title: The endocannabinoid system tonically regulates inhibitory transmission and depresses the effect of ethanol in central amygdala.
abstract: The central amygdala (CeA) has a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggests a role for the endocannabinoid (eCB) system in ethanol binging and dependence. We used a slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABA(A) receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, previous superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA in which the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.forename: Maureen
authors.initials: M
authors.lastname: Cruz
authors.forename: Michal
authors.initials: M
authors.lastname: Bajo
authors.forename: George R
authors.initials: GR
authors.lastname: Siggins
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
authors.forename: Paul
authors.initials: P
authors.lastname: Schweitzer
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000187:drug effects*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D002492:Central Nervous System Depressants; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant
references.citation: Neuron. 2008 Mar 13;57(5):746-59
references.pmid: 18341994
references.citation: J Neurophysiol. 2001 Jan;85(1):72-83
references.pmid: 11152707
references.citation: J Neurosci. 1997 Jan 15;17(2):796-803
references.pmid: 8987801
references.citation: Pharmacol Ther. 2006 Sep;111(3):533-54
references.pmid: 16427127
references.citation: Physiol Rev. 2003 Jul;83(3):803-34
references.pmid: 12843409
references.citation: Neuroscience. 2001;107(4):641-52
references.pmid: 11720787
references.citation: Behav Pharmacol. 2008 Oct;19(7):716-23
references.pmid: 18797248
references.citation: J Neurochem. 2003 Feb;84(4):698-704
references.pmid: 12562514
references.citation: Alcohol Alcohol. 2005 Jan-Feb;40(1):15-24
references.pmid: 15550443
references.citation: Neuropharmacology. 2002 Sep;43(4):503-10
references.pmid: 12367597
references.citation: Nature. 2002 Aug 1;418(6897):530-4
references.pmid: 12152079
references.citation: J Neurophysiol. 2008 Dec;100(6):3417-28
references.pmid: 18945815
references.citation: Alcohol Clin Exp Res. 2008 Mar;32(3):443-9
references.pmid: 18215217
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1362-7
references.pmid: 14734812
references.citation: J Neurochem. 2008 Nov;107(4):1001-13
references.pmid: 18796007
references.citation: Psychopharmacology (Berl). 2005 Dec;183(3):368-77
references.pmid: 16228194
references.citation: J Neurosci. 2009 Feb 4;29(5):1375-80
references.pmid: 19193884
references.citation: Learn Mem. 2003 Mar-Apr;10(2):116-28
references.pmid: 12663750
references.citation: Neuropsychopharmacology. 2005 Mar;30(3):497-507
references.pmid: 15280883
references.citation: Neuroscience. 1998 Mar;83(2):393-411
references.pmid: 9460749
references.citation: Pharmacol Ther. 2005 Jul;107(1):80-98
references.pmid: 15963352
references.citation: J Neurosci. 2004 Nov 10;24(45):10159-66
references.pmid: 15537886
references.citation: Neuropsychopharmacology. 2009 Jun;34(7):1733-42
references.pmid: 19158669
references.citation: J Neurosci Res. 2009 Feb 15;87(3):766-75
references.pmid: 18816788
references.citation: Eur Neuropsychopharmacol. 2003 Dec;13(6):442-52
references.pmid: 14636960
references.citation: Alcohol Clin Exp Res. 1998 Feb;22(1):3-9
references.pmid: 9514280
references.citation: Neurosci Lett. 2005 Feb 25;375(1):13-8
references.pmid: 15664114
references.citation: Nat Neurosci. 2002 May;5(5):446-51
references.pmid: 11976704
references.citation: Nature. 2001 Mar 29;410(6828):588-92
references.pmid: 11279497
references.citation: Pharmacol Biochem Behav. 2005 Jun;81(2):369-80
references.pmid: 15939463
references.citation: Ann N Y Acad Sci. 1999 Jun 29;877:217-41
references.pmid: 10415652
references.citation: Neuroscience. 2004;127(4):871-9
references.pmid: 15312899
references.citation: J Neurosci. 2008 Oct 15;28(42):10496-508
references.pmid: 18923026
references.citation: J Neurosci. 2005 Jun 29;25(26):6199-207
references.pmid: 15987949
references.citation: Mol Neurobiol. 2007 Aug;36(1):102-12
references.pmid: 17952655
references.citation: Neuropharmacology. 2004 Jan;46(1):115-25
references.pmid: 14654103
references.citation: J Neurosci Res. 1999 Dec 1;58(5):663-73
references.pmid: 10561694
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1393-8
references.pmid: 12538878
references.citation: Eur J Pharmacol. 1995 Sep 5;283(1-3):151-9
references.pmid: 7498304
references.citation: Psychopharmacology (Berl). 2002 Jan;159(2):181-7
references.pmid: 11862347
references.citation: J Physiol. 2007 Jan 1;578(Pt 1):233-47
references.pmid: 17053036
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2053-8
references.pmid: 12566570
references.citation: Trends Neurosci. 1994 May;17(5):208-14
references.pmid: 7520203
references.citation: Eur J Neurosci. 1999 Dec;11(12):4213-25
references.pmid: 10594647
references.citation: J Neurosci. 2005 Oct 19;25(42):9746-51
references.pmid: 16237178
references.citation: Science. 2004 Mar 5;303(5663):1512-4
references.pmid: 15001778
references.citation: J Neurophysiol. 1994 Jul;72(1):326-36
references.pmid: 7965017
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8410-5
references.pmid: 18541912
references.citation: J Neurosci. 2001 Dec 1;21(23):9506-18
references.pmid: 11717385
references.citation: Trends Neurosci. 2006 Apr;29(4):225-32
references.pmid: 16483675
references.citation: Drug News Perspect. 2008 Apr;21(3):149-57
references.pmid: 18560613