title: Different Hypothalamic Nicotinic α7 Receptor Expression and Response to Low Nicotine Dose in Alcohol-Preferring and Alcohol-Avoiding Rats.
abstract: BACKGROUND
  The aim of this study was to examine possible differences in nicotinic acetylcholine receptors and responses in rats with genetic preference or avoidance for alcohol. This was done by using 2 rat lines with high alcohol preference (Alko Alcohol [AA]) or alcohol avoidance (Alko Non-Alcohol [ANA]).
  
  
  METHODS
  Locomotor activity was measured following nicotine and histamine H3 receptor (H3R) antagonist treatment. In situ hybridization and receptor ligand binding experiments were used in drug-naïve animals to examine the expression of different α nicotinic receptor subunits.
  
  
  RESULTS
  The AA rats were found to be more sensitive to the stimulatory effect of a low dose of nicotine than ANA rats, which were not significantly activated. Combination of histamine H3R antagonist, JNJ-39220675, and nicotine resulted to similar locomotor activation as nicotine alone. To further understand the mechanism underlying the difference in nicotine response in AA and ANA rats, we studied the expression of α5, α6, and α7 nicotinic receptor subunits in specific brain areas of AA and ANA rats. We found no differences in the expression of α5 nicotinic receptor subunits in the medial habenula and hippocampus or in α6 subunit in the ventral tegmental area and substantia nigra. However, the level of α7 nicotinic receptor subunit mRNA was significantly lower in the tuberomamillary nucleus of posterior hypothalamus of alcohol-preferring AA rats than in alcohol-avoiding ANA rats. Also the hypothalamic [125I-α-bungarotoxin binding was lower in AA rats indicating lower levels of α7 nicotinic receptors.
  
  
  CONCLUSIONS
  The lower expression and receptor binding of α7 nicotinic receptors in the tuberomamillary nucleus of AA rats suggest a difference in the regulation of brain histamine neurons between the rat lines since the α7 nicotinic receptors are located in histaminergic neurons. Stronger nicotine-induced locomotor response, mediated partially via α7 receptors, and previously described high alcohol consumption in AA rats could be explained by the found difference in tuberomamillary α7 receptor levels.
authors: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.|Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors: Saara
authors: S
authors: Nuutinen
authors: Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors: Pertti
authors: P
authors: Panula
authors: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors: Outi
authors: O
authors: Salminen
mesh_terms: D064829:Alcohol Abstinence; D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000737:chemistry / Q000502:physiology; D007031:Hypothalamus / Q000737:chemistry / Q000502:physiology*; D017403:In Situ Hybridization; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: C559587:(4-cyclobutyl-(1,4)diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone; D001381:Azepines; D006633:Histamine Antagonists; D011725:Pyridines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine
keywords: Alcohol; Alpha7 Nicotinic Receptor; Histamine H3 Receptor; Nicotine; Nicotinic Receptors