Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction

Abstract

Nicotine is a highly addictive drug found in tobacco that drives its continued use despite the harmful consequences. The initiation of nicotine abuse involves the mesolimbic dopamine system, which contributes to the rewarding sensory stimuli and associative learning processes in the beginning stages of addiction. Nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs), which come in a diverse collection of subtypes. The nAChRs that contain the α4 and β2 subunits, often in combination with the α6 subunit, are particularly important for nicotine's ability to increase midbrain dopamine neuron firing rates and phasic burst firing. Chronic nicotine exposure results in numerous neuroadaptations, including the upregulation of particular nAChR subtypes associated with long-term desensitization of the receptors. When nicotine is no longer present, for example during attempts to quit smoking, a withdrawal syndrome develops. The expression of physical withdrawal symptoms depends mainly on the α2, α3, α5, and β4 nicotinic subunits in the epithalamic habenular complex and its target regions. Thus, nicotine affects diverse neural systems and an array of nAChR subtypes to mediate the overall addiction process. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Figure 1.

Didactic structure of nAChR subtypes. (A) A side view of the subunits’ arrangement like the staves of a barrel around the central water-filled pore. In the generic heteromeric nAChR subtype shown, there are two alpha subunits and three beta subunits with the ACh binding sites located at the interfaces between α-β subunits. Note that for clarity, this schematic illustration is not drawn to scale and shows the ligand binding-sites at the apex of the subunits rather than at their actual positions deep within the structure. (B) These top down views of subunit arrangements for a homomeric α7-nAChR and for 3 of the myriad potential heteromeric nAChRs.

Figure 2.

Didactic representation of the three main functional states of the nAChR. In the resting state, the ACh binding sites are not occupied, and the water-filled pore is closed and non-conducting to cations. In the open, activated state, the ion channel is open, providing a water-filled pore through the membrane that is permeable to small cations. In the desensitized state, the ACh binding sites are (usually) occupied, but the pore is closed and non-conducting. Note that for clarity, sodium to calcium ratios are lower in this schematic than in actuality and that the arrows do not indicate rate constants of conformation changes.