Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. Numerous studies have shown that the expression and/or function of nAChRs is compromised in many neurological and psychiatric diseases. Furthermore, recent studies have shown that neuronal nAChRs are found in a large number of nonneuronal cell types including endothelial cells, glia, immune cells, lung epithelia and cancer cells where they regulate cell differentiation, proliferation and inflammatory responses. The aim of this review is to describe the most recent findings concerning the structure and function of native nAChRs inside and outside the nervous system.

Recent studies suggest that the neuronal nicotinic receptors (nAChRs) present in the habenulo–interpeduncular (Hb–IPn) system can modulate the reinforcing effect of addictive drugs and the anxiolytic effect of nicotine. Hb and IPn neurons express mRNAs for most nAChR subunits, thus making it difficult to establish the subunit composition of functional receptors. We used immunoprecipitation and immunopurification studies performed in rat and wild-type (+/+) and β2 knock-out (−/−) mice to establish that the Hb and IPn contain significant β2* and β4* populations of nAChR receptors (each of which is heterogeneous). The β4* nAChR are more highly expressed in the IPn. We also identified novel native subtypes (α2β2*, α4β3β2*, α3β3β4*, α6β3β4*). Our studies on IPn synaptosomes obtained from +/+ and α2, α4, α5, α6, α7, β2, β3, and β4^−/−mice show that only the α3β4 and α3β3β4 subtypes facilitate acetylcholine (ACh) release. Ligand binding, immunoprecipitation, and Western blotting studies in β3^−/−mice showed that, in the IPn of these mice, there is a concomitant reduction of ACh release and α3β4* receptors, whereas the receptor number remains the same in the Hb. We suggest that, in habenular cholinergic neurons, the β3 subunit may be important for transporting the α3β4* subtype from the medial habenula to the IPn. Overall, these studies highlight the presence of a wealth of uncommon nAChR subtypes in the Hb–IPn system and identify α3β4 and α3β3β4, transported from the Hb and highly enriched in the IPn, as the subtypes modulating ACh release in the IPn.

Neuronal nicotinic receptors (nAChRs) are a heterogeneous family of ion channels differently expressed in the nervous system where, by responding to the endogenous neurotransmitter acetylcholine, they contribute to a wide range of brain activities and influence a number of physiological functions. Over recent years, the application of newly developed molecular and cellular biological techniques has made it possible to correlate the subunit composition of nAChRs with specific nicotine-elicited behaviours, and refine some of the in vivo physiological functions of nAChR subtypes. The major new findings are the widespread expression of nAChRs, outside the nervous system, their specific and complex organisation, and their relevance to normal brain function. Moreover, the combination of clinical and basic research has better defined the involvement of nAChRs in a growing number of nervous pathologies other than degenerative diseases. However, there are still only a limited number of nicotinic-specific drugs and, although some nicotinic agonists have an interesting pharmacology, their clinical use is limited by undesirable side effects. Some selective nicotinic ligands have recently been developed and used to explore the complexity of nAChR subtype structure and function in the expectation that they will become rational therapeutic alternatives in a number of neurodegenerative, neuropsychiatric and neurological disorders. In this review, we will discuss the molecular basis of brain nAChR structural and functional diversity mainly in pharmacological and biochemical terms, and summarise current knowledge concerning the newly discovered drugs used to classify the numerous receptor subtypes and treat the brain diseases in which nAChRs are involved.