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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bradley, Stefania Risso Uslaner, Jason M. Flick, Rose B. Lee, Ariel Groover, Kristina M. Hutson, Peter H. |
| Description | Country affiliation: United States Author Affiliation: Bradley SR ( MRL Department of Neuroscience, Merck & Co., Inc., West Point, PA, USA. Stefania_bradley@merck.com) |
| Abstract | Currently prescribed antidepressants affect the reuptake and/or metabolism of biogenic amines. Unfortunately for patients, these treatments require several weeks to produce significant symptom remission. However, recently it has been found that ketamine, a dissociative anesthetic agent that noncompetitively antagonizes NMDA (N-Methyl-d-aspartic acid) receptors, has rapid antidepressant effects at sub-anesthetic doses in clinically depressed patients. These findings indicate that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. For this reason, other mechanisms influencing glutamatergic functioning have gained interest. For example, the metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 (N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride) has been shown to be effective in the forced swim and tail-suspension test, behavioral assays sensitive to antidepressants. Here we extend the characterization of AMN082 by demonstrating its effects on differential reinforcement of low rates of responding (DRL)-30, another assay sensitive to antidepressants. Furthermore, we show the engagement of glutamatergic signaling by demonstrating the ability of the selective AMPA (2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid) receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione) to reverse the effects of AMN082 in the tail suspension test. In contrast, NBQX failed to reverse the effects of imipramine in the same behavioral test. Finally, we report that behaviorally efficacious doses of AMN082 modulate phosphorylation of AMPA and NMDA receptor subunits in the hippocampus. These results suggest that the antidepressant-like effects of AMN082 are, at least in part, due to modulation of AMPA and NMDA receptor activity. Therefore, our findings confirm the hypothesis that mGluR7 could represent a novel target for treating depression. |
| File Format | HTM / HTML |
| ISSN | 00913057 |
| Issue Number | 1 |
| Volume Number | 101 |
| e-ISSN | 18735177 |
| Journal | Pharmacology Biochemistry and Behavior |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2012-03-01 |
| Publisher Place | United States |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Behavioral Sciences Discipline Biochemistry Discipline Pharmacology Antidepressive Agents Pharmacology Benzhydryl Compounds Glutamic Acid Physiology Receptors, Metabotropic Glutamate Agonists Signal Transduction Drug Effects Animals Cho Cells Conditioning, Operant Cricetinae Cricetulus Cyclic Amp Metabolism Hindlimb Suspension Hippocampus Immunohistochemistry Male Mice Mice, Inbred C57bl Phosphorylation Quinoxalines Rats Rats, Sprague-dawley Receptors, Ampa Receptors, N-methyl-d-aspartate Reinforcement Schedule Journal Article |
| Content Type | Text |
| Resource Type | Article |
| Subject | Biological Psychiatry Behavioral Neuroscience Biochemistry Clinical Biochemistry Toxicology Pharmacology |
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