Peer-reviewed
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
Article, 2004