title: Nicotine and Nicotine Abstinence Do Not Interfere with GABAA Receptor Neuroadaptations During Alcohol Abstinence.
abstract: BACKGROUND
  Alcohol dependence and tobacco smoking are highly comorbid, and treating both conditions simultaneously is controversial. Previously, we showed that tobacco smoking interferes with GABAA receptor neuroadaptations during alcohol withdrawal in humans, while this effect did not occur with continued nicotine use during alcohol abstinence in nonhuman primates. Here, we extend our previous work by measuring GABAA receptor availability with positron emission tomography (PET) during drug abstinence in nonhuman primates exposed to alcohol alone, nicotine and alcohol together, and alcohol abstinence with continued nicotine exposure.
  
  
  METHODS
  Twenty-four adolescent male rhesus macaques orally self-administered alcohol and nicotine, available separately in water and saccharin, over 20 weeks. The groups included alcohol alone (n = 8); nicotine and alcohol with simultaneous abstinence (n = 8); nicotine and alcohol with alcohol abstinence while nicotine was still available (n = 8); and a pilot group of animals consuming nicotine alone (n = 6). Animals were imaged with [(11)C]flumazenil PET to measure binding potential (BPND), an index of GABAA receptor availability. Imaging occurred at baseline (drug-naíve), and following alcohol and/or nicotine cessation at 1 day, 8 days, and 12 weeks of abstinence. Generalized linear mixed models were used to examine the time course of [(11)C]flumazenil BPND during alcohol abstinence across groups.
  
  
  RESULTS
  Animals consumed 3.95 ± 1.22 g/kg/d alcohol and 55.4 ± 35.1 mg/kg/d nicotine. No significant group effects were observed in [(11)C]flumazenil BPND during alcohol abstinence; however, a main effect of time was detected. Post hoc analyses indicated that all groups abstaining from alcohol exhibited significantly increased GABAA receptor availability at 1 day and 8 days (but not 12 weeks) of abstinence relative to baseline, while no changes in [(11)C]flumazenil BPND during nicotine abstinence alone were observed.
  
  
  CONCLUSIONS
  These data indicate that neither nicotine nor nicotine abstinence interferes with GABAA receptor neuroadaptations during alcohol withdrawal. This conclusion is consistent with our previous study and does not contradict the use of nicotine replacement therapies or non-nicotinic-acting pharmaceuticals to quit smoking during alcohol withdrawal from a GABAergic perspective.
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut.|Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Ansel T
authors.initials: AT
authors.lastname: Hillmer
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Tracy
authors.initials: T
authors.lastname: Kloczynski
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.|Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sandiego
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Brian
authors.initials: B
authors.lastname: Pittman
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Anderson
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pulmonology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Deluliis
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: O'Malley
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut.|Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut.|Yale PET Center, Yale University School of Medicine, New Haven, Connecticut.|Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Cosgrove
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D064829:Alcohol Abstinence; D000437:Alcoholism / Q000000981:diagnostic imaging / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011963:Receptors, GABA-A / Q000378:metabolism*; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D000431:Ethanol; D009538:Nicotine
keywords: Alcohol Dependence; GABAA Receptors; Positron Emission Tomography Imaging; Tobacco Smoking