Circulating leptin levels are associated with increased craving to smoke in abstinent smokers
Research Highlights
► This study examined leptin's associations with craving for cigarettes and smoking relapse among smokers interested in cessation. ► It was conducted to extend recent evidence suggesting that leptin was associated with increased craving for alcohol. ► High circulating leptin levels were associated with increased craving, withdrawal symptoms, negative affect, physical symptoms, and reduced positive affect. ► The results indicate that circulating leptin is a promising biological marker of craving for smoking and warrant further investigation of the links between appetite regulation and nicotine dependence
Introduction
Craving to smoke is an important construct in understanding tobacco dependence, since it represents a strong motivational factor for smoking (Ferguson and Shiffman, 2009, West et al., 2007), and is a risk factor for relapse (al'Absi et al., 2004, Killen and Fortman, 1997). Intensity of craving to smoke experienced during the first few days of abstinence predicts who will relapse (al'Absi et al., 2007, al'Absi et al., 2004, Killen and Fortman, 1997, Shiffman et al., 1996). There is however little research to identify a specific biological marker of craving for cigarettes, although recent studies provide promising results. One study has shown that smokers who relapsed within the first week post quitting exhibited an exaggerated drop in morning cortisol concentrations during abstinence relative to their ad libitum smoking levels (al'Absi et al., 2004). Smokers who relapsed within four weeks after quitting showed attenuated adrenocorticotropin (ACTH) levels, diastolic blood pressure (BP), and smoking urges during acute stress (al'Absi et al., 2005). Similar results have also been reported in the context of treatment studies (Frederick et al., 1998, Ussher et al., 2006).
Leptin is a protein product of the ob gene that presents primarily in adipocytes (Campfield et al., 1995). It regulates hypothalamic centers involved in energy homeostasis, body weight, and gene expression of corticotropin-releasing hormone and pro-opiomelanocortin (Cheung et al., 1997, Enriori et al., 2006, Mantzoros, 1999). It also interacts with neuroendocrine systems that are involved in appetite regulation, such as neuropeptide Y and agouti-related peptide (AgRP; Cone, 2005, Mantzoros, 1999). Beyond its effects on hypothalamic centers and neuroendocrine pathways, leptin was shown to directly modulate activity of mesocorticolimbic reward pathways. Fulton et al. (2000) showed that the effectiveness of a rewarding electrical stimulation was attenuated by intra-cerebro-ventricular infusion of leptin. Leptin binds to specific receptors located on the dopamine neurons of the ventral tegmental area (VTA) and inhibits dopamine signalling in the nucleus accumbens (Palmiter, 2007). Given the influence of leptin on dopaminergic transmission and reward processing, a number of studies have been designed to examine whether leptin also affects the subjective reward value and the reinforcing properties of drugs of abuse (Kiefer et al., 2001a, Kiefer et al., 2001b).
Leptin modulates the hypothalamic-pituitary-adrenocortical (HPA) axis by blunting the cortisol stress response, presumably acting at the level of the hypothalamus (Ahima et al., 1996, Heiman et al., 1997). Dysregulation in the neuroendocrine stress system, in particular the HPA axis, has been linked to a variety of psychiatric disorders, including addiction. Preclinical and clinical data suggest that impaired functioning of the HPA axis and blunted stress response are directly associated with increased alcohol intake (Junghanns et al., 2003, Sillaber et al., 2002) and smoking relapse (al'Absi et al., 2005, Shaw and al'Absi, 2008). Recent research has also shown that leptin concentrations predicted craving and relapse among alcoholics under treatment (Kiefer et al., 2005, Hillemacher et al., 2007). Taken together, these findings suggest direct or indirect effects of leptin on motivational, mesolimbic structures and neuroendocrine stress systems of the brain (Inui, 1999, Fulton et al., 2000). It is therefore possible that leptin would be a promising biological correlate for craving and mood changes during smoking withdrawal.
Previous studies have examined leptin levels in smokers and have shown an association between this hormone and smoking status, although this was not consistently found (Eliasson and Smith, 1999, Reseland et al., 2005, Koc et al., 2009), and studies have not found consistent effects of short-term smoking abstinence on leptin (Klein et al., 2004, Perkins and Fonte, 2002). These inconsistencies may be related to different sample selection criteria and variable length of abstinence. The goal of this study was to examine the extent to which circulating leptin levels are associated with nicotine craving measured after a 24-hour period of abstinence, and explore the extent to which these levels predict relapse during a 4 week follow-up period. Measures of craving and withdrawal symptoms as well as plasma leptin levels were collected from a subgroup of smokers who were participating in a larger study that examined the extent to which their responses to stress predicted smoking relapse (al'Absi et al., 2005).
Section snippets
Participants
This study included 32 participants (14 women) between the ages of 18 and 68 (mean ± S.E.M. = 34.1 ± 14.6 years) who were dependent cigarette smokers and expressed a strong motivation to stop smoking. Inclusion criteria included absence of major physical illness or psychiatric disorders, weight within ± 30% of Metropolitan Life Insurance norms, and consumption of two or fewer alcoholic drinks a day. Qualified participants reviewed and signed a written consent form approved by the Institutional Review
Subject characteristics
Table 1 shows participant characteristics. Men and women did not differ significantly on age, education, alcohol intake, and average hours of nightly sleep (all Fs < 1.28; ps > 0.27). They also did not differ in number of cigarettes per day, scores on FTND, duration of smoking, motivation to quit, or number of previous quit attempts (all Fs < 3.7; ps > 0.07).
Men and women did not differ in craving as measured by the ‘desire to smoke’ item from the MNWS and by the QSU-B, and they also reported similar
Discussion
The primary finding of this study is the significant association between circulating leptin levels and craving for cigarettes after 24 h of abstinence. Increased circulating leptin levels were also associated with increased negative affect, physical symptoms, and reduced positive affect. While leptin was associated with abstinence-related measures, it was not associated with stress-related hormonal and cardiovascular changes. The current results are novel and rather striking considering the
Acknowledgements
This study was supported in part by National Institute of Health grants CA88272 and DA016351 to Dr. al'Absi.
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