Ketamine is a potent antidepressant in two rodent models of depression

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  • A. Mathe
  • ,
  • V. Sousa
  • ,
  • C. W. Fischer, Denmark
  • T. L. Stan, Denmark
  • Gregers Wegener
  • A. Lennartsson
  • ,
  • P. Svenningsson
Background: Mood disorders are the major cause of 'Years of life lived with disability' and a major cause of 'Years of life lost because of premature death'. The problem is growing due to the increased life-span and higher depression frequency with increasing age. Methods to prevent the onset of disease have not been developed and there has been no major clinical breakthrough since introduction of monoaminergic antidepressants in 1950ies, perhaps as a consequence of the prevailing hypothesis of dysregulation in neurotransmission of biogenic amines. Using currently available drugs, 30-40% of patients are only partial- or nonresponders and additional compounds based on same mechanisms will not solve the problem. Thus there exists a major unmet medical need to develop treatments based on different modes of action. Changes in the monoaminergic systems may be a sufficient but not a necessary pathophysiological factor and converging evidence indicates that other systems, such as the glutamatergic are of paramount importance. Indeed, work at the Yale University, NIMH, and Icahn School of Medicine at Mount Sinai demonstrated the marked antidepressant effects of intravenously infused ketamine to treatment resistant patients diagnosed with major depressive disorder. In order to better understand the mechanisms of ketamine effects we decided to test it on animal models. Methods: All experiments were approved by the Karolinska Institutet's Committee for Animal Protection. Two rat models, bred at the Karolinska Institutet, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL), and the SERT KO (homozygous, heterozygous, and the wild type rats) were used. Male animals were injected 10 mg ketamine/kg body weight or vehicle and the Open Field Test (OF) and Forced Swim Test (FST) carried out 30 respectively 40 min later. The tests were recorded and subsequently scored blindly using the NOLDUS system. One hour after the injection the animals were euthanized, the brains harvested, immediately deepfrozen, and stored for future analyses. Brains were dissected into frontal cortex, hippocampus and striatum and rtPCR and Western blot used for NMDA, AMPA, and mGlu2/3 receptors, neuropeptide Y and NPY-Y1 receptor, BDNF and mTor analyses. 2-way ANOVA and Bonferroni post-hoc test were used for statistical analysis. Results: Behavioral results are presented in this abstract. I.FSL and FRL. (1) OF: FSL moved significantly more (distance/cm) and faster (cm/sec) than FRL in the test (p'so0.01). Ketamine had no significant effect on locomotion. (2) FST: FSL showed greater baseline immobility compared to FRL (p
Original languageEnglish
JournalNeuropsychopharmacology
Volume38
Pages (from-to)S553-S554
ISSN0893-133X
Publication statusPublished - 2013

    Research areas

  • ketamine antidepressant agent receptor neuropeptide Y receptor biogenic amine brain derived neurotrophic factor alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid n methyl dextro aspartic acid open field test psychopharmacology rodent model college forced swim test animal model rat immobility brain antidepressant activity patient human wild type injection locomotion pathology lifespan protection death statistical analysis post hoc analysis rat model major depression school university disability Western blotting reverse transcription polymerase chain reaction corpus striatum hippocampus frontal cortex monoaminergic system body weight male mood disorder male animal hypothesis velocity model neurotransmission analysis of variance

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