title: Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR.
abstract: BACKGROUND
  A number of preclinical and clinical studies suggest that ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has a rapid and lasting antidepressant effect when administered either acutely or chronically. It has been postulated that this effect is due to stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
  
  
  OBJECTIVE
  In this study, we tested whether AMPA alone has an antidepressant effect and if the combination of AMPA and ketamine provides added benefit in Wistar-Kyoto rats, a putative animal model of depression.
  
  
  RESULTS
  Chronic AMPA treatment resulted in a dose-dependent antidepressant effect in both the forced swim test and sucrose preference test. Moreover, chronic administration (10-11 days) of combinations of AMPA and ketamine, at doses that were ineffective on their own, resulted in a significant antidepressant effect. The behavioral effects were associated with increases in hippocampal brain-derived neurotrophic factor, synapsin, and mammalian target of rapamycin.
  
  
  CONCLUSIONS
  These findings are the first to provide evidence for an antidepressant effect of AMPA and suggest the usefulness of AMPA-ketamine combination in treatment of depression. Furthermore, these effects appear to be associated with increases in markers of hippocampal neurogenesis and synaptogenesis, suggesting a mechanism of their action.
authors.affiliation: Department of Pharmacology, Howard University College of Medicine, 520 W Street NW, Washington, DC, 20059, USA.
authors.forename: Luli
authors.initials: L
authors.lastname: Akinfiresoye
authors.forename: Yousef
authors.initials: Y
authors.lastname: Tizabi
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013550:Swimming; D016704:Synapsins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate; D016704:Synapsins; D007649:Ketamine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases