Increasing evidence suggests a tight relationship exists between stress, amino acid neurotransmitter systems and Major Depressive Disorder (MDD). The relationship between stress and glutamatergic signaling is illustrated by the finding of elevated extracellular glutamate (Glu) concentrations in several brain regions following stress exposure. A recent series of studies demonstrate that several classes of Glu-modulating agents possess antidepressant-like properties in animal models, as well as in patients with mood disorders, thus providing additional support for the connection between Glu neurotransmission and MDD. Based on findings of abnormal GABA and Glu concentrations in individuals diagnosed with MDD, and a growing literature documenting significant reductions in the glial cell number and density associated with MDD, we have proposed a model whereby impaired astrocyte function and a disruption of glutamate/glutamine cycling serves a central role in the pathophysiology of MDD. Riluzole, an FDA-approved Glu-modulating agent used to delay ALS progression, exhibits anti-glutamatergic properties via modulation of neuronal Glu release and enhancement of Glu uptake. Several studies now also suggest a therapeutic action of riluzole in patients with MDD. Consistent with our hypothesized model, recently collected preliminary data from our laboratory demonstrate that riluzole attenuates and reverses the effects of behavioral stress in several rodent models that are commonly used to test for antidepressant drug activity. In addition, other work from our group using 13C- MRS to measure the rate of Glu, glutamine (Gln), and GABA synthesis, suggests that chronic stress reduces astrocyte metabolism and Glu/Gln and GABA/Gln cycling. Riluzole admnistration resulted in increased rates of Glu/Gln cycling and attenuates the effects of stress on astrocyte function. To further test the hypothesis that enhanced Glu uptake could prevent or attenuate the effects of stress and have antidepressant-like activity, we recently completed a study examining the effects of ceftriaxone, a ?-lactam that results in increased expression of the Glu transporter GLT1 and increased Glu uptake, in several rodent models used to assess antidepressant-like activity. The studies demonstrated that ceftriaxone has a profile consistent with antidepressant agents. We would now like to examine the effects of chronic stress and Glu-modulating drugs on Glu cycling, extracellular Glu content, and the relationship between these effects on glutamatergic neurotransmission and animal models of depression. We will also specifically explore the role of GLT1 mediated Glu uptake in stress and the mechanism of these drugs using pharmacological inhibitors of glutamate uptake and a genetic model of impaired GLT1 function in mice. The results of these studies could significantly expand our understanding relating the physiological response to stress to mental illness. Moreover, the results of the studies could potentially provide us with novel targets for antidepressant drug development.

Public Health Relevance

Recent studies have highlighted the limitations of our current armamentarium of antidepressant medications. The limitations of these treatments are likely to be related to the fact that they were discovered largely through serindipity, and not through a true understanding of the pathophysiological mechanisms underlying the disorders themselves. The research outlined in this proposal has direct relevance to public health and is consistent with the NIMH Director's Stategic plan by both helping to identify and better understand the causes of mental disorders, as well as seeking to develope new and better interventions for psychiatric illnesess based on the increased understanding of the pathophysiology of the disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081211-04
Application #
8259232
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Winsky, Lois M
Project Start
2009-07-10
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$376,082
Indirect Cost
$110,300
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Niciu, Mark J; Henter, Ioline D; Sanacora, Gerard et al. (2014) Glial abnormalities in substance use disorders and depression: does shared glutamatergic dysfunction contribute to comorbidity? World J Biol Psychiatry 15:2-16
Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian et al. (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742-9
Sanacora, Gerard; Banasr, Mounira (2013) From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry 73:1172-9
Krystal, John H; Sanacora, Gerard; Duman, Ronald S (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73:1133-41
Popoli, Maurizio; Yan, Zhen; McEwen, Bruce S et al. (2012) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22-37
Niciu, Mark J; Kelmendi, Benjamin; Sanacora, Gerard (2012) Overview of glutamatergic neurotransmission in the nervous system. Pharmacol Biochem Behav 100:656-64
Gourley, Shannon L; Espitia, Jonathan W; Sanacora, Gerard et al. (2012) Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice. Psychopharmacology (Berl) 219:805-14
Sanacora, Gerard; Treccani, Giulia; Popoli, Maurizio (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62:63-77