mTORC1 pathway is involved in the kappa opioid receptor activation-induced increase in excessive alcohol drinking in mice.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
/ administration & dosage
Animals
Binge Drinking
/ drug therapy
Central Nervous System Depressants
/ administration & dosage
Disease Models, Animal
Ethanol
/ administration & dosage
Gene Expression
/ drug effects
Male
Mechanistic Target of Rapamycin Complex 1
/ genetics
Mice
Mice, Inbred C57BL
Nucleus Accumbens
/ drug effects
Receptors, Opioid, kappa
/ agonists
Signal Transduction
/ drug effects
Sirolimus
/ administration & dosage
Transcriptome
Excessive alcohol drinking
KOP-r
RNA-seq
Rapamycin
U50,488H
mTORC1
Journal
Pharmacology, biochemistry, and behavior
ISSN: 1873-5177
Titre abrégé: Pharmacol Biochem Behav
Pays: United States
ID NLM: 0367050
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
27
01
2020
revised:
22
05
2020
accepted:
25
05
2020
pubmed:
30
5
2020
medline:
9
2
2021
entrez:
30
5
2020
Statut:
ppublish
Résumé
KOP-r agonist U50,488H produces strong aversion and anxiety/depression-like behaviors that enhance alcohol intake and promote alcohol seeking and relapse-like drinking in rodents. Mammalian target of rapamycin complex 1 (mTORC1) pathway in mouse striatum is highly involved in excessive alcohol intake and seeking, and in the U50,488H-induced conditioned place aversion. Therefore, we hypothesized that KOP-r activation increases alcohol consumption through the mTORC1 activation. This study focuses on: (1) how chronic excessive alcohol drinking (4-day drinking-in-the-dark paradigm followed by 3-week chronic intermittent access drinking paradigm [two-bottle choice, 24-h access every other day]) affected nuclear transcript levels of the mTORC1 pathway genes in mouse nucleus accumbens shell (NAcs), using transcriptome-wide RNA sequencing analysis; and (2) whether selective mTORC1 inhibitor rapamycin could alter excessive alcohol drinking and prevent U50,488H-promoted alcohol intake. Thirteen nuclear transcripts of mTORC1 pathway genes showed significant up-regulation in the NAcs, with two genes down-regulated, after excessive alcohol drinking, suggesting the mTORC1 pathway was profoundly disrupted. Single administration of rapamycin decreased alcohol drinking in a dose-dependent manner. U50,488H increased alcohol drinking, and pretreatment with rapamycin, at a dose lower than effective doses, blocked the U50,488H-promoted alcohol intake in a dose-dependent manner, indicating a mTORC1-mediated mechanism. Our results provide supportive and direct evidence relevant to the transcriptional profiling of the critical mTORC1 genes in mouse NAc shell: with functional and pharmacological effects of rapamycin, altered nuclear transcripts in the mTORC1 signaling pathway after excessive alcohol drinking may contribute to increased alcohol intake triggered by KOP-r activation.
Identifiants
pubmed: 32470351
pii: S0091-3057(20)30053-8
doi: 10.1016/j.pbb.2020.172954
pmc: PMC7442164
mid: NIHMS1609471
pii:
doi:
Substances chimiques
Central Nervous System Depressants
0
Receptors, Opioid, kappa
0
Ethanol
3K9958V90M
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
67198-13-4
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Sirolimus
W36ZG6FT64
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
172954Subventions
Organisme : NIAAA NIH HHS
ID : R03 AA021970
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest All authors declare that they have no conflicts of interest.
Références
Psychopharmacology (Berl). 2010 Jun;210(2):199-209
pubmed: 20401606
Addict Biol. 2013 May;18(3):425-33
pubmed: 21507157
Addict Biol. 2017 Nov;22(6):1856-1869
pubmed: 27766766
Alcohol Clin Exp Res. 2017 Aug;41(8):1402-1418
pubmed: 28425121
Neuropsychopharmacology. 2019 Sep;44(10):1728-1741
pubmed: 31141817
Int J Neuropsychopharmacol. 2017 Sep 1;20(9):758-768
pubmed: 28575455
Neuropsychopharmacology. 2018 Aug;43(9):1805-1812
pubmed: 29463912
Pharmacol Biochem Behav. 2015 Feb;129:87-96
pubmed: 25542586
Neuropsychopharmacology. 2008 Feb;33(3):643-52
pubmed: 17473837
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Physiol Behav. 2007 Sep 10;92(1-2):167-71
pubmed: 17610914
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20093-8
pubmed: 21041654
J Neurochem. 1990 Nov;55(5):1734-40
pubmed: 1976759
Am J Psychiatry. 2007 Aug;164(8):1149-59
pubmed: 17671276
J Neurosci. 2016 Jan 20;36(3):701-13
pubmed: 26791202
Regul Pept. 2014 Jun-Aug;192-193:6-14
pubmed: 25072633
Alcohol Clin Exp Res. 2016 Dec;40(12):2537-2547
pubmed: 27796078
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Neuropharmacology. 2016 Jun;105:164-174
pubmed: 26773198
J Pharmacol Exp Ther. 2018 Jul;366(1):9-20
pubmed: 29669731
PLoS One. 2012;7(11):e49274
pubmed: 23209567
Cell Rep. 2016 Mar 29;14(12):2774-83
pubmed: 26997280
Psychopharmacology (Berl). 2000 Dec;153(1):93-102
pubmed: 11255932
Addict Biol. 2013 Jul;18(4):678-88
pubmed: 22994904
Psychopharmacology (Berl). 2001 Sep;157(2):151-62
pubmed: 11594439
Genome Biol. 2014;15(12):550
pubmed: 25516281
Curr Top Behav Neurosci. 2013;13:31-86
pubmed: 21786203
Alcohol Clin Exp Res. 2019 Jun;43(6):1077-1090
pubmed: 30908671
Neuropharmacology. 2019 Apr;148:210-219
pubmed: 30659838
Neuropsychopharmacology. 2019 Apr;44(5):939-949
pubmed: 30082888
Physiol Behav. 2005 Jan 31;84(1):53-63
pubmed: 15642607
Biol Psychiatry. 2019 Dec 1;86(11):864-871
pubmed: 31399255
Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19802-7
pubmed: 24248345
Int J Neuropsychopharmacol. 2016 Apr 29;19(5):
pubmed: 26625893
Genes Brain Behav. 2019 Nov;18(8):e12600
pubmed: 31339663
Alcohol Clin Exp Res. 2011 Nov;35(11):1938-47
pubmed: 21631540
Biol Psychiatry. 2014 May 15;75(10):774-82
pubmed: 23611261
FASEB J. 2008 Jul;22(7):2393-404
pubmed: 18310464
Alcohol. 2011 Nov;45(7):621-30
pubmed: 21840158
J Proteome Res. 2019 Sep 6;18(9):3492-3502
pubmed: 31329447
Psychopharmacology (Berl). 2018 Jun;235(6):1727-1743
pubmed: 29654346
Neuropsychopharmacology. 2018 Jun;43(7):1539-1547
pubmed: 29497165
J Neurosci. 2015 Nov 25;35(47):15523-38
pubmed: 26609150
Neuropsychopharmacology. 2016 Jan;41(1):373-4
pubmed: 26657953
Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
pubmed: 19339977
Psychopharmacology (Berl). 2010 Jun;210(2):137-47
pubmed: 20401607
Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1:E131-40
pubmed: 22724395
Neuron. 2017 Sep 27;96(1):145-159.e8
pubmed: 28890345