It would be of interest to determine whether fast metabolizers and slow metabolizers have different levels of basal D 2 and D 3 receptors and whether the response to smoking a cigarette is different. By comparison, D 3 receptor levels (in the SN) are reportedly higher in drug dependence ( Boileau et al., 2012). Further, it is also known from PET studies that DA D 2 receptor availability is lower in the striatum of people who are nicotine dependent ( Fehr et al., 2008), similar to other drugs of abuse ( Volkow et al., 1993 Martinez et al., 2004). In our previous study ( Le Foll et al., 2014b), we demonstrated a good magnitude of change in -(+)-PHNO BP ND due to smoking (approximately 12%) in the LST and VP using -(+)-PHNO. In some studies, changes in DA were limited to subjects that had a hedonic response, as measured with a 10-point scale of subjective ratings while in the scanner ( Barrett et al., 2004). Studies with -raclopride showed smoking-induced changes in binding potential (BP ND) ( Brody et al., 2004, 2009, 2010). PET imaging has also been used to study smoking-induced change in DA. The ventral pallidum (VP 75%), globus pallidus (GP 65%), and ventral/limbic striatum (LST 50%) provide intermediate D 3 fractions. By contrast, the entire signal from striatal regions was due to the D 2 receptor. In an elegant study by Tziortizi et al., gradients of binding to D 3 or D 2 receptors were demonstrated, with 100% of the signal obtained from the substantia nigra (SN) being attributed to D 3 ( Tziortzi et al., 2011). An advantage of PET imaging with -(+)-PHNO is the ability to measure not only D 2/3 receptors (as with traditional -raclopride), but to explore the expression of D 2 vs D 3 receptors, based on a regional signal analysis approach ( Kiss et al., 2011 Le Foll et al., 2014a). (+)-PHNO ( Wilson et al., 2005) allows for the measurement of DA D 2 and D 3 receptors, but also provides a more sensitive measure of DA fluctuations compared with the traditionally used -raclopride ( Shotbolt et al., 2012). PET imaging provides a noninvasive means to measure neurotransmitter levels and receptors.
Although these studies are informative, dopamine (DA) is a final common path in addiction ( Di Chiara et al., 1992), and the effects of NMR on baseline DA receptor levels and on DA transmission after a smoking challenge are currently unknown. It was also found that, in smokers, those with the faster nicotine metabolizer genotype had higher brain activation in the anterior cingulate and ventral striatum no genotype group differences were observed among nonsmokers ( Li et al., 2017). In 2 fMRI studies, FM had greater neural response to smoking cues than did the SM ( Tang et al., 2012) ( Falcone et al., 2016). Studies have begun to delineate differences in brain responses in SM vs FM.
Consistent with these findings, FM and SM also differ in response to both placebo and active smoking cessation treatments, with SM showing greater success in quitting ( Lerman et al., 2006, 2015 Patterson et al., 2008 Schnoll et al., 2009 Chenoweth et al., 2013, 2016 Vaz et al., 2015 Ebbert et al., 2016). Perhaps due to more cigarette smoking and higher levels of dependence, FM have higher craving ( Kaufmann et al., 2015) and reward ( Sofuoglu et al., 2012) and greater withdrawal ( Rubinstein et al., 2008). When stratified by NMR, it has been shown that fast metabolizers (FM) smoke more than slow metabolizers (SM) ( Benowitz et al., 2003 Johnstone et al., 2006 Malaiyandi et al., 2006 Mwenifumbo et al., 2007 Schnoll et al., 2009, 2014) and take larger puff volumes ( Strasser et al., 2011), suggesting an attempt to titrate smoking.
One biomarker of individual differences is the rate at which nicotine is metabolized, or the nicotine metabolite ratio (NMR) ( Dempsey et al., 2004). There is increasing interest in understanding the biological basis of individual differences in smoking characteristics. Thus, the rate of nicotine metabolism may contribute to dopaminergic signaling in the brain. We found that slow metabolizers had fewer dopamine receptors (of the D2-type) than fast metabolizers, but the two groups had a similar dopamine response to smoking a cigarette. The aim of the present study was to determine the impact of the rate of metabolism of nicotine on the brain reward system in tobacco smokers. Smoking is a serious public health problem, and it is known that the rate of metabolism of nicotine can influence key smoking characteristics such as the amount smoked and the ability to quit.
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