title: The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN.
abstract: We have reported the antidepressant effects of both metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and ketamine in several animal models, and proposed that serotonergic (5-HTergic) transmission is involved in these actions. Given that the projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN), where the majority of serotonin (5-HT) neurons exist, are reportedly involved in the antidepressant effects, in this study, we investigated using the forced swimming test (FST) of C57BL/6J male mice, the role of 5-HT neurons in the DRN regulated by the mPFC-DRN projections in the antidepressant effects of an mGlu2/3 receptor antagonist, LY341495, and ketamine. Following systemic administration/microinjection into the mPFC, both LY341495 and ketamine were found to exert antidepressant effects in the FST, and the effects were attenuated by depletion of 5-HT by treatment with an inhibitor of 5-HT synthesis, PCPA. The antidepressant effects of LY341495 and ketamine were also blocked by systemic administration/microinjection into the mPFC of an AMPA receptor antagonist, NBQX. Moreover, systemic administration/microinjection into the mPFC of LY341495 and ketamine significantly increased the c-Fos expression in the 5-HT neurons in the DRN, and the effect of systemic administration of these drugs on the neuronal c-Fos expression was attenuated by microinjection of NBQX into the mPFC. Our findings suggest that activation of 5-HT neurons in the DRN regulated by stimulation of the AMPA receptor in the mPFC may be involved in the antidepressant effects of an mGlu2/3 receptor antagonist and ketamine.
authors.affiliation: Pharmacology I, Pharmacology Laboratories, Taisho Pharmaceutical, Saitama, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fukumoto
authors.affiliation: Pharmacology I, Pharmacology Laboratories, Taisho Pharmaceutical, Saitama, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Pharmacology I, Pharmacology Laboratories, Taisho Pharmaceutical, Saitama, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D003863:Depression / Q000517:prevention & control*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000502:physiology*; D010134:Fenclonine / Q000008:administration & dosage; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011810:Quinoxalines / Q000008:administration & dosage; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000008:administration & dosage
chemical_list: D000596:Amino Acids; D000928:Antidepressive Agents; C114624:LY 341495; D011810:Quinoxalines; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007649:Ketamine; D010134:Fenclonine