duration of efficacy. Here we review the evidence for and against two hypotheses that have been proposed to explain how NMDAR antagonism initiates protein synthesis and increases excitatory synaptic drive in corticolimbic brain regions, either through selective antagonism of inhibitory interneurons and cortical disinhibition, or by direct inhibition of cortical pyramidal neurons. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Asunto(s)

Antidepresivos/farmacología; Encéfalo/efectos de los fármacos; Trastorno Depresivo Mayor/metabolismo; Trastorno Depresivo Resistente al Tratamiento/metabolismo; Antagonistas de Aminoácidos Excitadores/farmacología; Ketamina/farmacología; Inhibición Neural; Neuronas/efectos de los fármacos; Animales; Antidepresivos/uso terapéutico; Encéfalo/metabolismo; Trastorno Depresivo Mayor/terapia; Trastorno Depresivo Resistente al Tratamiento/terapia; Terapia Electroconvulsiva; Antagonistas de Aminoácidos Excitadores/uso terapéutico; Ácido Glutámico/metabolismo; Humanos; Interneuronas/efectos de los fármacos; Interneuronas/metabolismo; Ketamina/uso terapéutico; Modelos Neurológicos; Plasticidad Neuronal; Neuronas/metabolismo; Subunidades de Proteína/metabolismo; Receptores AMPA/metabolismo; Receptores de N-Metil-D-Aspartato/metabolismo

Palabras clave

AMPA receptor; AMPAR; Ambient glutamate; Cortex; Depression; Disinhibition; Folimycin (PubChem CID: 6438151); GluN2B; Glutamate (PubChem CID: 33032); Homeostatic synaptic plasticity; Inhibition; Ketamine; Ketamine (PubChem CID: 3821); MK-801 (PubChem CID: 180081); Memantine (PubChem CID: 4054); NBQX (PubChem CID: 3272524); NMDA receptor; NMDAR; Picrotoxin (PubChem CID: 5360688); Protein synthesis; Rapamycin (PubChem CID: 5284616); Riluzole (PubChem CID: 5070); Ro 25-6981 (PubChem CID: 6604887)

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Antagonistas de Aminoácidos Excitadores / Trastorno Depresivo Mayor / Trastorno Depresivo Resistente al Tratamiento / Ketamina / Antidepresivos / Inhibición Neural / Neuronas Límite: Animals / Humans Idioma: En Revista: Neuropharmacology Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido

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