title: Acute ethanol suppresses glutamatergic neurotransmission through endocannabinoids in hippocampal neurons.
abstract: Ethanol exposure during fetal development is a leading cause of long-term cognitive impairments. Studies suggest that ethanol exposure have deleterious effects on the hippocampus, a brain region that is important for learning and memory. Ethanol exerts its effects, in part, via alterations in glutamatergic neurotransmission, which is critical for the maturation of neuronal circuits during development. The current literature strongly supports the growing evidence that ethanol inhibits glutamate release in the neonatal CA1 hippocampal region. However, the exact molecular mechanism responsible for this effect is not well understood. In this study, we show that ethanol enhances endocannabinoid (EC) levels in cultured hippocampal neurons, possibly through calcium pathways. Acute ethanol depresses miniature post-synaptic current (mEPSC) frequencies without affecting their amplitude. This suggests that ethanol inhibits glutamate release. The CB1 receptors (CB1Rs) present on pre-synaptic neurons are not altered by acute ethanol. The CB1R antagonist SR 141716A reverses ethanol-induced depression of mEPSC frequency. Drugs that are known to enhance the in vivo function of ECs occlude ethanol effects on mEPSC frequency. Chelation of post-synaptic calcium by EGTA antagonizes ethanol-induced depression of mEPSC frequency. The activation of CB1R with the selective agonist WIN55,212-2 also suppresses the mEPSC frequency. This WIN55,212-2 effect is similar to the ethanol effects and is reversed by SR141716A. In addition, tetani-induced excitatory post-synaptic currents (EPSCs) are depressed by acute ethanol. SR141716A significantly reverses ethanol effects on evoked EPSC amplitude in a dual recording preparation. These observations, taken together, suggest the participation of ECs as retrograde messengers in the ethanol-induced depression of synaptic activities.
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA. Basavaraj@nki.rfmh.org
authors.forename: Balapal S
authors.initials: BS
authors.lastname: Basavarajappa
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D048588:Benzoxazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein; D063388:Endocannabinoids; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D009435:Synaptic Transmission / Q000187:drug effects; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D002492:Central Nervous System Depressants; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D063388:Endocannabinoids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D016708:Synaptophysin; D000431:Ethanol; D018698:Glutamic Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D051528:Guanylate Kinases; D000077285:Rimonabant; D002118:Calcium
references.citation: Nat Neurosci. 2005 Sep;8(9):1139-41
references.pmid: 16116451
references.citation: J Neurophysiol. 2003 Feb;89(2):806-13
references.pmid: 12574458
references.citation: J Physiol. 2001 May 1;532(Pt 3):731-48
references.pmid: 11313442
references.citation: Am J Pathol. 2004 Sep;165(3):795-805
references.pmid: 15331404
references.citation: Annu Rev Neurosci. 2006;29:37-76
references.pmid: 16776579
references.citation: Brain Res. 1998 May 18;793(1-2):212-8
references.pmid: 9630633
references.citation: Neurotoxicol Teratol. 2003 Jul-Aug;25(4):447-58
references.pmid: 12798962
references.citation: J Neurophysiol. 1997 Jul;78(1):43-50
references.pmid: 9242259
references.citation: Alcohol Clin Exp Res. 1998 Oct;22(7):1437-42
references.pmid: 9802525
references.citation: Eur J Neurosci. 2003 Apr;17(8):1646-54
references.pmid: 12752382
references.citation: Biochim Biophys Acta. 2000 Dec 15;1535(1):78-86
references.pmid: 11113634
references.citation: Alcohol Clin Exp Res. 2008 Mar;32(3):443-9
references.pmid: 18215217
references.citation: Alcohol Clin Exp Res. 1995 Dec;19(6):1480-5
references.pmid: 8749814
references.citation: J Neurosci. 2005 Aug 31;25(35):8027-36
references.pmid: 16135760
references.citation: Psychopharmacology (Berl). 2005 Dec;183(3):368-77
references.pmid: 16228194
references.citation: Alcohol. 2004 Jan;32(1):9-18
references.pmid: 15066698
references.citation: J Neurochem. 2005 Sep;94(6):1500-11
references.pmid: 16000153
references.citation: J Neurosci. 2006 Mar 15;26(11):2991-3001
references.pmid: 16540577
references.citation: Pain. 2004 Jun;109(3):319-327
references.pmid: 15157693
references.citation: Eur J Pharmacol. 2003 Apr 11;466(1-2):73-83
references.pmid: 12679143
references.citation: Protein Pept Lett. 2007;14(3):237-46
references.pmid: 17346227
references.citation: Alcohol Clin Exp Res. 2007 May;31(5):855-67
references.pmid: 17386072
references.citation: J Neurosci. 2002 Mar 1;22(5):1690-7
references.pmid: 11880498
references.citation: Front Biosci. 1997 Jun 15;2:d309-16
references.pmid: 9206984
references.citation: Nat Neurosci. 2004 Jul;7(7):697-8
references.pmid: 15184902
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8384-8
references.pmid: 12060781
references.citation: Science. 1997 Aug 22;277(5329):1094-7
references.pmid: 9262477
references.citation: Pharmacol Rev. 1999 Mar;51(1):7-61
references.pmid: 10049997
references.citation: Brain Res. 1998 Feb 2;783(1):77-84
references.pmid: 9479052
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: J Neurosci. 1999 Jun 1;19(11):4544-58
references.pmid: 10341254
references.citation: J Neurosci. 2004 Feb 18;24(7):1673-9
references.pmid: 14973237
references.citation: J Physiol. 2005 Dec 1;569(Pt 2):501-17
references.pmid: 16179366
references.citation: Neuroscientist. 2002 Apr;8(2):143-53
references.pmid: 11954559
references.citation: Neuropharmacology. 2006 Jun;50(7):834-44
references.pmid: 16448676
references.citation: Jpn J Pharmacol. 1995 Apr;67(4):395-7
references.pmid: 7650874
references.citation: Alcohol. 1994 May-Jun;11(3):259-67
references.pmid: 7914730
references.citation: J Neurosci. 2002 May 15;22(10):3864-72
references.pmid: 12019305
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2002 Mar;131(3):395-404
references.pmid: 11912064
references.citation: Neuroscience. 2005;136(2):509-17
references.pmid: 16216426
references.citation: Biochem Pharmacol. 2001 Aug 15;62(4):401-5
references.pmid: 11448448
references.citation: JAMA. 2003 Dec 10;290(22):2996-9
references.pmid: 14665662
references.citation: J Neurosci. 2001 Oct 15;21(20):RC174
references.pmid: 11588204
references.citation: Psychopharmacology (Berl). 2008 Feb;196(3):483-95
references.pmid: 17968532
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4269-74
references.pmid: 12655057
references.citation: Alcohol Clin Exp Res. 2004 Jan;28(1):143-52
references.pmid: 14745313
references.citation: Nat Neurosci. 2004 Apr;7(4):327-32
references.pmid: 15048120
references.citation: Alcohol Clin Exp Res. 2006 Feb;30(2):222-32
references.pmid: 16441271
references.citation: Biochem Pharmacol. 1995 Jun 29;50(1):83-90
references.pmid: 7605349
references.citation: Neuropharmacology. 2005 Oct;49(5):660-8
references.pmid: 15950248
references.citation: Neuropsychopharmacology. 2007 Jul;32(7):1570-82
references.pmid: 17164820
references.citation: J Neurophysiol. 2004 Jun;91(6):2568-77
references.pmid: 14749312
references.citation: Alcohol Clin Exp Res. 2007 Sep;31(9):1528-37
references.pmid: 17760787
references.citation: Science. 1992 Dec 18;258(5090):1946-9
references.pmid: 1470919
references.citation: Mol Pharmacol. 2001 Jul;60(1):155-63
references.pmid: 11408610
references.citation: Nature. 2007 Feb 8;445(7128):643-7
references.pmid: 17287809
references.citation: Neuron. 2001 Mar;29(3):729-38
references.pmid: 11301031
references.citation: Neuron. 2004 Apr 8;42(1):129-41
references.pmid: 15066270
references.citation: Nature. 2001 Mar 29;410(6828):588-92
references.pmid: 11279497
references.citation: Alcohol. 1999 Oct;19(2):107-11
references.pmid: 10548153
references.citation: Alcohol Clin Exp Res. 2000 May;24(5):706-15
references.pmid: 10832913
references.citation: J Neurosci. 2001 Jan 1;21(1):109-16
references.pmid: 11150326
references.citation: Nat Med. 2003 Jan;9(1):76-81
references.pmid: 12461523
references.citation: J Neurochem. 1999 Feb;72(2):522-8
references.pmid: 9930723
references.citation: Neurochem Int. 2006 Nov;49(6):619-25
references.pmid: 16822589
references.citation: Neuroreport. 2000 Apr 27;11(6):1231-5
references.pmid: 10817598
references.citation: Alcohol Clin Exp Res. 1997 May;21(3):404-8
references.pmid: 9161598
references.citation: Brain Res. 1995 Dec 1;701(1-2):238-48
references.pmid: 8925287
references.citation: Neuron. 2001 Mar;29(3):717-27
references.pmid: 11301030
references.citation: Biochem J. 2007 May 15;404(1):97-104
references.pmid: 17302558
references.citation: J Neurosci. 2002 Jan 1;22(1):200-8
references.pmid: 11756503
references.citation: J Neurosci. 2000 Apr 1;20(7):2470-9
references.pmid: 10729327
references.citation: Biochem Biophys Res Commun. 1995 Oct 4;215(1):89-97
references.pmid: 7575630
references.citation: J Neurosci. 2007 Apr 4;27(14):3695-702
references.pmid: 17409233
references.citation: Gen Pharmacol. 1986;17(2):231-3
references.pmid: 3699450
references.citation: J Neurochem. 2000 Dec;75(6):2434-44
references.pmid: 11080195
references.citation: Brain Res. 1999 Jan 2;815(1):89-97
references.pmid: 9974126
references.citation: Alcohol Clin Exp Res. 1998 Apr;22(2):416-21
references.pmid: 9581648
references.citation: Alcohol Alcohol. 2004 Mar-Apr;39(2):88-92
references.pmid: 14998822
references.citation: Nature. 1990 Aug 9;346(6284):561-4
references.pmid: 2165569
references.citation: J Neurosci. 2004 Feb 18;24(7):1594-603
references.pmid: 14973247
references.citation: J Physiol. 2006 Nov 15;577(Pt 1):263-80
references.pmid: 16973696
references.citation: Brain Res. 1990 Dec 24;537(1-2):203-8
references.pmid: 2150775