title: Ketamine-like effects of a combination of olanzapine and fluoxetine on AMPA and NMDA receptor-mediated transmission in the medial prefrontal cortex of the rat.
abstract: Preclinical studies indicate that the rapid antidepressant effect of ketamine is dependent on activation of AMPA receptors in the medial prefrontal cortex (mPFC) resulting in a prolonged enhancement of glutamatergic transmission in the mPFC. In similarity, addition of atypical antipsychotic drugs (APDs) to SSRIs has also been found to induce a rapid and potent antidepressant effect. Using intracellular recordings in layer V/VI pyramidal cells of the rat mPFC in vitro, we found that a combination of low, clinically relevant concentrations of the atypical APD olanzapine and the SSRI fluoxetine facilitated NMDA and AMPA-induced currents in pyramidal cells via activation of dopamine D1 receptors. A single ketamine injection (10mg/kg, 24h before the experiment) enhanced AMPA-and apparently to some extent also NMDA-induced currents. Our results propose that the rapid and potent antidepressant effects of both treatments may be related to a common mechanism of action, namely facilitation of glutamatergic, in particular AMPA receptor-mediated transmission, in the mPFC.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Björkholm
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Jardemark
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: Torgny.Svensson@ki.se.
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D014150:Antipsychotic Agents / Q000008:administration & dosage; D001569:Benzodiazepines / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005473:Fluoxetine / Q000008:administration & dosage*; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D005473:Fluoxetine; D007649:Ketamine; D000077152:Olanzapine; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Antidepressive agents; Antipsychotic agents; Dopamine D1 receptors; Electrophysiology; Glutamate receptors; Major depressive disorder