Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans

Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task (BART). The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the BART during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1, and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7777 allelic combinations) was tested on brain function in an independently defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that the combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting the cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function, and decision making vary as a function of dopamine signaling capacity.

Section: Image Analysismentioning

confidence: 99%

Functional Genetic Variation in Dopamine Signaling Moderates Prefrontal Cortical Activity During Risky Decision Making

Kohno

Nurmi

Laughlin

et al. 2015

“…In humans, tobacco use has been associated with both increased striatal dopamine synthesis capacity (Salokangas et al, 2000) and dopamine release in response to acute cigarette use in smokers (Brody et al, 2004;Le Foll et al, 2013). However, two studies found that acute nicotine use did not elicit a significant dopamine release in smokers (Barrett et al, 2004;Montgomery et al, 2007), although these did find that the subjective hedonic response to acute nicotine was related to dopamine release.…”

Section: Introductionmentioning

confidence: 96%

Dopamine Function in Cigarette Smokers: An [18F]-DOPA PET Study

Bloomfield

Pepper

Egerton

et al. 2014

Tobacco addiction is a global public health problem. Addiction to tobacco is thought to involve the effects of nicotine on the dopaminergic system. Only one study has previously investigated dopamine synthesis capacity in cigarette smokers. This study, exclusively in male volunteers, reported increased dopamine synthesis capacity in heavy smokers compared with non-smokers. We sought to determine whether dopamine synthesis capacity was elevated in a larger sample of cigarette smokers that included females. Dopamine synthesis capacity was measured in 15 daily moderate smokers with 15 sex-and age-matched control subjects who had never smoked tobacco. Dopamine synthesis capacity (indexed as the influx rate constant K i cer ) was measured with positron emission tomography and 3,4-dihydroxy-6-[ 18 F]-fluoro-l-phenylalanine. There was no significant group difference in dopamine synthesis capacity between smokers and non-smoker controls in the whole striatum (t 28 ¼ 0.64, p ¼ 0.53) or any of its functional subdivisions. In smokers, there were no significant relationships between the number of cigarettes smoked per day and dopamine synthesis capacity in the whole striatum (r ¼ À 0.23, p ¼ 0.41) or any striatal subdivision. These findings indicate that moderate smoking is not associated with altered striatal dopamine synthesis capacity.

“…Dopamine (DA) is a neurotransmitter believed to be important in the final common path in drug dependence, including nicotine (Pich et al, 1997). DA is believed to mediate both the rewarding (Brody et al, 2004;Corrigall et al, 1992;Le Foll et al, 2014) and withdrawal-associated (Rada et al, 2001;Rahman et al, 2004) effects of nicotine. That is, increased DA is associated with ratings of positive subjective measures (Montgomery et al, 2007), and decreased DA is believed to mediate the negative state during withdrawal (Hildebrand et al, 1998;Le Foll et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Varenicline-Induced Elevation of Dopamine in Smokers: A Preliminary [11C]-(+)-PHNO PET Study

Ciano

Guranda

Lagzdins

et al. 2015

Self Cite

Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here we used PET imaging with [11 C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment-seeking smokers underwent two PET scans with [11 C]-(+)-PHNO, each following 12-h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (ie, at steady-state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [11 C]-(+)-PHNO binding in the dorsal caudate (p = 0.008) and reduced some craving measures. These findings provide the first evidence that varenicline is able to increase DA levels in the human brain, a factor that may contribute to its therapeutic efficacy.