Nicotine is extremely addictive, but it can also improve cognitive performance. Attempts to unravel the complex pathways underlying these effects pinpoint a single type of receptor in just one brain region.
Neuroscience is a somewhat unusual field, as it studies the workings of a single organ from microscopic to holistic levels. But a major technical challenge is how to link the two ends of the spectrum — how do specific molecules in the brain control behaviour? In this issue, Changeux and colleagues (Maskos et al., Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors )1 find that just one subunit of a neurotransmitter receptor, when active in a tiny region of the brain, is responsible for characteristic behavioural responses to nicotine in mice.
The addictive effects of nicotine are notorious. Smoking-related disease is responsible for many preventable deaths each year — up to 20% of mortality in developed countries alone2. Nicotine binds exclusively to receptors called nicotinic acetylcholine receptors (nAChRs) on the surface of neurons in the brain. Normally, these receptors are activated by the neurotransmitter acetylcholine, and loss of acetylcholine-releasing neurons is implicated in Alzheimer's disease. Moreover, nicotine enhances cognitive performance. So understanding the molecular interactions of nicotine with its receptors may have significant benefits for human health, and provide clues to normal cognition.
Nicotinic acetylcholine receptors consist of five subunits, of which there are 16 varieties. The numerous resulting receptor combinations expressed throughout the nervous system thus potentially mediate the various behavioural effects of nicotine and its natural counterpart acetylcholine.
In the brain, nAChRs containing the β2 subunit are most prevalent, so in 1995 Changeux's laboratory produced genetically engineered mice lacking this subunit (termed β2−/− mice) to discover how it contributes to normal function3,4. The mice showed mild learning impairment in certain tasks (but not in others), supporting a role for β2 nAChRs in cognition4. Furthermore, whereas normal mice rapidly learned to self-administer nicotine by pressing a lever, the β2−/− mice did not, implicating these receptor subunits in mediating the reinforcing or rewarding properties of nicotine5. But such studies are imperfect: a behavioural deficit may result not from the absence of a certain molecule in the adult, but from abnormal development at an earlier stage. Moreover, the presence of β2-containing receptors throughout the brain made it difficult to assign altered behaviours in the β2−/− animals to specific brain pathways.
Changeux's laboratory has now addressed1 these issues by judicious reintroduction of the β2 subunit into a specific brain region of β2−/− mice. The midbrain ventral tegmental area (VTA) is strongly implicated in the response to natural rewards, such as food or sex, as well as the reinforcing effects of various drugs of abuse. All addictive drugs, for example, elicit release of the neurotransmitter dopamine, which is manufactured in neurons of the VTA, and rodents will self-administer nicotine (or cocaine or morphine) directly into this region. Changeux and colleagues injected a virus encoding the β2 nAChR subunit directly into the VTA of β2−/− mice. In the following few days, the β2 subunit began to be expressed in VTA neurons, forming functional receptors with other nAChR subunits already expressed there.
In normal mice, nicotine excites dopamine-containing cells in the VTA, resulting in dopamine release at nerve terminals; in β2−/− mice, these responses are lost. But when the β2 subunit was reintroduced into the VTA of β2−/− animals, both responses to nicotine were restored. How does this translate into behaviour? Whereas β2−/− animals did not self-administer nicotine, remarkably, β2−/− mice with the reintroduced β2 gene did — and did so nearly as often as control animals, suggesting that the rewarding effects of nicotine are entirely restored by local reintroduction of this receptor subunit. Given the intricacies of the brain, it is striking that reintroduction of a single molecule to just one small area of the brain should so dramatically affect behaviour.
One issue still to be addressed is whether β2-treated β2−/− animals will self-administer nicotine if it is introduced into the bloodstream rather than the VTA. If so, it could be concluded that activation of β2-containing nAChRs in the VTA is sufficient to make nicotine rewarding, and drugs selectively targeting such receptors might be useful in reducing nicotine addiction. Recently, another nAChR subunit, α4, has also been implicated in nicotine-induced reward6, so one would predict that reintroduction of the α4 subunit into the VTA of an α2−/− mouse would also reinstate nicotine self-administration behaviour. If so, α4β2 receptors in the VTA are the key nAChRs necessary for nicotine addiction.
To explore the function of the VTA cells further, the authors examined the effects of the β2 subunit on exploratory behaviour (in the absence of nicotine). Brain circuits linked to the VTA are involved in the development of adaptive responses to environmental stimuli, and this can be analysed by measuring exploratory behaviour and navigation, the difference being whether the animals investigate their surroundings as they move, or whether they travel through the environment without much interaction with it. The authors found that mice lacking β2 showed increased navigation and decreased exploratory behaviour, implicating acetylcholine in these behaviours. Reintroduction of the β2 gene into the VTA of these animals restored exploratory behaviour, but did not affect navigation movements. This is a strong indication that endogenous acetylcholine triggers exploratory behaviour by binding to nAChRs on cells originating in the VTA.
Changeux and colleagues' experiments firmly connect exploratory behaviour with VTA cell function, as well as providing a causal link between a specific nAChR subunit and this behaviour. It remains to be determined which human behaviours are analogous to exploratory behaviour in the mouse. Might there be a link between exploratory behaviour, or risk-taking behaviours in general, and addictive drug self-administration?
Maskos, U. et al. Nature 436, 103–107 (2005).
Peto, R. et al. Br. Med. Bull. 52, 12–21 (1996).
Champtiaux, N. & Changeux, J. P. Prog. Brain Res. 145, 235–251 (2004).
Picciotto, M. R. et al. Nature 374, 65–67 (1995).
Picciotto, M. R. et al. Nature 391, 173–177 (1998).
Tapper, A. R. et al. Science 306, 1029–1032 (2004).
About this article
Epilepsy & Behavior (2013)
Region-Specific Effects of Nicotine on Brain Activity: A Pharmacological MRI Study in the Drug-Naïve Rat
Practice Nursing (2005)
Practice Nursing (2005)