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Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.

To identify novel phenotypic associations related to Cytochrome P450 Family 2 Subfamily A Member 6 ( CYP2A6 ), we investigated the human phenome in a total of 11,271 individuals. Initially, we conducted a phenome-wide association study in 3,401 nicotine-exposed elderly subjects considering 358 phenotypic traits. We identified a significant association between CYP2A6 rs113288603 and hearing loss symptoms (p = 5.75 × 10 −5 ). No association was observed in a sample of 3,245 nicotine-unexposed individuals from the same discovery cohort, consistent with the conclusion that the finding is related to CYP2A6 involvement in nicotine metabolism. Consistent results were obtained (p < 0.1) in an independent sample of 2,077 nicotine-exposed elderly subjects, and similarly, no significance was observed in the nicotine-unexposed sample (n = 2,548) of the replication cohort. Additional supporting evidence for this association was provided by gene expression data: rs113288603 is associated with increased CYP2A6 expression in cerebellar hemispheres (p = 7.8 × 10 −4 ). There is a well-known correlation between smoking and age-related hearing loss. Cigarette smoking is associated with structural changes in the brain and CYP2A6 mediates these changes. In this context, the regulatory role of rs113288603 in cerebellum appears to be consistent with the known involvement of this brain region in auditory function.

RationaleThe nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate.ObjectiveWe developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate, and blood pressure.MethodsEighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 years old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions, in which they were randomly assigned to a saline infusion, or a 1 mg per 70-kg body weight dose of nicotine delivered over 1, 5, or 10 min at rates of 0.24, 0.048, or 0.024 μg/kg/s, respectively.ResultsSmoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1- and 5-min infusion, but not the 10-min infusion. Although the 1- and 5-min infusions reduced smoking urges to a similar extent, the 1-min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate, and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes.ConclusionsWe have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~ 1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.

Abstract Introduction Characterizing flavors are widely available in e-cigarettes and motivate initiation and continued use. Flavors may enhance appeal and facilitate development of addiction to tobacco products through modulation of tobacco products’ reinforcing or aversive actions. Palatable flavors (eg, fruit) may increase appeal through primary reinforcing properties. Menthol’s cooling and anesthetic effects may increase appeal by counteracting nicotine’s aversive effects. Genetics provide a method for modeling individual differences in sensitivity to nicotine’s effects. A common polymorphism, rs16969968, encoded in the α5 nicotinic acetylcholine receptor subunit gene (CHRNA5), is a well-recognized marker for smoking risk and reduces sensitivity to nicotine aversiveness. Methods This pilot study tested how flavors impacted e-cigarette appeal and self-administration. In a single testing day, cigarette smokers (N = 32; 94% menthol-smokers) self-administered e-cigarettes containing e-liquids differing in nicotine level (0 mg/mL, 24 mg/mL) and flavor (unflavored, menthol, fruit-flavored) within directed and ad libitum e-cigarette paradigms. Subjective drug effects, number of puffs, rs16969968 genotype, plasma nicotine, and menthol glucuronide levels were collected. Results Menthol partially ameliorated nicotine aversiveness; fruit did not. In nicotine’s absence, fruit flavor increased self-reported preference and ad libitum use relative to menthol-containing or unflavored e-liquids. Individuals with high-smoking-risk rs16969968 genotype (N = 7) reported greater craving alleviation following directed administration of nicotine-containing e-liquids, showed a trend rating nicotine-containing e-liquids as less harsh, and self-administered more nicotine during ad libitum compared to individuals with low-smoking-risk genotype (N = 23). Conclusions While menthol countered aversiveness of nicotine-containing e-liquids, fruit flavor increased appeal of nicotine-free e-liquids. These preliminary findings suggest menthol and fruit flavor increase e-cigarettes’ appeal through distinct mechanisms. Implications This study provides a detailed characterization of the effects of flavors (unflavored, menthol, fruit), nicotine (0 mg/mL, 24 mg/mL) and their interactions on the subjective drug effects and ad libitum self-administration of e-cigarettes. Genetics were used to assess these effects in higher-smoking-risk (diminished sensitivity to nicotine aversiveness) and lower-risk groups. Findings could inform impact of regulation of flavors or nicotine in e-cigarettes, and their impacts on vulnerable sub-populations.

Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer’s disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Single-nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the 'missing heritability' might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genome-wide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genome-wide (eg, P=2 × 10(-8) and OR (95% CI)=0.64 (0.54-0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, whereas others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication.

The neurotransmitter dopamine (DA) plays a central role in addictive disorders, including nicotine addiction. Specific DA-related gene variants have been studied to identify responsiveness to treatment for nicotine addiction. Genetic variants in , , , , and genes show some promise in informing personalized prescribing of smoking cessation pharmacotherapies. However, many trials studying these variants had small samples, used retrospective design or were composed of mainly self-identified Caucasian individuals. Furthermore, many of these studies lacked a comprehensive measurement of nicotine metabolism rate, did not assess the roles of sex or the menstrual cycle, and did not investigate the role of rare variants and/or epigenetic factors. Future work should be conducted addressing these limitations to more effectively utilize DA genetic information to unlock the potential of smoking cessation pharmacogenetics.

Alcohol use contributes to numerous diseases and injuries. The nervous system is affected by alcohol in diverse ways, though the molecular mechanisms of these effects are not clearly understood. Using human-induced pluripotent stem cells (iPSCs), we developed a neural cell culture model to identify the mechanisms of alcohol’s effects. iPSCs were generated from fibroblasts and differentiated into forebrain neural cells cultures that were treated with 50 mM alcohol or sham conditions (same media lacking alcohol) for 7 days. We analyzed gene expression using total RNA sequencing (RNA-seq) for 34 samples derived from 10 subjects and for 10 samples from 5 subjects in an independent experiment that had intermittent exposure to the same dose of alcohol. We also analyzed genetic effects on gene expression and conducted a weighted correlation network analysis. We found that differentiated neural cell cultures have the capacity to recapitulate gene regulatory effects previously observed in specific primary neural tissues and identified 226 genes that were differentially expressed (FDR < 0.1) after alcohol treatment. The effects on expression included decreases in INSIG1 and LDLR, two genes involved in cholesterol homeostasis. We also identified a module of 58 co-expressed genes that were uniformly decreased following alcohol exposure. The majority of these effects were supported in independent alcohol exposure experiments. Enrichment analysis linked the alcohol responsive genes to cell cycle, notch signaling, and cholesterol biosynthesis pathways, which are disrupted in several neurological disorders. Our findings suggest that there is convergence between these disorders and the effects of alcohol exposure.