title: Repeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice.
abstract: One of the most striking discoveries in the treatment of major depression was the finding that infusion of a single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant effects in treatment-resistant depressed patients. However, ketamine's antidepressant-like actions are transient and can only be sustained by repeated drug treatment. Despite the fact that women experience major depression at roughly twice the rate of men, research regarding the neurobiological antidepressant-relevant effects of ketamine has focused almost exclusively on the male sex. Importantly, knowledge regarding the sex-differentiated effects, the frequency and the dose on which repeated ketamine administration stops being beneficial, is limited. In the current study, we investigated the behavioral, neurochemical and synaptic molecular effects of repeated ketamine treatment (10mg/kg; 21days) in male and female C57BL/6J mice. We report that ketamine induced beneficial antidepressant-like effects in male mice, but induced both anxiety-like (i.e., decreased time spent in the center of the open field arena) and depressive-like effects (i.e., enhanced immobility duration in the forced swim test; FST) in their female counterparts. Moreover, repeated ketamine treatment induced sustained sex-differentiated neurochemical and molecular effects, as it enhanced hippocampal synapsin protein levels and serotonin turnover in males, but attenuated glutamate and aspartate levels in female mice. Taken together, our findings indicate that repeated ketamine treatment induces opposite behavioral effects in male and female mice, and thus, present data have far-reaching implications for the sex-oriented use of ketamine in both experimental and clinical research settings.
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320 OH, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Thelen
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320 OH, USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Sens
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320 OH, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mauch
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320 OH, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Pandit
authors.affiliation: Department of Biology & Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, 300 College Park, Dayton, 45469-2320 OH, USA. Electronic address: ppitychoutis1@udayton.edu.
authors.forename: Pothitos M
authors.initials: PM
authors.lastname: Pitychoutis
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000139:chemically induced*; D001224:Aspartic Acid / Q000378:metabolism; D003863:Depression / Q000139:chemically induced*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050600:SNARE Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012727:Sex Characteristics; D016704:Synapsins / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D050600:SNARE Proteins; D016704:Synapsins; D050827:Syntaxin 1; D001224:Aspartic Acid; D012701:Serotonin; D018698:Glutamic Acid; D006897:Hydroxyindoleacetic Acid; D007649:Ketamine
keywords: 5-HIAA; 5-HT; 5-hydroxy-indoleacetic acid; ADRs; ANOVA; Antidepressant; DRN; Depression; EAA; FST; Gender; HIPP; HNK; Ketamine; MDD; N-methyl-d-aspartate; NMDA; OFT; PFC; SNARE; SYX; Stress; VEH; adverse drug reactions; analysis of variance; dorsal raphe nucleus; excitatory amino acid neurotransmitters; forced swim test; hippocampus; hydroxynorketamine; major depressive disorder; open field test; prefrontal cortex; serotonin (5-hydroxytryptamine); soluble N-ethylmaleimide-sensitive factor attachment protein receptor; syntaxin-I; vehicle