Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating.
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.
Radek
Richard J
RJ
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
Miner
Holly M
HM
Bratcher
Natalie A
NA
Decker
Michael W
MW
Gopalakrishnan
Murali
M
Bitner
Robert S
RS
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
D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; D008464:Mecamylamine; D009538:Nicotine