Unraveling the neurobiology of nicotine dependence using genetically engineered mice

Abstract

This review article provides an overview of recent studies of nicotine dependence and withdrawal that used genetically engineered mice. Major progress has been made in recent years with mutant mice that include knockout and gain-of-function of specific neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. Nicotine exerts its actions by binding to these neuronal nAChRs, which consist of five subunits. The different nAChR subunits that combine to compose a receptor determine the distinct pharmacological and kinetic properties of the specific nAChR. Recent findings in genetically engineered mice have indicated that while α4- and β2-containing nAChRs are involved in the acquisition and initial stages of nicotine dependence, α7 homomeric nAChRs appear to be involved in the later stages of nicotine dependence. In the medial habenula, α5-, α3- and β4-containing nAChRs were shown to be crucially important in the regulation of the aversive aspects of nicotine. Studies of the involvement of α6 nAChR subunits in nicotine dependence have only recently emerged. The use of genetically engineered mice continues to vastly improve our understanding of the neurobiology nicotine dependence and withdrawal.

Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states

“…Mice with genetic deletion of different nAChR subunits will be valuable for dissecting the mechanism by which nicotine influences aggressive behavior (Changeux, 2010; Stoker and Markou, 2013). A recent study investigating how social behavior is regulated by cholinergic and norepinephrine transmission in the prefrontal cortex (PFC) used β2 subunit knockout mice (β2 −/− ) in a social interaction task, which included a measure of aggressivity (Coura et al, 2013).…”

Anticipated Motivation for Genetic Testing among Smokers, Nonsmokers, and Former Smokers: An Exploratory Qualitative Study of Decision Making

“…Research in this area has generally focused on (1) genes related to nicotine metabolic enzymes, and (2) genes related to neurotransmitters involved in the brain's dopaminergic reward system [8]. For example, recent studies have identified genetic polymorphisms associated with nicotine dependence and the efficacy of smoking cessation treatments, including variants in CYP2A6 (encoding nicotine-metabolizing enzyme cytochrome P450 2A6) [9], the CHRNA5/CHRNA3/CHRNB4 gene cluster (encoding neuronal nicotinic acetylcholine receptor subunits) [10,11,12], and several other loci [9,13]. …”

Alanine Scan of α-Conotoxin RegIIA Reveals a Selective α3β4 Nicotinic Acetylcholine Receptor Antagonist

“…In addition, genome-wide studies identified associations between lung cancer and several single nucleotide polymorphisms within the gene cluster encoding the ␣3, ␣5, and ␤4 nAChR subunits (10). Additionally, activation of the ␣3␤4 nAChR, a predominant subtype expressed in sympathetic and parasympathetic neurons of mammalian autonomic ganglia (11)(12)(13), is known to be associated with nicotine addiction and drug abuse (14,15). However, our understanding of the physiological relationship is limited.…”