Lower [3H]LY341495 binding to mGlu2/3 receptors in the anterior cingulate of subjects with major depressive disorder but not bipolar disorder or schizophrenia.

Abstract

INTRODUCTION:

The glutamatergic system has recently been implicated in the pathogenesis and treatment of major depressive disorders(MDD) and mGlu2/3 receptors play an important role in regulating glutamatergic tone. We therefore measured cortical levels of mGlu2/3 to determine if they were changed in MDD.

METHODS:

Binding parameters for [(3)H]LY341495 (mGlu2/3 antagonist) were determined to allow optimized in situ binding with autoradiography to be completed using a number of CNS regions. Subsequently, density of [(3)H]LY341495 binding was measured in BA24(anterior cingulate cortex), BA17(visual cortex) and BA46(dorsolateral prefrontal cortex) from subjects with MDD, Bipolar Disorder(BPD), Schizophrenia(SCZ), and controls, as well as rats treated with imipramine (20mg/kg), fluoxetine (10mg/kg), or vehicle.

RESULTS:

mGlu2/3 are widely expressed throughout the brain with high levels observed in cortex. [(3)H]LY341495 binding was significantly lower in BA24 from subjects with MDD (mean ± SEM=141.3 ± 14.65 fmol/ETE) relative to controls (184.9 ± 7.76 fmol/ETE; Cohen's d=1.005, p<0.05). There were no other differences with diagnoses, and chronic antidepressant treatment in rats had minimal effect on binding.

LIMITATIONS:

Using this approach we are unable to determine whether the change represents fluctuations in mGlu2, mGlu3, or both. Moreover, using postmortem tissue we are unable to dissociate the irrevocable confound of suicidality upon binding levels.

CONCLUSION:

We have demonstrated lower [(3)H]LY341495 binding levels in MDD in BA24-a brain region implicated in depression. Moreover we show that the lower levels are unlikely to be the result of antidepressant treatment. These data suggest that levels of either mGlu2 and/or mGlu3 are affected in the aetiology of MDD.

• Authors: Caitlin E McOmish, Geoff Pavey, Andrew Gibbons, Shaun Hopper, Madhara Udawela, Elizabeth Scarr, Brian Dean
• Journal: Journal of affective disorders (J Affect Disord) Vol. 190 Pg. 241-248 (Jan 15 2016) ISSN: 1573-2517 [Electronic] Netherlands
• PMID: 26521087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Amino Acids
• Antidepressive Agents
• Excitatory Amino Acid Antagonists
• LY 341495
• Receptors, Metabotropic Glutamate
• Xanthenes
• metabotropic glutamate receptor 2
• metabotropic glutamate receptor 3
• Fluoxetine
• Tritium
• Imipramine

Topics

• Amino Acids (metabolism)
• Animals
• Antidepressive Agents (therapeutic use)
• Bipolar Disorder (diagnostic imaging, metabolism)
• Brain (drug effects, metabolism)
• Depressive Disorder, Major (diagnostic imaging, metabolism)
• Excitatory Amino Acid Antagonists (metabolism)
• Female
• Fluoxetine (pharmacology)
• Gyrus Cinguli (diagnostic imaging, metabolism)
• Humans
• Imipramine (pharmacology)
• Male
• Middle Aged
• Radioligand Assay
• Radionuclide Imaging
• Rats
• Receptors, Metabotropic Glutamate (metabolism)
• Schizophrenia (diagnostic imaging, metabolism)
• Tritium (metabolism)
• Xanthenes (metabolism)