Orexin and leptin are associated with nicotine craving: A link between smoking, appetite and reward
Introduction
Smoking is a major risk factor for a number of preventable diseases including lung cancer, cardiovascular and chronic obstructive pulmonary diseases. It is estimated that in the year 2000, cigarette smoking caused approximately 2.5 million deaths in the industrialized countries (Ezzati and Lopez, 2003). In subjects addicted to nicotine, relapse is often preceded by an urge to smoke (“craving”) that has been discussed as a major risk factor for relapse (Piasecki, 2006). Indeed, subjective craving for tobacco is the psychopathological symptom most commonly experienced during nicotine withdrawal and is anticipated as the most bothersome aspect of quitting to smoke (West et al., 1989, Orleans et al., 1991, Tiffany et al., 2009). The conceptualization of cigarette craving may thus have major theoretical and clinical implications for a better understanding of continuing cigarette use and relapse to tobacco consumption (Cox et al., 2001).
Nicotine, the primary psychoactive component of smoked tobacco, has been shown to modulate the mesolimbic system by binding to nicotinergic acetylcholine receptors located at neurons facilitating γ-aminobutyric acid (GABA) and dopamine transmission within different brain regions, such as the ventral tegmental area (VTA), the nucleus accumbens (NAc) and prefrontal areas (PFC) (Picciotto and Corrigall, 2002, Laviolette and van der Kooy, 2004, Wonnacott et al., 2005). Converging evidence from preclinical and clinical studies implicates the VTA and its associated efferent projections to the NAc and the PFC as an integrative center that mediates the reinforcing effects of nicotine (Adinoff, 2004, Markou, 2008).
Initially, the appetite regulating peptides orexin and leptin were studied almost exclusively as hormonal inputs to the bidirectional control of the homeostatic system being involved primarily in the balancing of energy expenditure and food craving (Arora and Anubhuti, 2006). However, rather than being under the exclusive control of the homeostatic system, food consumption can also be influenced by mechanisms involved in reward processing and reinforcement learning. In an environment deficient of nourishment, mechanisms of reinforcement initiate learning processes that result in food seeking behavior and the motivation to consume (Wise, 2004, von der Goltz and Kiefer, 2008). In support of the idea that orexin and leptin are involved in food-related reward mechanisms, both peptides have been shown to directly affect mesolimbic reward pathways (Palmiter, 2007). Both hormones bind to specific receptors located on VTA dopamine neurons, either stimulating (orexin) or inhibiting (leptin) dopamine signaling in the NAc (Narita et al., 2006, Hommel et al., 2006). Given their influence on dopaminergic transmission in the NAc and reward processing during feeding behavior, a number of studies have examined whether orexin and leptin also affect the subjective reward value and the reinforcing properties of nicotine (and other drugs of abuse) and, hence, the motivation to smoke.
Orexins (hypocretins) are neuropeptides initially identified as neurotransmitters in lateral hypothalamus (LH) neurons (de Lecea et al., 1998, Sakurai et al., 1998). The symptoms and pathophysiology of the sleep disorder narcolepsy, caused by an orexin deficiency, provided first insight into the physiological roles of orexin (Peyron et al., 2000, Thannickal et al., 2000). Whereas these earlier studies associated the function of orexin neurons mainly with the regulation of arousal and sleep, more recent investigations on the projections to reward-associated brain regions, including the NAc and VTA, have suggested a possible role of orexins in addictive disorders (Harris et al., 2005). Supporting this proposition, the results of a recent study by Hollander et al. (2008) point towards a crucial role of insular orexin transmission in the motivational properties of nicotine and suggest that orexin transmission in reward-related brain areas might represent a neurobiological substrate of tobacco addiction in humans.
Leptin, a protein hormone secreted by white adipocytes, also serves as an endocrine signal involved in the regulation of appetite and energy expenditure (Campfield et al., 1995, Halaas et al., 1995, Pelleymounter et al., 1995). As with orexin, leptin has recently been implicated in addictive disorders such as alcoholism (Kiefer et al., 2001a, Kiefer et al., 2001b, Kiefer et al., 2005, Hillemacher et al., 2007). Clinical studies have reported an association between plasma leptin concentrations and intensity of craving in cohorts of alcohol-dependent individuals following acute inpatient detoxification (Kiefer et al., 2001a, Kiefer et al., 2001b, Hillemacher et al., 2007). Leptin furthermore modulates the hypothalamo–pituitary–adrenocortical (HPA) axis on a hypothalamic level by inhibiting the HPA axis activity in response to stress (Stephens and Flier, 1997). The HPA axis is a hierarchically organized endocrine stress system, the key elements of which are the corticotropin-releasing hormone (CRH), the adrenocorticotropic hormone (ACTH) and cortisol. Its dysregulation has been implicated in addictive diseases (Koob and Le Moal, 2008). al’Absi et al. (2004) found that changes in cortisol concentrations during the first day of abstinence was associated with higher craving and an increased risk for relapse during the first week of abstinence. These effects of HPA axis activity on nicotine craving and relapse may also be modulated by leptin.
The aim of this study was to compare orexin and leptin plasma concentrations between tobacco smokers and non-smoking controls, and to test whether the plasma concentrations of these two peptides are associated with intensity of nicotine craving in a standardized setting.
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Participants
Participants were drawn from a representative sample of current smokers and non-smokers recruited from the general community of a mid-size city in Germany (Mannheim). All participants were non-treatment seeking individuals, randomly selected from official local residents’ registers and contacted by letter with an invitation to participate in the study. Responders underwent an initial 10-min pre-screening conducted by telephone. Only individuals meeting the following inclusion/exclusion criteria
Sample
In total, 124 subjects were included, 60 smokers and 64 non-smokers. Smokers and non-smokers differed significantly in years spent in education, body weight, BMI and exhaled air CO but did not differ in any of the other variables. The total sample was aged 33.7 ± 0.86 years, employed (40%) or students (41.2%). On average, the smokers consumed 12.8 ± 1.3 cigarettes per day and had been smoking for 15.6 ± 0.4 years. Sample characteristics are provided in Table 1.
Hormonal measures
In the total sample, orexin plasma
Discussion
The main results of this study suggest a bidirectional association between the appetite regulating peptides orexin and leptin and craving for nicotine during early withdrawal. Our data provide further evidence that the appetite/weight (homeostasis) regulating peptides orexin and leptin are involved in motivational (exostatic) pathways (Kalra and Kalra, 2004, Palmiter, 2007). However, the significant difference in body weight between smokers and non-smokers indicates that nicotine influences not
Role of funding source
Funding for this study was provided by a grant from the German Research Foundation (DFG KI 782/5-1 and Wi1316/9-1).
Conflict of interest
All authors state that there is no conflict of interest.
Acknowledgments
We would like to thank Carsten Wied for his assistance in data collection and Iris Remmlinger-Marten for excellent assistance in hormonal analyses.
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