The endocannabinoid system tonically regulates inhibitory transmission and depresses the effect of ethanol in central amygdala.
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.
Roberto
Marisa
M
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, USA.
Cruz
Maureen
M
Bajo
Michal
M
Siggins
George R
GR
Parsons
Loren H
LH
Schweitzer
Paul
P
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*
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
Neuron. 2008 Mar 13;57(5):746-59
18341994
J Neurophysiol. 2001 Jan;85(1):72-83
11152707
J Neurosci. 1997 Jan 15;17(2):796-803
8987801
Pharmacol Ther. 2006 Sep;111(3):533-54
16427127
Physiol Rev. 2003 Jul;83(3):803-34
12843409
Neuroscience. 2001;107(4):641-52
11720787
Behav Pharmacol. 2008 Oct;19(7):716-23
18797248
J Neurochem. 2003 Feb;84(4):698-704
12562514
Alcohol Alcohol. 2005 Jan-Feb;40(1):15-24
15550443
Neuropharmacology. 2002 Sep;43(4):503-10
12367597
Nature. 2002 Aug 1;418(6897):530-4
12152079
J Neurophysiol. 2008 Dec;100(6):3417-28
18945815
Alcohol Clin Exp Res. 2008 Mar;32(3):443-9
18215217
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1362-7
14734812
J Neurochem. 2008 Nov;107(4):1001-13
18796007
Psychopharmacology (Berl). 2005 Dec;183(3):368-77
16228194
J Neurosci. 2009 Feb 4;29(5):1375-80
19193884
Learn Mem. 2003 Mar-Apr;10(2):116-28
12663750
Neuropsychopharmacology. 2005 Mar;30(3):497-507
15280883
Neuroscience. 1998 Mar;83(2):393-411
9460749
Pharmacol Ther. 2005 Jul;107(1):80-98
15963352
J Neurosci. 2004 Nov 10;24(45):10159-66
15537886
Neuropsychopharmacology. 2009 Jun;34(7):1733-42
19158669
J Neurosci Res. 2009 Feb 15;87(3):766-75
18816788
Eur Neuropsychopharmacol. 2003 Dec;13(6):442-52
14636960
Alcohol Clin Exp Res. 1998 Feb;22(1):3-9
9514280
Neurosci Lett. 2005 Feb 25;375(1):13-8
15664114
Nat Neurosci. 2002 May;5(5):446-51
11976704
Nature. 2001 Mar 29;410(6828):588-92
11279497
Pharmacol Biochem Behav. 2005 Jun;81(2):369-80
15939463
Ann N Y Acad Sci. 1999 Jun 29;877:217-41
10415652
Neuroscience. 2004;127(4):871-9
15312899
J Neurosci. 2008 Oct 15;28(42):10496-508
18923026
J Neurosci. 2005 Jun 29;25(26):6199-207
15987949
Mol Neurobiol. 2007 Aug;36(1):102-12
17952655
Neuropharmacology. 2004 Jan;46(1):115-25
14654103
J Neurosci Res. 1999 Dec 1;58(5):663-73
10561694
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1393-8
12538878
Eur J Pharmacol. 1995 Sep 5;283(1-3):151-9
7498304
Psychopharmacology (Berl). 2002 Jan;159(2):181-7
11862347
J Physiol. 2007 Jan 1;578(Pt 1):233-47
17053036
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2053-8
12566570
Trends Neurosci. 1994 May;17(5):208-14
7520203
Eur J Neurosci. 1999 Dec;11(12):4213-25
10594647
J Neurosci. 2005 Oct 19;25(42):9746-51
16237178
Science. 2004 Mar 5;303(5663):1512-4
15001778
J Neurophysiol. 1994 Jul;72(1):326-36
7965017
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8410-5
18541912
J Neurosci. 2001 Dec 1;21(23):9506-18
11717385
Trends Neurosci. 2006 Apr;29(4):225-32
16483675
Drug News Perspect. 2008 Apr;21(3):149-57
18560613