Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression.
Summary of "Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression."
A growing body of evidence has suggested that the dysfunction of glutamatergic systems plays a pivotal role in major depressive disorder (MDD). In clinical studies, an N-methyl-d-aspartate receptor antagonist, ketamine, was shown to exert both rapid and sustained antidepressant effects in patients with treatment-resistant MDD. The objective of the present study was to confirm the rapid onset of action of ketamine and to investigate the mechanisms underlying both the rapid and sustained antidepressant-like effects of ketamine in rodent models of depression. The intraperitoneal administration of ketamine (10mg/kg) 30min prior to testing significantly reduced the number of escape failures in the learned helplessness (LH) paradigm in rats in which currently prescribed antidepressants exerted an effect only after repeated administrations. Ketamine also significantly reduced the immobility time in the tail suspension test (TST), and this effect lasted for 72h, indicating that ketamine may possess a sustained antidepressant-like effect. The rapid antidepressant-like effects of ketamine in both the LH paradigm and the TST were significantly blocked by subcutaneous treatment with 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX), an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. In addition, the sustained antidepressant-like effect of ketamine in the TST was partially abolished by treatment with NBQX. In conclusion, we confirmed the faster onset of the action of ketamine, compared with clinically prescribed antidepressants. Moreover, the present results suggested that direct AMPA receptor activation may play an important role in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression, although other mechanisms might be involved in the sustained action.
Affiliation
Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
Journal Details
This article was published in the following journal.
Name: Behavioural brain research
ISSN: 1872-7549
Pages: 107-11
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21669235
- DOI: http://dx.doi.org/10.1016/j.bbr.2011.05.035
Medical and Biotech [MESH] Definitions
Receptors, Ampa
Cell surface proteins that bind glutamate and directly gate ion channels in cell membranes. AMPA receptors were originally discriminated from other glutamate receptors by their affinity for the agonist AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid). They are probably the most common mediators of fast excitatory synaptic transmission in the central nervous system. Several subtypes have been cloned, and for some types the traditional distinction from kainate receptors may not apply.
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
An IBOTENIC ACID homolog and glutamate agonist. The compound is the defining agonist for the AMPA subtype of glutamate receptors (RECEPTORS, AMPA). It has been used as a radionuclide imaging agent but is more commonly used as an experimental tool in cell biological studies.
Sulpiride
A dopamine D2-receptor antagonist. It has been used therapeutically as an antidepressant, antipsychotic, and as a digestive aid. (From Merck Index, 11th ed)
Receptor, Macrophage Colony-stimulating Factor
A receptor for MACROPHAGE COLONY-STIMULATING FACTOR encoded by the c-fms proto-oncogene (GENES, FMS). It contains an intrinsic protein-tyrosine kinase activity. When activated the receptor undergoes autophosphorylation, phosphorylation of down-stream signaling molecules and rapid down-regulation.
Receptor, Epidermal Growth Factor
A cell surface receptor involved in regulation of cell growth and differentiation. It is specific for EPIDERMAL GROWTH FACTOR and EGF related peptides including TRANSFORMING GROWTH FACTOR ALPHA, amphiregulin, and heparin-binding EGF-like growth factor. The binding of ligand to the receptor causes activation of its intrinsic tyrosine kinase activity and rapid internalization of the receptor-ligand complex into the cell.
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