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Mol Psychiatry ; 20(7): 889-900, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25092247

ABSTRACT

Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress and impaired HPA function without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2(-/-) mice were potently more sensitive to the action of unpredictable chronic mild stress (UCMS) on depression-related behaviors involving self-care, spatial memory, social interaction and stress-sensitive spontaneous behavior. The functional state of the glycogen synthase kinase-3ß (GSK3ß) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2(-/-) mice. In vivo pharmacology and western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3ß signaling in OCT2(-/-) mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.


Subject(s)
Brain/physiopathology , Glycogen Synthase Kinase 3/metabolism , Organic Cation Transport Proteins/metabolism , Stress, Psychological/metabolism , Action Potentials/drug effects , Acute Disease , Animals , Brain/drug effects , Chronic Disease , Corticosterone/administration & dosage , Corticosterone/metabolism , Depression/metabolism , Glycogen Synthase Kinase 3 beta , Hormones/administration & dosage , Hormones/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Norepinephrine/metabolism , Organic Cation Transport Proteins/genetics , Organic Cation Transporter 2 , Proto-Oncogene Proteins c-akt/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Resilience, Psychological , Serotonin/metabolism , Uncertainty
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