title: Ketamine modulates TRH and TRH-like peptide turnover in brain and peripheral tissues of male rats.
abstract: Major depression is the largest single healthcare burden with treatments of slow onset and often limited efficacy. Ketamine, a NMDA antagonist used extensively as a pediatric and veterinary anesthetic, has recently been shown to be a rapid acting antidepressant, making it a potential lifesaver for suicidal patients. Side effects and risk of abuse limit the chronic use of ketamine. More complete understanding of the neurobiochemical mechanisms of ketamine should lead to safer alternatives. Some of the physiological and pharmacological actions of ketamine are consistent with increased synthesis and release of TRH (pGlu-His-Pro-NH2), and TRH-like peptides (pGlu-X-Pro-NH2) where "X" can be any amino acid residue. Moreover, TRH-like peptides are themselves potential therapeutic agents for the treatment of major depression, anxiety, bipolar disorder, epilepsy, Alzheimer's and Parkinson's diseases. For these reasons, male Sprague-Dawley rats were anesthetized with 162 mg/kg ip ketamine and then infused intranasally with 20 μl of sterile saline containing either 0 or 5 mg/ml Glu-TRH. One, 2 or 4h later, the brain levels of TRH and TRH-like peptides were measured in various brain regions and peripheral tissues. At 1h in brain following ketamine only, the levels of TRH and TRH-like peptides were significantly increased in 52 instances (due to increased biosynthesis and/or decreased release) or decreased in five instances. These changes, listed by brain region in order of decreasing number of significant increases (↑) and/or decreases (↓), were: hypothalamus (9↑); piriform cortex (8↑); entorhinal cortex (7↑); nucleus accumbens (7↑); posterior cingulate (5↑); striatum (4↑); frontal cortex (2↑,3↓); amygdala (3↑); medulla oblongata (1↑,2↓); cerebellum (2↑); hippocampus (2↑); anterior cingulate (2↑). The corresponding changes in peripheral tissues were: adrenals (8↑); epididymis (4↑); testis (1↑,3↓); pancreas (1↑); prostate (1↑). We conclude that TRH and TRH-like peptides may be downstream mediators of the rapid antidepressant actions of ketamine.
authors.affiliation: Research Services, VA Greater Los Angeles Healthcare System, University of California, Los Angeles, CA 90073, United States; Center for Ulcer Research and Education, VA Greater Los Angeles Healthcare System, University of California, Los Angeles, CA 90073, United States; Department of Medicine, University of California, Los Angeles, CA 90073, United States. Electronic address: Albert.Pekary@va.gov.
authors.forename: A Eugene
authors.initials: AE
authors.lastname: Pekary
authors.affiliation: Research Services, VA Greater Los Angeles Healthcare System, University of California, Los Angeles, CA 90073, United States; Psychiatry Services, VA Greater Los Angeles Healthcare System, University of California, Los Angeles, CA 90073, United States; Departments of Psychiatry & Biobehavioral Sciences, University of California, Los Angeles, CA 90073, United States; Brain Research Institute, University of California, Los Angeles, CA 90073, United States.
authors.forename: Albert
authors.initials: A
authors.lastname: Sattin
authors.affiliation: Department of Psychology, University of Minnesota, 332 Bohannon Hall, 10 University Drive, Duluth, MN 55812-2494, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013405:Suicide; D013973:Thyrotropin-Releasing Hormone / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D010455:Peptides; D013973:Thyrotropin-Releasing Hormone; D016202:N-Methylaspartate; D007649:Ketamine
keywords: Anxiety; Depression; Limbic system; Neuroendocrine