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Nicotine addiction and nicotinic receptors: lessons from genetically modified mice

Key Points

  • The contribution of different nicotinic acetylcholine (ACh) receptor (nAChR) oligomers to nicotine addiction is being explored in mice, using novel strategies including deletion of nAChR subunit genes or targeted knock-in gene mutations; re-expression of a deleted gene using stereotaxic injection of a lentiviral vector carrying the missing gene; repression of a wild-type gene using stereotaxic injection of the relevant small interfering RNA; and the quantitative analysis of the neuronal firing patterns and the behaviours elicited by nicotine in these mice.

  • Spontaneous locomotor and cognitive behaviour is under the control of α4-containing (α4*), α6* and β2*nAChR activation by endogenous ACh, with a possible contribution of the β3 subunit.

  • α4*, β2* and α6*nAChRs mediate the rewarding effects of nicotine, with a possible contribution of the α7 subunit.

  • In addition to the β2 subunit, the α4 subunit (but not the α6 subunit) is required for the transition from tonic to phasic firing of dopaminergic neurons in the ventral tegmental area (VTA) that is crucial for reinforcement.

  • α4 and α6 subunits are necessary for efficient dopamine release in the nucleus accumbens.

  • There is evidence that, through activation of α4β2* and α7*nAChRs, acute nicotine exposure influences a global 'gating' circuit that includes the striatum, hippocampus and amygdala and is under top-down control of the prefrontal cortex.

  • Several mechanisms may account for the sensitization of dopaminergic neurons in the VTA that occurs during long-term exposure to nicotine, including upregulation of nAChR expression, presynaptic compensation by α7-mediated cholinergic transmission, and a top-down increase in bursting activity of dopamine neuron activity in the VTA.

  • Nicotine withdrawal syndromes mobilize brain circuits that are distinct from those involved in reward processing, with α2, α5, α6, α7 and β4 nAChR subunits regulating the expression of somatic symptoms, and β2 and α6 subunits contributing to affective symptoms.

Abstract

The past decades have seen a revolution in our understanding of brain diseases and in particular of drug addiction. This has been largely due to the identification of neurotransmitter receptors and the development of animal models, which together have enabled the investigation of brain functions from the molecular to the cognitive level. Tobacco smoking, the principal — yet avoidable — cause of lung cancer is associated with nicotine addiction. Recent studies in mice involving deletion and replacement of nicotinic acetylcholine receptor subunits have begun to identify the molecular mechanisms underlying nicotine addiction and might offer new therapeutic strategies to treat this addiction.

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Figure 1: Structure of nAChRs.
Figure 2: Neuronal mechanisms involved in nicotine addiction: a model.
Figure 3: Method of β2 subunit gene re-expression using a lentiviral vector.
Figure 4: nAChR subunits control the afferent and efferent connectivity of dopaminergic neurons from the VTA.
Figure 5: Role of nAChR subunits in spontaneous spike firing and burst firing in VTA dopaminergic neurons.
Figure 6: Possible mechanisms for short- to long-term changes caused by chronic nicotine exposure.
Figure 7: Contribution of nAChR subunits to nicotine withdrawal symptoms at the level of the medial habenula–interpeduncular system.

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Acknowledgements

I thank I. Damaj, P. Faure, G. Koob, U. Maskos and S. Tolu for helpful comments. The work was supported by CNRS URA 2182 and by the IPSEN foundation (neuronal plasticity award).

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Jean-Pierre Changeux received the IPSEN foundation award Neuronal Plasticity 2008 specifically on the theme of this Review. He has also been a consultant for Servier Laboratories on the design of nicotinic drugs in 2009 and 2010.

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Glossary

Resident–intruder test

A test for social interaction and aggressive behaviour in rodents. An unfamiliar mouse (the 'intruder') is introduced into the cage of a mouse that has been kept isolated in its 'resident' cage for several months.

Navigation

Spontaneous locomotor behaviour characterized by large movements at fast speed, aimed at acquiring general information about the environment.

Exploration

Spontaneous locomotor behaviour characterized by small and slow movements, enabling more precise investigation of the environment.

Nigrostriatal pathway

The dopaminergic pathway from the substantia nigra to the striatum, which is associated with motor control.

Mesolimbic pathway

The dopaminergic pathway from the ventral tegmental area to the nucleus accumbens and limbic areas, which is associated with reward processing.

Fear conditioning

A form of learning in which an aversive stimulus (for example, an electric shock) is associated with a particular neutral context (for example, a room) or neutral stimulus (for example, a tone), resulting in the expression of fear responses to the originally neutral stimulus or context.

Fractional anisotropy

A parameter in diffusion tensor imaging, which images brain structures by measuring the diffusion properties of water molecules. It provides information about the microstructural integrity of the white matter.

Gene cluster

A group of neighbouring genes on a chromosome.

Conditioned place preference task

A test for nicotine addiction potential in which the mouse receives a dose of nicotine in a distinct environment, after which the amount of time the mouse spends in that environment is assessed.

Nicotine discrimination

The ability of mice to discriminate nicotine from saline using a two-bar operant procedure with a tandem schedule of food reinforcement.

Spike timing-dependent plasticity

A form of plasticity that results from functional changes in neurons and/or synapses and that depends on the precise timing of action potentials in connected neurons.

Giant depolarizing potentials

An early type of electrical activity that arises in the course of development and is probably due to excitatory actions of GABA.

Intracranial electrical self-stimulation

A procedure in which rats work (for example, pressing a lever) to obtain rewarding electrical self-stimulation through an electrode implanted in the brain's reward system. It is used to measure the sensitivity of the brain reward system in vivo.

Contextual fear conditioning

A behavourial test in which an aversive stimulus is given to an animal in a conditioning chamber, such that the fear response can subsequently be elicited in the conditioning chamber in the absence of the aversive stimulus.

Conditioned place aversion

A form of classical Pavlovian conditioning in which an animal learns to avoid a compartment that was previously paired with an aversive stimulus; for example, the aversive stimulus can be the negative affective state caused by nicotine withdrawal.

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Changeux, JP. Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci 11, 389–401 (2010). https://doi.org/10.1038/nrn2849

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