Chronic nicotine pretreatment is sufficient to upregulate α4* nicotinic receptors and increase oral nicotine self-administration in mice.

Anthony Renda,Raad Nashmi

doi:10.1186/1471-2202-15-89

Abstract

BackgroundUnderstanding the underlying causes of nicotine addiction will require a multidisciplinary approach examining the key molecular, cellular and neuronal circuit functional changes that drive escalating levels of nicotine self-administration. In this study, we examined whether mice pretreated with chronic nicotine, at a dosing regimen that results in maximal nicotinic acetylcholine receptor (nAChR) upregulation, would display evidence of nicotine-dependent behaviour during nicotine self-administration.ResultsWe investigated oral self-administration of nicotine using a two-bottle choice paradigm in which one bottle contained the vehicle (saccharine-sweetened water), while the other contained nicotine (200 μg/ml) in vehicle. Knock-in mice with YFP-tagged α4 nAChR subunits (α4YFP) were implanted with osmotic pumps delivering either nicotine (2 mg/kg/hr) or saline for 10 days. After 10 days of pretreatment, mice were exposed to the nicotine self-administration paradigm, consisting of four days of choice followed by three days of nicotine abstinence repeated for five weeks. Mice pre-exposed to nicotine had upregulated α4YFP nAChR subunits in the hippocampal medial perforant path and on ventral tegmental area GABAergic neurons as compared to chronic saline mice. Compared to control saline-pretreated mice, in a two bottle-choice experiment, nicotine-primed mice ingested a significantly larger daily dose of nicotine and also exhibited post-abstinence binge drinking of nicotine.ConclusionsChronic forced pre-exposure of nicotine is sufficient to induce elevated oral nicotine intake and supports the postulate that nAChR upregulation may be a key factor influencing nicotine self-administration.

Highlights

Understanding the underlying causes of nicotine addiction will require a multidisciplinary approach examining the key molecular, cellular and neuronal circuit functional changes that drive escalating levels of nicotine self-administration
Chronic nicotine administered via pumps upregulates α4YFP nicotinic acetylcholine receptors (nAChRs) Nicotinic receptor upregulation is a biochemical hallmark in the brains of smokers and chronic nicotine infusion in mice can upregulate nAChRs in various brain regions
We examined whether oral nicotine self-administration in the three groups of mice correlated with α4YFP nAChR subunit upregulation in three different brain regions: the medial perforant path of the hippocampus, GABAergic neurons of the ventral tegmental area (VTA) and GABAergic neurons of the substantia nigra (SNR)

Summary

Introduction

Understanding the underlying causes of nicotine addiction will require a multidisciplinary approach examining the key molecular, cellular and neuronal circuit functional changes that drive escalating levels of nicotine self-administration. We examined whether mice pretreated with chronic nicotine, at a dosing regimen that results in maximal nicotinic acetylcholine receptor (nAChR) upregulation, would display evidence of nicotine-dependent behaviour during nicotine self-administration. The behaviours of drug seeking, reinforcement, tolerance and withdrawal associated with nicotine addiction are mediated at the molecular level by nicotinic acetylcholine receptors (nAChRs) [2,3,4,5]. There are a total of 12 neuronal subunits in vertebrates (α2-10, β2-4) assembling into a variety of nAChR subtypes, of which the major subtype in the brain is the heteropentameric α4β2* nAChR (* denotes that the Nicotine provides positive reinforcement by activating α4-containing (α4*) and β2-containing (β2*) nAChRs in the ventral tegmental area [3,4,5,14,15] and chronic administration of nicotine upregulates high-affinity α4β2 nAChR expression in mice [6,7,16] and rats [17], altering the molecular circuitry that governs reward. There are some conflicting data concerning whether nAChR upregulation correlates with withdrawal, but little is known about whether upregulation contributes to heightened nicotine self-administration

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