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α4β2 Nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating

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Abstract

Rationale

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 α7 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 α4β2 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 α4β2 antagonist dihydro-β-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-β-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 α4β2 receptors by nicotine increases CAMP. However, under conditions where α4β2 receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as α7. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases.

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Acknowledgement

Financial support came from Abbott Laboratories.

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Authors and Affiliations

  1. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Dept. R4N5, AP9A/LL, 100 Abbott Park Road, Abbott Park, IL, 60064, USA

    Richard J. Radek, Holly M. Miner, Natalie A. Bratcher, Michael W. Decker, Murali Gopalakrishnan & Robert S. Bitner

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  1. Richard J. Radek
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  2. Holly M. Miner
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  3. Natalie A. Bratcher
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Correspondence to Richard J. Radek.

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Radek, R.J., Miner, H.M., Bratcher, N.A. et al. α4β2 Nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. Psychopharmacology 187, 47–55 (2006). https://doi.org/10.1007/s00213-006-0394-3

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  • DOI: https://doi.org/10.1007/s00213-006-0394-3

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