title: Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring.
abstract: Clinical and animal studies indicate that maternal consumption of ethanol during pregnancy increases alcohol drinking in the offspring. Possible underlying mechanisms may involve orexigenic peptides, which are stimulated by prenatal ethanol exposure and themselves promote drinking. Building on evidence that ethanol stimulates neuroimmune factors such as the chemokine CCL2 that in adult rats is shown to colocalize with the orexigenic peptide, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), the present study sought to investigate the possibility that CCL2 or its receptor CCR2 in LH is stimulated by prenatal ethanol exposure, perhaps specifically within MCH neurons. Our paradigm of intraoral administration of ethanol to pregnant rats, at low-to-moderate doses (1 or 3g/kg/day) during peak hypothalamic neurogenesis, caused in adolescent male offspring twofold increase in drinking of and preference for ethanol and reinstatement of ethanol drinking in a two-bottle choice paradigm under an intermittent access schedule. This effect of prenatal ethanol exposure was associated with an increased expression of MCH and density of MCH(+) neurons in LH of preadolescent offspring. Whereas CCL2(+) cells at this age were low in density and unaffected by ethanol, CCR2(+) cells were dense in LH and increased by prenatal ethanol, with a large percentage (83-87%) identified as neurons and found to colocalize MCH. Prenatal ethanol also stimulated the genesis of CCR2(+) and MCH(+) neurons in the embryo, which co-labeled the proliferation marker, BrdU. Ethanol also increased the genesis and density of neurons that co-expressed CCR2 and MCH in LH, with triple-labeled CCR2(+)/MCH(+)/BrdU(+) neurons that were absent in control rats accounting for 35% of newly generated neurons in ethanol-exposed rats. With both the chemokine and MCH systems believed to promote ethanol consumption, this greater density of CCR2(+)/MCH(+) neurons in the LH of preadolescent rats suggests that these systems function together in promoting alcohol drinking during adolescence.
authors.affiliation: Laboratory of Behavioral Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: G-Q
authors.initials: GQ
authors.lastname: Chang
authors.affiliation: Laboratory of Behavioral Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: O
authors.initials: O
authors.lastname: Karatayev
authors.affiliation: Laboratory of Behavioral Neurobiology, The Rockefeller University, New York, NY 10065, USA. Electronic address: leibow@rockefeller.edu.
authors.forename: S F
authors.initials: SF
authors.lastname: Leibowitz
mesh_terms: D000367:Age Factors; D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D000831:Animals, Newborn; D002492:Central Nervous System Depressants / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000378:metabolism*
chemical_list: C491766:Ccl2 protein, rat; C515336:Ccr2 protein, rat; D002492:Central Nervous System Depressants; D018932:Chemokine CCL2; D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D054390:Receptors, CCR2; D000431:Ethanol; C019463:melanin-concentrating hormone; D010751:Phosphopyruvate Hydratase
keywords: CCL2; CCR2; lateral hypothalamus; melanin-concentrating hormone; neurogenesis; prenatal ethanol