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Bupropion (BUP), which in its slow-release formulation (Zyban^®) is used as a smoking-cessation drug, increases dopamine overflow in the nucleus accumbens and serves as a reinforcer in animal experiments, both suggesting that BUP may possess some abuse liability. The present study examined if BUP produced subjective effects indicative of abuse liability in a quasi-naturalistic setting, with caffeine (CAF) serving as a positive control. In a randomized double-blind crossover design, male smokers (n = 50) ingested two doses (interdosing interval, 6 h) of placebo (PLC), 178 mg CAF, or 150 mg slow-release BUP in their normal mid-week work environment. They completed questionnaires administered by telephone at regular intervals. CAF significantly increased ratings of ‘pleasant effects’ (p = 0.008) and ‘high’ (p = 0.03), whereas BUP produced a ‘high’ of only very moderate size (p = 0.02). In 3 subjects each, BUP or CAF produced ratings of ‘pleasant effects’ that were >9-fold higher than those for PLC. Finally, BUP increased the number of cigarettes smoked by 29% (i.e., from 24 to 31 per day; p = 0.004) only in those subjects who were unable to report any effect of either BUP or CAF. CAF had no effect on cigarette consumption. These findings suggest that BUP, like CAF, might be of some abuse liability in a small subgroup of smokers (i.e., 6% each of the present sample), and it may transiently increase, rather than decrease, smoking during early phases of treatment in continuing smokers.

Background-Spatial and timely variations in QT interval, even within its normal range, may underlie susceptibility to cardiac arrhythmias and sudden cardiac death. Given its important role in cardiac electrophysiology, we hypothesized that common genetic variation in ankyrin-B gene (ANK2) might modify QT interval length. Methods and Results-The study population consisted of 1188 participants of the World Health OrganizationalMultinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) general population survey Cooperative Health Research in the Region of Augsburg (KORA S3). Corrected QT interval was calculated using population specific linear regression formulas. A total of 22 single-nucleotide polymorphisms in the genomic region of ANK2 gene were genotyped using TaqMan technology. In a replication study, 6 single nucleotide polymorphisms were genotyped in 3890 individuals from a second population study (KORA S4). The rare variant of the single-nucleotide polymorphism rs6850768 (allele frequency, 0.28) significantly influenced duration of the QT interval, both in KORA S3 and KORA S4 populations. In homozygotes, the shortening of the QT interval was 3.79 ms (95% CI, 1.48 to 5.58; Pϭ0.001 and Pϭ0.0008 for log-additive and dominant model, respectively) in KORA S3 and 2.94 ms (95% CI, 1.11 to 4.77; Pϭ0.001 and Pϭ0.006 for log-additive and dominant genetic model, respectively) in KORA S4. A common 2-locus haplotype (rs11098171-rs6850768; population frequency, 28%) was associated with a QT interval difference of 2.85 ms (permutation; Pϭ0.006) in KORA S3 and 1.23 ms (permutation; Pϭ0.009) in KORA S4. Reverse transcription-polymerase chain reaction expression analysis of the human ANK2 5Ј genomic region in the human left ventricular tissue revealed 2 previously unidentified ANK2 5Ј exons in the proximity of the identified variants. Key Words: arrhythmia Ⅲ genetics Ⅲ long-QT syndrome Ⅲ physiology Ⅲ sudden cardiac death T he QT interval on 12-lead ECG reflects ion channel events of both myocardial depolarization and repolarization. The length of the QT interval is influenced by various determinants, such as heart rate, age, sex, electrolyte levels, and many medications. In the general population, the QT interval is normally distributed. 1 Individuals with longer QTc display increased risk of malignant cardiac arrhythmias and sudden cardiac death, particularly in case of increased cardiovascular risk 2 or manifest coronary artery disease. 3 QT interval is a complex quantitative trait with a heritability of Ͼ30%. 4 Genetic linkage of the QTc interval to LQT4 with its underlying gene ANK2 was demonstrated. 5 Further studies identified single-nucleotide polymorphisms (SNPs) in multiple genomic regions that were associated with the QTc interval. 1,6 ANK2 loss-of-function monogenic syndromes are responsible for a variety of cardiac phenotypes. However, currently no data support the role of common genetic variants in the ANK2 in normal cardiac repolarization. ANK2 encodes the adapter protein ankyrin...

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