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The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour

Key Points

  • Nicotine affects the nervous system through the action of nicotinic acetylcholine receptors (nAChRs) — ionotropic receptors that are widely distributed through the brain.

  • In the context of nicotine addiction, the involvement of the ventral tegmental area (VTA) has been extensively studied. The contribution of its dopamine (DA) and GABA (γ-aminobutyric acid) neurons, and their afferences and efferences, are crucially involved in the addiction process. Also, the contribution of glutamatergic transmission to this process has begun to gain prominence.

  • Nicotine activates nAChRs in DA neurons of the VTA, an activation that is followed by desensitization on continued exposure to nicotine. So, whereas the acute action might signal the rewarding effect of nicotine, the long-lasting desensitization might represent a cellular correlate of tolerance.

  • GABA neurons inhibit DA neurons in the VTA. But, whereas the acute effects of nicotine in the VTA predominantly affect GABA neurons, the nAChRs in these cells desensitize rapidly, leading to a long-lasting excitation of the DA neurons through removal of their inhibition. This shift would favour increased activity of the DA output pathways of the VTA.

  • Acetylcholine from brainstem nuclei might exert a profound modulatory effect on both populations of VTA neurons through the activation of nAChRs. In addition, it seems that the α7 subunit is a key component of the relevant receptors.

  • In addition to its rewarding properties, nicotine also has aversive properties. DA has been traditionally considered to relate only to the rewarding properties, but recent evidence indicates that its role might mediate its aversive properties. Moreover, a GABA system in the brainstem might have a previously unrecognized and prominent role in the rewarding effects of nicotine.

  • The shift from the acute effects of nicotine to the development of a dependence state might involve a switch in the balance between the role of DA and GABA neurons in the VTA. In the acute stage, the initial activation of GABA neurons in the VTA produces rewarding effects through a GABA system that projects to the brainstem. With repeated nicotine exposure, the GABA system becomes desensitized, leading to a shift in the action of nicotine to the DA neurons. This shift in balance might lead to a dysregulated DA signal in the VTA, which leads to the aversive effects of nicotine, and/or to the potentiation of the incentive salience of nicotine and its compulsive use.


Nicotine, the primary psychoactive component of tobacco smoke, produces diverse neurophysiological, motivational and behavioural effects through several brain regions and neurochemical pathways. Recent research in the fields of behavioural pharmacology, genetics and electrophysiology is providing an increasingly integrated picture of how the brain processes the motivational effects of nicotine. The emerging characterization of separate dopamine- and GABA (γ-aminobutyric acid)-dependent neural systems within the ventral tegmental area (VTA), which can mediate the acute aversive and rewarding psychological effects of nicotine, is providing new insights into how functional interactions between these systems might determine vulnerability to nicotine use.

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Figure 1: The structure of neuronal nicotinic acetylcholine receptors (nAChRs).
Figure 2: The ventral tegmental area (VTA), and its efferent and afferent systems.
Figure 3: Different roles for dopamine (DA) signalling in the acute versus chronic phases of nicotine exposure.
Figure 4: An integrated model for nicotine reward signalling in the ventral tegmental area (VTA).


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The authors thank CIHR for their support.

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Correspondence to Steven R. Laviolette.

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nicotinic acetylcholine receptors



A technique that allows the sampling of neurochemicals in the brain of live animals. It commonly uses a small U-shaped cannula that serves a dual function: it allows the injection of molecules of interest to test their effect, and it provides a pathway for the flow and subsequent collection of perfusate from a small brain area.


Oligonucleotides with a sequence that is complementary to the mRNA of a given molecule can be used to block its translation. The subsequent temporary elimination of the protein of interest often provides useful information on its biological function.


Complex fibre tract that runs through the diencephalon. It contains descending fibres from telencephalic structures such as the basal olfactory regions, the periamygdaloid region and the septal nuclei, and ascending fibres from the aminergic brainstem nuclei. Intracranial stimulation along this tract can simulate motivational states and reinforce behaviour.


A psychological process whereby the perception of stimuli is transformed by increasing their salience, making them more attractive or wanted.


This term was originally coined to refer to the effects of early antipsychotic agents on cognition and behaviour.

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Laviolette, S., van der Kooy, D. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5, 55–65 (2004).

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