Polymorphisms in CHRNA5 — which encodes the α5 subunit of the nicotinic acetylcholine receptor (nAChR) — are associated with an increased risk of tobacco addiction, but the reason for this has remained unclear. Now, Kenny and colleagues show that α5-containing nAChRs are crucially involved in an inhibitory motivational pathway that limits nicotine consumption.

The authors began by studying mice lacking the α5 subunit (Chrna5−/− mice) which, like wild-type mice, showed a vigorous response of self administration to low doses of nicotine. However, wild-type mice limited their nicotine intake when higher unit doses were available, whereas knockout mice continued to consume more nicotine. Thus, the inhibitory effects of high doses of nicotine that normally limit nicotine intake are absent in mice lacking α5-containing nAChRs.

The authors next focused on the medial habenula (MHb)–interpeduncular nucleus (IPN) pathway, as it is activated by high doses of nicotine and is enriched for α5-containing nAChRs. Lentiviral delivery of the α5 subunit to the MHb of Chrna5−/− mice rescued the inhibitory effect of high-dose nicotine on consumption. Moreover, in rats, delivery of α5-specific short hairpin RNA (α5 shRNA) to the MHb produced an increase in nicotine consumption that was most pronounced at high doses. The increased neuronal activity in the IPN of wild-type mice in response to high-dose nicotine, as measured by FOS immunoreactivity, was almost completely abolished in Chrna5−/− mice. Glutamatergic transmission between the MHb and the IPN seems to play a key part in these processes, as pharmacological inhibition of NMDA receptors specifically in these sites increased self administration of nicotine in rats.

It was previously shown that low doses of nicotine reduce the threshold for experiencing reward in a brain-stimulation reward paradigm, whereas high doses of nicotine increase it. However, in α5 shRNA-treated rats, the threshold for reward remained low even if they received high doses of nicotine. Thus, in the absence of α5-containing nAChR signalling, high doses of nicotine do not have an inhibitory effect on reward circuitries.

These studies highlight the importance of the α5 nAChR subunit in limiting nicotine consumption, suggesting that it could be a therapeutic target for smoking cessation.