Nicotine increases alcohol self-administration in male rats via a μ-opioid mechanism within the mesolimbic pathway.
alcohol
comorbidity
nicotine
κ receptors
μ
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
10
08
2019
revised:
25
06
2020
accepted:
30
06
2020
pubmed:
23
7
2020
medline:
22
6
2021
entrez:
23
7
2020
Statut:
ppublish
Résumé
Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of μ and κ-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats. Chronic nicotine was tested on alcohol self-administration and motivation to obtain alcohol. We then tested the effect of the κ antagonist CERC-501 and the preferential μ receptor antagonist naltrexone on basal and nicotine-escalated alcohol self-administration. To probe μ or κ receptor adaptations, receptor binding and G-protein coupling assays were performed in reward-related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP-32 in nucleus accumbens as a biomarker. Nicotine robustly induced escalation of alcohol self-administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC-501. Escalation of alcohol self-administration was associated with decreased DAMGO-stimulated μ receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP-32 in the nucleus accumbens shell in response to alcohol. Collectively, these results suggest that nicotine contributes to escalate alcohol self-administration through a dysregulation of μ receptor activity in the VTA. These data imply that targeting μ rather than κ receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.
Sections du résumé
BACKGROUND AND PURPOSE
Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of μ and κ-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats.
EXPERIMENTAL APPROACH
Chronic nicotine was tested on alcohol self-administration and motivation to obtain alcohol. We then tested the effect of the κ antagonist CERC-501 and the preferential μ receptor antagonist naltrexone on basal and nicotine-escalated alcohol self-administration. To probe μ or κ receptor adaptations, receptor binding and G-protein coupling assays were performed in reward-related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP-32 in nucleus accumbens as a biomarker.
KEY RESULTS
Nicotine robustly induced escalation of alcohol self-administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC-501. Escalation of alcohol self-administration was associated with decreased DAMGO-stimulated μ receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP-32 in the nucleus accumbens shell in response to alcohol.
CONCLUSIONS AND IMPLICATIONS
Collectively, these results suggest that nicotine contributes to escalate alcohol self-administration through a dysregulation of μ receptor activity in the VTA. These data imply that targeting μ rather than κ receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.
Identifiants
pubmed: 32697329
doi: 10.1111/bph.15210
pmc: PMC7484560
doi:
Substances chimiques
Analgesics, Opioid
0
Receptors, Opioid, kappa
0
Receptors, Opioid, mu
0
Nicotine
6M3C89ZY6R
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4516-4531Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG), German Research Foundation
ID : Project-ID 402170461 - TRR 265
Organisme : Bundesministerium für Bildung und Forschung (BMBF) SysMedSUDs - FKZ
ID : 01ZX1909
Organisme : Swedish Research Council
ID : 2013-07434
Informations de copyright
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Mol Psychiatry. 2020 Aug;25(8):1749-1758
pubmed: 29942043
J Clin Psychopharmacol. 2012 Oct;32(5):630-6
pubmed: 22926596
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003086
pubmed: 17054160
Eur J Pharmacol. 2001 Apr 6;417(1-2):117-23
pubmed: 11301066
Front Behav Neurosci. 2017 Feb 22;11:25
pubmed: 28275339
PLoS One. 2011;6(5):e19372
pubmed: 21602922
Front Psychiatry. 2011 Nov 29;2:64
pubmed: 22144966
Psychopharmacology (Berl). 2002 Feb;160(1):19-29
pubmed: 11862370
Arch Gen Psychiatry. 2005 Jan;62(1):57-64
pubmed: 15630073
Peptides. 1989 May-Jun;10(3):499-522
pubmed: 2550910
J Neural Transm (Vienna). 1997;104(1):1-10
pubmed: 9085189
Am J Drug Alcohol Abuse. 2017 Mar;43(2):186-196
pubmed: 27439453
Addict Biol. 2020 Jul;25(4):e12799
pubmed: 31240842
Neuropharmacology. 2009;56 Suppl 1:205-12
pubmed: 18718480
J Psychopharmacol. 2014 Jan;28(1):8-22
pubmed: 24048097
Neurosci Biobehav Rev. 2019 Nov;106:141-164
pubmed: 30243576
Alcohol Clin Exp Res. 2018 Apr;42(4):751-760
pubmed: 29431852
J Biol Chem. 2007 Oct 12;282(41):29803-11
pubmed: 17702750
J Vis Exp. 2017 Jan 29;(119):
pubmed: 28190044
Neuron. 2013 Aug 7;79(3):530-40
pubmed: 23871233
Br J Pharmacol. 2018 Apr;175(7):987-993
pubmed: 29520785
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Alcohol. 2012 Jun;46(4):359-70
pubmed: 22459870
Drug Alcohol Depend. 2010 May 1;108(3):183-94
pubmed: 19945803
J Chem Neuroanat. 1995 May;8(4):283-305
pubmed: 7669273
AAPS J. 2005 Oct 05;7(2):E353-60
pubmed: 16353915
Alcohol Clin Exp Res. 2012 Jan;36(1):43-54
pubmed: 21689122
PLoS Biol. 2010 Jun 29;8(6):e1000412
pubmed: 20613859
Nat Neurosci. 2005 Nov;8(11):1445-9
pubmed: 16251986
J Clin Pharmacol. 2014 Sep;54(9):968-78
pubmed: 24619932
Neurosci Biobehav Rev. 2010 Nov;35(2):220-31
pubmed: 20170672
Eur J Pharmacol. 2006 Jan 13;530(1-2):95-102
pubmed: 16364288
Biol Psychiatry. 2005 Nov 15;58(10):779-86
pubmed: 16018986
Alcohol Clin Exp Res. 2009 Jun;33(6):1044-50
pubmed: 19302083
Psychopharmacology (Berl). 2011 Feb;213(4):735-44
pubmed: 20941594
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3024-9
pubmed: 26903621
Alcohol. 2012 Feb;46(1):17-27
pubmed: 21962974
Science. 1961 Sep 29;134(3483):943-4
pubmed: 13714876
Arch Gen Psychiatry. 2004 Nov;61(11):1107-15
pubmed: 15520358
Neuropsychopharmacology. 2018 Aug;43(9):1805-1812
pubmed: 29463912
Alcohol. 2014 May;48(3):205-8
pubmed: 24811154
Neuropsychopharmacology. 2008 Feb;33(3):643-52
pubmed: 17473837
Psychopharmacology (Berl). 2014 Oct;231(20):4019-29
pubmed: 24696081
J Cell Sci. 2002 Feb 1;115(Pt 3):455-65
pubmed: 11861753
Life Sci. 2003 Dec 12;74(4):489-508
pubmed: 14609727
Psychopharmacology (Berl). 2013 Dec;230(3):439-49
pubmed: 23779257
Neuropsychopharmacology. 2010 Jun;35(7):1453-63
pubmed: 20200505
Psychopharmacology (Berl). 2003 Jul;168(1-2):216-221
pubmed: 12536264
Biol Psychiatry. 2012 Nov 15;72(10):832-8
pubmed: 22541040
J Neurochem. 1997 Mar;68(3):1053-61
pubmed: 9048750
J Neurosci. 2015 Apr 15;35(15):6241-53
pubmed: 25878294
Psychopharmacology (Berl). 2014 Dec;231(23):4561-8
pubmed: 24858375
Eval Health Prof. 2011 Mar;34(1):3-56
pubmed: 20876085
Biol Psychiatry. 2014 May 15;75(10):774-82
pubmed: 23611261
Neuropharmacology. 2014 Feb;77:131-44
pubmed: 24071566
Neuropsychopharmacology. 2017 Feb;42(3):606-614
pubmed: 27510425
Br J Pharmacol. 2018 Feb;175(3):407-411
pubmed: 29350411
Brain Res. 1999 Mar 20;822(1-2):107-13
pubmed: 10082888
Pharmacol Biochem Behav. 2000 Jul;66(3):563-72
pubmed: 10899371
Prog Neurobiol. 2010 Jan 11;90(1):1-15
pubmed: 19800387
Alcohol Alcohol. 2003 Nov-Dec;38(6):606-12
pubmed: 14633650
Br J Pharmacol. 2015 Aug;172(16):3964-79
pubmed: 25988826
JAMA. 2014 May 14;311(18):1889-900
pubmed: 24825644
Br J Pharmacol. 2019 Dec;176 Suppl 1:S21-S141
pubmed: 31710717
Mol Psychiatry. 2004 Jun;9(6):557-69
pubmed: 15098002
Front Integr Neurosci. 2014 Nov 05;8:87
pubmed: 25414648
Physiol Behav. 1993 Dec;54(6):1215-20
pubmed: 8295967
Eur J Neurosci. 1998 Mar;10(3):1179-87
pubmed: 9753186
Nicotine Tob Res. 2002 Nov;4(4):405-22
pubmed: 12521400
Alcohol. 2009 Mar;43(2):119-26
pubmed: 19251113
Drug Alcohol Depend. 2006 Feb 1;81(2):197-204
pubmed: 16054779
J Pharmacol Exp Ther. 1993 Jan;264(1):489-95
pubmed: 8093731
Br J Pharmacol. 2020 Oct;177(19):4516-4531
pubmed: 32697329
Alcohol. 1998 May;15(4):281-9
pubmed: 9590512
Neuron. 2005 Jun 16;46(6):933-43
pubmed: 15953421
Life Sci. 1996;58(19):1671-9
pubmed: 8632704
J Neurosci. 1992 Feb;12(2):483-8
pubmed: 1346804
Br J Pharmacol. 2015 Jul;172(13):3189-93
pubmed: 25964986