Tobacco smoking is one of the most persistent and widespread addictions and is driven by the nicotine in tobacco smoke. Among humans, tobacco is a highly addictive drug, however, in animal models, the major addictive component of tobacco, nicotine, is less reinforcing than other drugs of abuse, such as cocaine. There are probably many reasons for this discrepancy. First, tobacco is legal and access is nearly universal, so there is more chance of exposure to tobacco than illicit drugs, and the stigma of using it may be lower. Second, there are more than 4,000 constituents of tobacco smoke, and constituents other than nicotine can contribute to tobacco use. Third, and perhaps most importantly, nicotine has many effects on brain circuitry and behavior beyond its ability to stimulate neuronal systems involved in primary reinforcement; and complex actions on these systems may contribute to smoking behavior and relapse in smokers.
Smoking remains the leading preventable cause of death in developed countries, and some smokers report smoking as a method of weight control. Smokers have a significantly lower body mass index than non-smokers and gain weight when they quit smoking. These effects on body weight were attributed to nicotine because nicotine decreases feeding in animal models. Nicotine has some effects on peripheral energy metabolism, but little is known about potential central nervous system pathways that mediate nicotine’s effects on food intake and body weight. Identifying these pathways could help determine potential cholinergic modulation of appetite and weight control, but also lead to the development of novel appetite suppressants that could also aid in smoking cessation. Studies of the biological basis for nicotine reinforcement have aided in the design of new smoking cessation treatments such as varenicline.
However, smokers report smoking for many reasons, including the ability to control symptoms of anxiety and depression or a desire to control appetite. Varenicline, a partial α4/β2 receptor activator currently used for smoking cessation, is thus an example of selective drug design that has contributed to smoking cessation. Consistent with nicotine’s ability to enhance dopamine (DA) signaling, peripheral nicotine delivery can increase extracellular DA levels for more than one hour. The ability of nicotine to enhance glutamate signaling on dopamine neurons has been proposed as a mechanism underlying this sustained nicotine-induced DA release, which survives the acute effects of nicotine on the activity of DA-using neurons. Thus, nicotine is highly effective in stimulating the DA system, a circuit necessary for the reinforcement of drugs.
One of the drugs originally used to control hunger in smoking is cytisine, an alkaloid extracted from the broom of charcoal burners (Cytisus scoparius). The pharmacological specificity of cytisine and the relatively low dose (1.5 mg/kg) required to reduce food intake suggest that activation of central α3β4 receptors is essential for the anorexic effects of nicotine. Furthermore, mecamylamine (a non-competitive nicotinic antagonist) has no effect by itself, but prevents the acute and chronic undereating caused by cytisine. This suggests that central activation of AChR receptors are essential for reducing food intake. By blocking the β4 receptors in the region of the brain called the arcuate nucleus (ARC), the anorexic effect of cytisine is abolished. This suggested the hypothalamic system’s involvement of melanocortin, an essential metabolic pathway involved in the regulation of energy balance and food intake, as a target for nicotinic drugs.
Specifically, activation of pro-opiomelanocortin (POMC) cells in the ARC decreases food intake and increases energy expenditure, and loss of function of the POMC gene leads to obesity in humans and animals. Previous studies have shown that activation of the melanocortin receptor (MC4R) by melanocortins is critical for the regulation of food intake and energy expenditure. Among others, POMC neurons express cholinergic markers (the cholinesterase enzyme and the AChT transporter). These observations underscore a possible role of acetylcholine in metabolic regulation via POMC neurons. It has also been suggested that cholinergic projections to the ventral hypothalamus could be provided by highly localized clusters of neurons found in the median eminence. This brain region hosts cells that secrete hormones acting on the pituitary, including ACTH-releasing hormone (CRH), all known to affect metabolism.
All of these mechanisms could therefore alter POMC neuron activity and neurotransmitter release from synapses, which could in turn affect energy expenditure and feeding patterns. Thus, α3β4 acetylcholine receptors are critical for mediating these effects. β4 agonists may therefore be useful for limiting weight gain after smoking cessation, and nicotinic drugs may also be useful for controlling obesity and related metabolic disorders.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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