Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates

Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the inv...

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Main Authors:	Guo, M, Lu, X-Y
Format:	Online
Language:	English
Published:	Nature Publishing Group 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270309/

id	pubmed-4270309
recordtype	oai_dc
spelling	pubmed-42703092014-12-23 Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates Guo, M Lu, X-Y Original Article Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex. Nature Publishing Group 2014-12 2014-12-02 /pmc/articles/PMC4270309/ /pubmed/25463972 http://dx.doi.org/10.1038/tp.2014.126 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Guo, M Lu, X-Y
spellingShingle	Guo, M Lu, X-Y Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
author_facet	Guo, M Lu, X-Y
author_sort	Guo, M
title	Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
title_short	Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
title_full	Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
title_fullStr	Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
title_full_unstemmed	Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
title_sort	leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates
description	Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex.
publisher	Nature Publishing Group
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270309/
_version_	1613168731856306176

Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates

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