A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

Abstract

Whole-genome searches have identified nicotinic acetylcholine receptor α5-α3-β4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key α5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.genetics | imaging | smoking | functional connectivity | nAChR S moking is influenced by both genetic and environmental factors, although the major factors associated with persistent smoking are genetics [heritability at 75% with minimal shared environmental contribution (1, 2)] and mental illnesses [smoking rate at 50-80% in many mental illnesses (3, 4)]. The brain mechanisms linking these factors to smoking behavior are not clear. In this context, the recent discovery of several polymorphisms at the 15q nicotinic acetylcholine receptor (nAChR) α5-α3-β4 gene cluster is important because they were found based on genomewide searches (5-7), have been replicated a considerable number of times (SI Methods), and provide a starting point to dissect the neurobiological pathways leading to persistent smoking. The most replicated functional marker associated with smoking, and secondarily to lung cancer, is the α5 subunit gene (CHRNA5) rs16969968 or Asp398Asn polymorphism that changes aspartic acid (Asp) to asparagine (Asn) (5-7), with the Asn risk allele reducing α4β2α5 receptor function (6). The α4β2 nAChR is a key regulator of nicotine addiction (8-10), and the participation of the α5 subunit substantially impacts α4β2 function (11).Identifying relevant genes is only the first step in finding more effective therapeutic agents. Identifying the brain circuit(s) linking the "risk alleles" to smoking is an important next step. Brain regions consistently associated with smoking-related behaviors and nicotine actions are the cingulate, striatum, orbitofrontal and prefrontal cortex, insula, and thalamus (12-16). The extant literature suggests that the α5 subunit is expressed cortically mainly in the cingulate; its mRNA expression is found in layer VIb in rats, with the highest concentration in the cingulate (17) and the cortical expression pattern of α5 seen in the cingulate and retrosplenial cortex (18). Subcortically, the α5 subunit is expressed in striatum, thalamus, hippocampus, and amygdala (SI Methods) (17,...

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

“…Our data showed the presence of reduced bCBV in the cingulated gyrus, prefrontal cortex, orbitofrontal cortex, as well as in striatal and hippocampal areas of cocaine SA subjects. The frontostriatal effect is in excellent agreement with clinical neuroimaging research of cocaine addiction, where reduced frontal and striatal activities have been consistently observed (Strickland et al, 1993;Tumeh et al, 1990;London et al, 1999;Volkow et al, 1992Volkow et al, , 1988 and found to correlate with the cognitive impairments, compulsion, and loss of inhibitory control over drug taking that may lead to relapse (Goldstein et al, 2010;Kalivas et al, 2005;Kalivas, 2004;Hong et al, 2010;Strickland et al, 1993). Importantly, cognitive deficits have been observed in rats allowed extended (but not limited) access to cocaine (Briand et al, 2008;George et al, 2007), a phenomenon that involved working memory and sustained attention tasks (two prefrontal cortex-dependent tasks) as well as object recognition measures (a hippocampus-dependent task).…”

Organic Cation Transporter Variation and Response to Smoking Cessation Therapies

“…For example, plasma concentrations of varenicline could be measured in individuals prescribed this medication 34 to test for the effect of functional OCT2 alleles on medication plasma levels, to test association between medication plasma levels and prospective abstinence, and on the influence of the functional OCT2 alleles on prospective abstinence, as has been reported for the bupropion metabolite hydoxybupropion and CYP2B6 variation. 81 Effects of the functional OCT2 allele on brain structure and function may be observable, given prior studies that have identified effects on brain structure 82 and function 83 of cholinergic 47,84 and dopaminergic 40,85 alleles that influence smoking cessation.…”

Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence

“…The relevance of preclinical animal models to nicotine dependence is questioned because their predictive validity is considered poor (Hong et al, 2010). In spite of this, preclinical animal models of nicotine seeking have been proved useful, as they have helped in understanding the mechanisms underlying nicotine seeking.…”