title: Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression.
abstract: Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice.
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Dogra
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
authors.forename: Ajeet
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
authors.forename: Deepmala
authors.initials: D
authors.lastname: Umrao
authors.affiliation: Division of molecular and structural biology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
authors.forename: Amogh A
authors.initials: AA
authors.lastname: Sahasrabuddhe
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
authors.forename: Prem N
authors.initials: PN
authors.lastname: Yadav
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D061218:Depressive Disorder, Treatment-Resistant / Q000628:therapy*; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D021122:Protein Subunits / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; C109643:Ro 25-6981; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020830:rac1 GTP-Binding Protein