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Glutamate—Hypothalamic-Pituitary-Adrenal Axis Interactions: Implications for Mood and Anxiety Disorders

  • Sanjay J. Mathew, Jeremy D. Coplan, Eric L.P. Smith, Darryle D. Schoepp, Leonard A. Rosenblum and Jack M. Gorman...

Abstract

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

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1. Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477501.
2. Heim, C, Newport, DJ, Heit, S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA. 2000;284:592597.
3. Coplan, JD, Andrews, MW, Rosenblum, LA, et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci U S A. 1996;93:16191623.
4. Sapolsky, RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57:925935.
5. Lopez, JF, Akil, H, Watson, SJ. Neural circuits mediating stress. Biol Psychiatry. 1999;46:14611471.
6. Skolnick, P. Antidepressants for the new millennium. Eur J Pharmacol. 1999;375;3140.
7. Cotman, CW, Kahle, JS, Miller, SE, et al. Excitatory amino acid neurotransmission. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven; 1995:7585.
8. Krystal, JH, D'Souza, CD, Petrakis, IL, et al. NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harvard Rev Psychiatry. 1999;7:125143.
9. Marek, GJ, Aghajanian, GK. Excitation of interneurons in piriform cortex by 5-hydroxytryptamine (5-HT): blockade by MDL 100,907, a highly selective 5-HT2A antagonist. Eur J Pharmacol. 1994;259:137141.
10. Maragakis, NJ, Rothstein, JD. Glutamate transporters in neurologic disease. Arch Neurol. 2001;58:365370.
11. Brauner-Osborne, H, Egebjerb, J, Nielsen, EO, et al. Ligands for glutamate receptors: design and therapeutic prospects. J Med Chem. 2000;43:26092645.
12. Gabr, RW, Birkle, DL, Azzaro, AJ. Stimulation of the amygdala by glutamate facilitates corticotropin-releasing factor release from the median eminence and activation of the hypothalamic-pituitary-adrenal axis in stressed rats. Neuroendocrinology. 1995;62:333339.
13. Crafty, MS, Birkle, DL. N-methyl-D-aspartate (NMDA)-mediated corticotropin-releasing factor (CRF) release in cultured rat amygdala neurons. Peptides. 1999;20:93100.
14. Feldman, S, Weidenfeld, J. Hypothalamic mechanisms mediating glutamate effects on the hypothalamie-pituitary-adrenocortical axis. J Neural Transm. 1997:104:633642.
15. Singewald, N, Zhou, GY, Chen, F, et al. Corticotropin-releasing factor modulates basal and stress-induced excitatory amino acid release in the locus ceruleus of conscious rats. Neurosci Lett. 1996;204:4548.
16. McEwen, BS, Albeck, D, Cameron, H, et al. Stress and brain: a paradoxical role for adrenal steroids. In: Litwack, GD, ed. Vitamins and Hormones. San Diego, CA: Academic Press; 1995:371402.
17. Moghaddam, B, Bolinao, ML, Stein-Behrens, B, et al. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res. 1994;655:251254.
18. Gould, E, Tanapat, P. Stress and hippocampal neurogenesis. Biol Psychiatry. 1999;46:14721479.
19. Cameron, HA, McEwen, BS, Gould, E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci. 1995;15:46874692.
20. Jacobs, BL, van Praag, H, Gage, FH. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry. 2000;5:262269.
21. Kocsis, K, Kiss, J, Gores, T, et al. Metabotropic glutamate receptor in vasopressin, CRF and VIP hypothalamic neurons. Neuroreport. 1998;9:40294033.
22. Mathew, SJ, Smith, ELP, Trost, RC, et al. Effects of chronic treatment with the novel metabotropic glutamate receptor agonist LY354740 in nonhuman primates: evidence for uncoupling of the HPA axis and noradrenergic system [abstract]. Young Investigators Abstract presented at American Psychiatric Association annual meeting; May 5-10, 2001; New Orleans, La.
23. Joanny, P, Steinberg, J, Oliver, C, et al. Glutamate and N-methyl-D-aspartate stimulate rat hypothalamic corticotropin-releasing factor secretion in vitro. J Neuroendocrinol. 1997;9:9397.
24. Tokarev, D, Jezova, D. Effect of central administration of the non-NMDA receptor antagonist DNQX on ACTH and corticosterone release before and during immobilization stress. Methods Find Exp Clin Pharmacol. 1997;19:323328.
25. Zelena, D, Makara, GB, Jezova, D. Simultaneous blockade of two glutamate receptor subtypes (NMDA and AMPA) results in stressor-specific inhibition of prolactin and corticotropin release. Neuroendocrinology. 1999;69:316323.
26. Calabrese, JR, Bowden, CL, Sachs, GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:7988.
27. Berman, RM, Cappiello, A, Anand, A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351354.
28. Nowak, G, Ordway, GA, Paul, IA. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res. 1995;675:157164.
29. Levine, J, Panchalingam, K, Rapoport, A, et al. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry. 2000;47:586593.
30. Auer, DP, Putz, B, Kraft, E, et al. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry. 2000;47:305313.
31. Rosenberg, DR, MacMaster, FP, Keshavan, MS, et al. Decrease in caudate glutamatergic concentrations in pediatric obsessive compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psych. 2000;39:10961103.
32. Duman, RS, Heninger, GR, Nestler, EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54:597606.
33. Nibuya, M, Morinobu, S, Duman, RS. Regulation of BDNF and trkB mRNA following chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15:75397547.
34. Altar, CA. Neurotrophins and depression. Trends Pharmacol Sci. 1999;20:5961.
35. Brandoli, C, Sanna, A, De Bernardi, MA, et al. Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells. J Neurosci. 1998;18:79537961.
36. Hayashi, T, Umemori, H, Mishina, M. The AMPA receptor interactions with and signals through the protein tyrosine kinase Lyn. Nature. 1999;397:7276.
37. Caldji, C, Francis, D, Sharma, S, et al. The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and nov elty-induced fearfulness in the rat. Neuropsychopharmacology. 2000;22:219229.
38. Tanaka, K, Watase, K, Mabe, T, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276:16991702.

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Glutamate—Hypothalamic-Pituitary-Adrenal Axis Interactions: Implications for Mood and Anxiety Disorders

  • Sanjay J. Mathew, Jeremy D. Coplan, Eric L.P. Smith, Darryle D. Schoepp, Leonard A. Rosenblum and Jack M. Gorman...

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