Journal Article

Habenular α5 nicotinic receptor subunit signalling controls nicotine intake

Lu, Qun, Fowler, Christie D., Johnson, Paul M., Marks, Michael J., Kenny, Paul J.

2011

Overview

Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5 . This effect was ‘rescued’ in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake. Anti-smoking drug target Genetic association studies implicate variation in CHRNA5 , the gene for the α5 neuronal nicotinic acetylcholine receptor (nAChR) subunit, in susceptibility to tobacco dependence, lung cancer and chronic obstructive pulmonary disease. The mechanisms linking this gene to behaviour are unknown. Using knockout mice, lentiviral rescue and RNAi knockdown in rats, Fowler et al . show that manipulating the levels of this subunit alters the drive to obtain nicotine, particularly at high doses. Altering activity levels in the habenulo-interpeduncular tract of the brain, where this subunit is highly expressed, changes the amount of nicotine the animals consume. This work identifies α5-containing nAChRs as potential targets for smoking-cessation therapies. In humans, vulnerability to tobacco addiction has been linked to variations in the gene encoding the α5 nicotinic acetylcholine receptor subunit, but the functional mechanisms linking gene to behaviour are unknown. Using a combination of knockout mice, lentiviral rescue, and RNAi knockdown in rats, this study shows that manipulating the levels of this subunit alters the drive to obtain nicotine, particularly at high doses that are aversive to wild-type animals. Furthermore, these subunits are implicated in the projection between medial habenula and interpeduncular nucleus in integrating negative side effects of high doses of nicotine and reward signals. It is proposed that this projection provides a negative motivational signal that limits nicotine consumption.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biological and medical sciences / Female / Gene mutations / Genetic aspects / Habenula - drug effects / Habenula - metabolism / Habenula - physiology / Health aspects / Humanities and Social Sciences / Lung cancer / Male / Medical sciences / Mice / Mice, Knockout / multidisciplinary / Nicotine / Nicotine - metabolism / Nicotine - pharmacokinetics / Nicotine - pharmacology / Nicotinic receptors / Physiological aspects / Rats / Receptors, Nicotinic - deficiency / Receptors, Nicotinic - genetics / Receptors, Nicotinic - metabolism / Reward / Risk factors / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Tobacco Use Disorder - genetics / Tobacco Use Disorder - metabolism / Tobacco, tobacco smoking / Toxicology