title: Alpha 4 beta 2* nicotinic acetylcholine receptors modulate the effects of ethanol and nicotine on the acoustic startle response.
abstract: BACKGROUND
  Ethanol modulates the functional activity of alpha4beta2 neuronal nicotinic cholinergic receptors (nAChR) when measured in vitro, but the potential role of alpha4beta2 nAChRs in regulating behavioral effects of ethanol is unknown. Recently, Tritto et al. (Tritto T, Stitzel JA, Marks MJ, Romm E, Collins AC (2002) Variability in response to nicotine in the LSxSS RI strains: potential role of polymorphisms in alpha4 and alpha6 nicotinic receptor genes. Pharmacogenetics 12:197-208) reported that a polymorphism (A529T) in the alpha4 nAChR subunit gene is associated with variability in nicotine's effects on startle in the LSxSS recombinant inbred (RI) strains. Ethanol also alters the acoustic startle response. Thus, we evaluated the potential role of alpha4beta2 nAChRs in modulating ethanol's effects on acoustic startle.
  
  
  METHODS
  The effects of ethanol on acoustic startle were determined in the LSxSS RI strains. In addition, the effects of ethanol and nicotine were also measured in alpha4 gain of function and beta2 null mutant mice. The beta2 mutants do not express the major variant of alpha4 nAChRs, alpha4beta2.
  
  
  RESULTS
  An association between the alpha4 A529T polymorphism and ethanol's effects on startle was found in the LSxSS RI strains; those strains that express the A529 variant of alpha4 were more sensitive to ethanol-induced depression of startle. The alpha4 gain of function mutants were more sensitive to the effects of both nicotine and ethanol and the beta2 null mutants were less sensitive to both drugs.
  
  
  CONCLUSIONS
  alpha4beta2-containing nAChRs may play important roles in modulating the effects of both ethanol and nicotine on the acoustic startle response. We suggest that nAChR subunit genes should be evaluated as potential contributors to both alcoholism and tobacco abuse.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder 80309-0447, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Owens
authors.forename: Seth A
authors.initials: SA
authors.lastname: Balogh
authors.forename: Tristan D
authors.initials: TD
authors.lastname: McClure-Begley
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Butt
authors.forename: Cesar
authors.initials: C
authors.lastname: Labarca
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Wehner
authors.forename: Allan C
authors.initials: AC
authors.lastname: Collins
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009538:Nicotine / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology
chemical_list: D021122:Protein Subunits; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000431:Ethanol; D009538:Nicotine