title: The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf⁺/⁻ heterozygous null mice.
abstract: Accumulating evidence suggests that biogenic amine-based antidepressants act, at least in part, via regulation of brain-derived neurotrophic factor (BDNF) signaling. Biogenic amine-based antidepressants increase BDNF synthesis and activate its signaling pathway through TrkB receptors. Moreover, the antidepressant-like effects of these molecules are abolished in BDNF deficient mice. Glutamate-based drugs, including the NMDA antagonist ketamine, and the AMPA receptor potentiator LY 451646, mimic the effects of antidepressants in preclinical tests with high predictive validity. In humans, a single intravenous dose of ketamine produces an antidepressant effect that is rapid, robust and persistent. In this study, we examined the role of BDNF in expression of the antidepressant-like effects of ketamine and an AMPA receptor potentiator (LY 451646) in the forced swim test (FST). Ketamine and LY 451646 produced antidepressant-like effects in the FST in mice at 45 min after a single injection, but no effects were observed one week after a single ketamine injection. As previously reported, the effects of imipramine in the forced swim test were blunted in heterozygous BDNF knockout (bdnf(+/-)) mice. However ketamine and LY 451646 produced similar antidepressant-like responses in wildtype and bdnf(+/-) mice. Neither ketamine nor LY 451646 significantly influenced the levels BDNF or TrkB phosphorylation in the hippocampus when assessed at 45 min or 7 days after the drug administration. These data demonstrate that under the conditions tested, neither ketamine nor the AMPA-potentiator LY 451656 activate BDNF signaling, but produce a characteristic antidepressant-like response in heterozygous bdnf(+/-) mice. These data indicate that unlike biogenic amine-based agents, BDNF signaling does not play a pivotal role in the antidepressant effects of glutamate-based compounds. This article is part of a Special Issue entitled 'Anxiety and Depression'.
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Jesse S O
authors.initials: JS
authors.lastname: Lindholm
authors.forename: Henri
authors.initials: H
authors.lastname: Autio
authors.forename: Liisa
authors.initials: L
authors.lastname: Vesa
authors.forename: Hanna
authors.initials: H
authors.lastname: Antila
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamäki
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency* / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D020917:Receptor, trkA / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C430915:LY 404187; D013449:Sulfonamides; D007649:Ketamine; D020917:Receptor, trkA; D007099:Imipramine