A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine

TY - JOUR

T1 - A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine

AU - Elmeseiny, Ola Sobhy A.

AU - Müller, Heidi Kaastrup

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024/2

Y1 - 2024/2

N2 - Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has received much attention for its rapid antidepressant effects. A single administration of ketamine elicits rapid and sustained antidepressant effects in both humans and animals. Current efforts are focused on uncovering molecular mechanisms responsible for ketamine's antidepressant activity. Ketamine primarily acts via the glutamatergic pathway, and increasing evidence suggests that ketamine induces synaptic and structural plasticity through increased translation and release of neurotrophic factors, activation of mammalian target of rapamycin (mTOR), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated synaptic potentiation. However, the initial events triggering activation of intracellular signaling cascades and the mechanisms responsible for the sustained antidepressant effects of ketamine remain poorly understood. Over the last few years, it has become apparent that in addition to the fast actions of the ligand-gated AMPARs and NMDARs, metabotropic glutamate receptors (mGluRs), and particularly mGluR5, may also play a role in the antidepressant action of ketamine. Although research on mGluR5 in relation to the beneficial actions of ketamine is still in its infancy, a careful evaluation of the existing literature can identify converging trends and provide new interpretations. Here, we review the current literature on mGluR5 regulation in response to ketamine from a molecular perspective and propose a possible mechanism linking NMDAR inhibition to mGluR5 modulation.

AB - Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has received much attention for its rapid antidepressant effects. A single administration of ketamine elicits rapid and sustained antidepressant effects in both humans and animals. Current efforts are focused on uncovering molecular mechanisms responsible for ketamine's antidepressant activity. Ketamine primarily acts via the glutamatergic pathway, and increasing evidence suggests that ketamine induces synaptic and structural plasticity through increased translation and release of neurotrophic factors, activation of mammalian target of rapamycin (mTOR), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated synaptic potentiation. However, the initial events triggering activation of intracellular signaling cascades and the mechanisms responsible for the sustained antidepressant effects of ketamine remain poorly understood. Over the last few years, it has become apparent that in addition to the fast actions of the ligand-gated AMPARs and NMDARs, metabotropic glutamate receptors (mGluRs), and particularly mGluR5, may also play a role in the antidepressant action of ketamine. Although research on mGluR5 in relation to the beneficial actions of ketamine is still in its infancy, a careful evaluation of the existing literature can identify converging trends and provide new interpretations. Here, we review the current literature on mGluR5 regulation in response to ketamine from a molecular perspective and propose a possible mechanism linking NMDAR inhibition to mGluR5 modulation.

KW - Antidepressant

KW - Homer1a

KW - Ketamine

KW - mGluR5

KW - Molecular mechanism

KW - Humans

KW - Antidepressive Agents/pharmacology

KW - Receptors, N-Methyl-D-Aspartate

KW - Brain-Derived Neurotrophic Factor/metabolism

KW - Animals

KW - Depression/metabolism

KW - Mammals/metabolism

KW - Ketamine/pharmacology

UR - http://www.scopus.com/inward/record.url?scp=85183658312&partnerID=8YFLogxK

U2 - 10.1016/j.phrs.2024.107081

DO - 10.1016/j.phrs.2024.107081

M3 - Review

C2 - 38278430

AN - SCOPUS:85183658312

SN - 1043-6618

VL - 200

JO - Pharmacological Research

JF - Pharmacological Research

M1 - 107081

ER -