title: Anandamide-CB1 receptor signaling contributes to postnatal ethanol-induced neonatal neurodegeneration, adult synaptic, and memory deficits.
abstract: The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable with the third trimester in human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB1R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB1R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively. N-Arachidonoyl phosphatidylethanolamine-phospholipase D (NAPE-PLD), glycerophosphodiesterase (GDE1), and CB1R protein expression were enhanced by transcriptional activation of the genes encoding NAPE-PLD, GDE1, and CB1R proteins, respectively. In addition, ethanol inhibited ERK1/2 and AKT phosphorylation. The blockade of CB1Rs before ethanol treatment at P7 relieved ERK1/2 but not AKT phosphorylation and prevented neurodegeneration. CB1R knock-out mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2 phosphorylation. The protective effects of CB1R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA/CB1R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Subbanna
authors.forename: Madhu
authors.initials: M
authors.lastname: Shivakumar
authors.forename: Delphine
authors.initials: D
authors.lastname: Psychoyos
authors.forename: Shan
authors.initials: S
authors.lastname: Xie
authors.forename: Balapal S
authors.initials: BS
authors.lastname: Basavarajappa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000096:biosynthesis*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D063388:Endocannabinoids / Q000096:biosynthesis*; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D005989:Glycerides / Q000096:biosynthesis; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology; D010739:Phospholipase D / Q000096:biosynthesis; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000473:pathology*
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D000431:Ethanol; D005989:Glycerides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010739:Phospholipase D; D010727:Phosphoric Diester Hydrolases; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; C094503:glyceryl 2-arachidonate; C506062:Napepld protein, mouse; C038133:glycerophosphodiester phosphodiesterase; C078814:anandamide