Targeting glial physiology and glutamate cycling in the treatment of depression.
Accumulating evidence indicates that dysfunction in amino acid neurotransmission contributes to the pathophysiology of depression. Consequently, the modulation of amino acid neurotransmission represents a new strategy for antidepressant development. While glutamate receptor ligands are known to have antidepressant effects, mechanisms regulating glutamate cycling and metabolism may be viable drug targets as well. In particular, excitatory amino acid transporters (EAATs) that are embedded in glial processes constitute the primary means of clearing extrasynaptic glutamate. Therefore, the decreased glial number observed in preclinical stress models, and in postmortem tissue from depressed patients provides intriguing, yet indirect evidence for a role of disrupted glutamate homeostasis in the pathophysiology of depression. More direct evidence for this hypothesis comes from studies using magnetic resonance spectroscopy (MRS), a technique that non-invasively measures in vivo concentrations of glutamate and other amino acids under different experimental conditions. Furthermore, when combined with the infusion of (13)C-labeled metabolic precursors, MRS can measure flux through discrete metabolic pathways. This approach has recently shown that glial amino acid metabolism is reduced by chronic stress, an effect that provides a link between environmental stress and the decreased EAAT activity observed under conditions of increased oxidative stress in the brain. Furthermore, administration of riluzole, a drug that enhances glutamate uptake through EAATs, reversed this stress-induced change in glial metabolism. Because riluzole has antidepressant effects in both animal models and human subjects, it may represent the prototype for a novel class of antidepressants with the modulation of glial physiology as a primary mechanism of action.
Valentine
Gerald W
GW
Yale University, Department of Psychiatry, CNRU, 34 Park Street, New Haven, CT 06508, USA.
Sanacora
Gerard
G
D000818:Animals; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D019782:Riluzole / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D019782:Riluzole