title: Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating.
abstract: BACKGROUND
  Nicotine improves the deficiencies of sensory gating function in schizophrenic patients and in dilute brown non-Agouti (DBA/2) mice. This effect of nicotine has been attributed to activation of the alpha7 nicotinic acetylcholine receptor (nAChR) subtype.
  
  
  OBJECTIVE
  The aim of this study was to determine whether the activation of another nAChR subtype, the central nervous system (CNS) prominent alpha4beta2 receptor, also contributes to the effects of nicotine on sensory gating in DBA/2 mice.
  
  
  METHODS
  Unanesthetized DBA/2 mice were treated either with nicotine, the alpha4beta2 antagonist dihydro-beta-erythroidine, the noncompetitive nAChR antagonist mecamylamine, or a combination of an antagonist and nicotine. Thereafter, gating was assessed by recording hippocampal evoked potentials (EP), which were elicited by pairs of auditory clicks. The EP response to the second click, or test amplitude (TAMP), was divided by the EP response to the first click, or condition amplitude (CAMP), to derive gating T:C ratios.
  
  
  RESULTS
  Nicotine significantly (p<0.05) lowered T:C ratios by 42%, while significantly increasing CAMP by 55%. After a pretreatment with dihydro-beta-erythroidine, nicotine still significantly lowered T:C ratios by 28%; however, the nicotine-induced increase of CAMP was blocked. Mecamylamine blocked the effect of nicotine on both T:C ratios and CAMP.
  
  
  CONCLUSIONS
  Activation of alpha4beta2 receptors by nicotine increases CAMP. However, under conditions where alpha4beta2 receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as alpha7. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Dept. R4N5, AP9A/LL, 100 Abbott Park Road, Abbott Park, IL 60064, USA. rich.j.radek@abbott.com
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Radek
authors.forename: Holly M
authors.initials: HM
authors.lastname: Miner
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bratcher
authors.forename: Michael W
authors.initials: MW
authors.lastname: Decker
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bitner
mesh_terms: D000818:Animals; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008464:Mecamylamine / Q000494:pharmacology; D008606:Mental Processes / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D009538:Nicotine / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; D008464:Mecamylamine; D009538:Nicotine