Actions of Nicotine

J. N. Langley maintained an interest in the action of plant alkaloids throughout his fife. Through his work with nicotine (which can contract skeletal muscle) and curare (which abolishes this action of nicotine and also blocks the response of the muscle to nerve stimulation, as first shown by Claude Bernard), he was able to infer in 1905 that the muscle must possess a receptive substance ... 

Hill, A. V., The mode of action of nicotine and curari, determined by the form of the contraction curve and the method of temperature coefficients, J. Physiol., 39, 361-373, 1909. 

Perhaps the largest gap in the evidence surrounds the primary site of action of nicotine in the brain - the acetylcholine receptor itself. Studies on links with tobacco dependence in humans will await closer definition of the complex interaction between nicotine and its receptor and the identification of the receptor sub-types that are important in addiction pathways (see Section 22.4). 

Recently nicotinic acid has been found to lower serum cholesterol in hypercholesteremia, and also in normal persons and rabbits (A3, F2). It was shown that the hypercholesteremia, induced by a 48-hour fast, could be completely corrected by giving the animals large doses of nicotinic acid during the fast. In contrast to nicotinic acid, nicotinamide does not lower the cholesterol level (M10). Several explanations are offered for the action of nicotinic acid (1) it inhibits cholesterol biosynthesis, (2) it interferes with coenzyme A, and (3) it involves a hitherto unknown pharmacologic effect. The renewed clinical interest in nicotinic acid induced us to look for a more specific and sensitive assay for nicotinic acid (B7, M8). 

Claude Bernard s early discovery (1856) that curare, the South American arrow poison (woorari), blocked muscle contraction elicited by stimulation of motor neurons, but not that elicited by direct stimulation of the muscle, provided the first demonstration that drugs could be used to study, what we now know are, nAChR-regulated functions. Bernard s early experiment served as the model for Langley s demonstration that the actions of nicotine on skeletal muscle could be blocked by pretreatment with curare (Langley 1880, 1907) and mimicked by pituri, the active... 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

The agonist radioligands [ HJnicotine and [ HJepibatidine, which are most commonly used to monitor nAChR numbers, freely cross lipid bilayers. Therefore, they do not discriminate between intracellular and surface nAChRs and the majority of the increase in high-affinity binding sites appears to be intracellular (Whiteaker et al. 1998 Vallejo et al. 2005). It is now appreciated that nicotine can accumulate within cells and a new consensus is emerging that supports an intracellular action of nicotine that enhances assembly and/or maturation of nAChRs (Nashmi et al. 2003 Darsow et al. 2005 Kuryatov et al. 2005 Sallette et al. 2004, 2005 Nashmi and Lester 2007 Fig. 4). 

Fig. 4 Current model for nicotine upregulation of a4p2 nAChRs. a Schematic of a ceU indicating major steps in the lifecycle of a nAChR. Nicotine accumulates within the cell. Within the endoplasmic reticulum, nicotine binds to nAChR subunits to facilitate assembly, or binds at the interface of an aP subunit pair to enhance maturation of a pentameric nAChR (Sallette et al. 2004, 2005). The strong influence of nicotine on maturation of the P2 subunit might also favour a change in nAChR stoichiometry, from (a4)3(P2)2 to (a4)2(P2)3 (Moroni et al. 2006). These actions could result in an increase in the membrane insertion of competent nAChRs. The possibflity of an additional action of nicotine to impede nAChR turnover or degradation is indicated by the dotted line, b Binding of nicotine to the extracellular domain of unassembled nAChR subunits facilitates assembly, c Binding of nicotine at an aP interface facilitates maturation of a pentameric nAChR. Items b and c adapted from Nashmi and Lester (2007), with permission from Elsevier...

Di Chiara G (2000a) Role of dopamine in the behavioural actions of nicotine related to addiction,... 

Pauly JR (2008) Gender differences in tobacco smoking dynamics and the neuropharmacological actions of nicotine. Front Biosci 13 505-516... 

Rose JE, Behm FM, Westman EC, Bates JE (2003a) Mecamylamine acutely increases human intravenous nicotine self-administration. Pharmacol Biochem Behav 76 307-313 Rose JE, Behm FM, Westman EC, Bates JE, SaUey A (2003b) Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76 243-250 Rosecrans JA (1979) Nicotine as a discriminative stimulus to behavior its characterization and relevance to smoking behavior. NIDA Res Monogr 23 58-69 Rosecrans JA, Meltzer LT (1981) Central sites and mechanisms of action of nicotine. Neurosci Biobehav Rev 5 497-501... 

It is well established that nicotine stimulation of the mesolimbic dopamine (DA) pathway is essential to the reinforcing action of nicotine (Balfour 2004 Corrigall and Coen 1991). Considerable evidence suggests that alterations in this pathway may also be essential to the nicotine abstinence syndrome, particularly to its depression-like dimension. During withdrawal from continuous nicotine infusion, rats displayed reduced activity levels and reduced DA content in the striatum... 

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