title: Differential Contributions of Alcohol and the Nicotine-Derived Nitrosamine Ketone (NNK) to Insulin and Insulin-Like Growth Factor Resistance in the Adolescent Rat Brain.
abstract: OBJECTIVE
  Since epidemiologic studies suggest that tobacco smoke toxins, e.g. the nicotine-derived nitrosamine ketone (NNK) tobacco-specific nitrosamine, can be a co-factor in alcohol-related brain disease (ARBD), we examined the independent and additive effects of alcohol and NNK exposures on spatial learning/memory, and brain insulin/IGF signaling, neuronal function and oxidative stress.
  
  
  METHODS
  Adolescent Long Evans rats were fed liquid diets containing 0 or 26% caloric ethanol for 8 weeks. During weeks 3-8, rats were treated with i.p. NNK (2 mg/kg, 3×/week) or saline. In weeks 7-8, ethanol groups were binge-administered ethanol (2 g/kg; 3×/week). In week 8, at 12 weeks of age, rats were subjected to Morris Water Maze tests. Temporal lobes were used to assess molecular indices of insulin/IGF resistance, oxidative stress and neuronal function.
  
  
  RESULTS
  Ethanol and NNK impaired spatial learning, and NNK ± ethanol impaired memory. Linear trend analysis demonstrated worsening performance from control to ethanol, to NNK, and then ethanol + NNK. Ethanol ± NNK, caused brain atrophy, inhibited insulin signaling through the insulin receptor and Akt, activated GSK-3β, increased protein carbonyl and 3-nitrotyrosine, and reduced acetylcholinesterase. NNK increased NTyr. Ethanol + NNK had synergistic stimulatory effects on 8-iso-PGF-2α, inhibitory effects on p-p70S6K, tau and p-tau and trend effects on insulin-like growth factor type 1 (IGF-1) receptor expression and phosphorylation.
  
  
  CONCLUSIONS
  Ethanol, NNK and combined ethanol + NNK exposures that begin in adolescence impair spatial learning and memory in young adults. The ethanol and/or NNK exposures differentially impair insulin/IGF signaling through neuronal growth, survival and plasticity pathways, increase cellular injury and oxidative stress and reduce expression of critical proteins needed for neuronal function.
authors.affiliation: Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Yu
authors.affiliation: Biotechnology Graduate Program, Brown University, Providence, RI, USA.
authors.forename: Chetram
authors.initials: C
authors.lastname: Deochand
authors.affiliation: Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA suzanne_delamonte_md@brown.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009538:Nicotine / Q000031:analogs & derivatives*; D009602:Nitrosamines / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000378:metabolism*; D065853:Spatial Learning / Q000187:drug effects; D013702:Temporal Lobe / Q000187:drug effects* / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D009602:Nitrosamines; D013002:Somatomedins; D016875:tau Proteins; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D000431:Ethanol; D014443:Tyrosine; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D015237:Dinoprost; D017526:Receptor, IGF Type 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3; D000110:Acetylcholinesterase