Nicotine addiction is the largest cause of preventable mortality in the world and leads to more than 4 million smoking-related deaths every year. Until recently, it has been unclear which nicotinic receptors elicit the acute and chronic effects of nicotine dependence. Reporting in Science, Tapper and colleagues show that activation of α4 receptors is sufficient to mediate nicotine-induced reward, tolerance and sensitization.

Nicotine dependence begins with the binding of nicotine to nicotinic acetylcholine receptors (nAChRs) — pentameric cation-permeable ligand-gated ion channels that are normally activated by the endogenous neurotransmitter acetylcholine. At present, 12 nAChRs subunits have been identified, and many combinations can give rise to functional receptors. In this study, the authors generated 'knock-in' mice, in which the wild-type α4 subunit is replaced with one that contains a point mutation, leucine to alanine, within the putative pore-forming M2 domain and, as a result, is hypersensitive to nicotine.

They found that nicotine could induce calcium influx in cultured ventral midbrain neurons from mutant mice at a concentration that was 40-fold lower than for the wild-type cultures. Chronic administration of low doses of nicotine (50-fold lower than that found in the blood of smokers) resulted in a robust functional upregulation — an increase in the neuron's responsiveness to acetylcholine — in cultures from mutant but not wild-type mice. In addition, low concentrations of nicotine resulted in increased action potential firing frequency in the dopaminergic neurons from mutant mice, but had little effect on those from wild-type animals.

The mutant mice were also more prone to addiction-related effects at low concentrations of nicotine. In the 'conditioned place preference' test, mutant mice clearly preferred nicotine-paired boxes — an indication of a behavioural reinforcement response. Chronic administration of nicotine causes hypothermia, and tolerance to this effect is thought to be important in the development and maintenance of dependence. When single daily injections of nicotine were given at doses that induce hypothermia, only the mutant animals developed tolerance. Finally, repeated systemic injections of nicotine resulted in a steady increase in locomotor activity in mutant but not wild-type mice, which indicates that mutant animals became more sensitive to nicotine.

This elegant study not only provides direct evidence of which receptors promote nicotine dependence, but also raises fundamental questions about the genetics of addiction. Future work should shed light on whether polymorphisms in the human population could determine our susceptibility to addiction.