This K23 award advances the Candidate's long term goal of integrating pharmacogenetic and psychiatric genetic approaches in the study of smoking/nicotine dependence (ND) and its co-occurrence with Attention Deficit Hyperactivity Disorder (ADHD). The proposed training will enable the PI to develop the skills needed for an independent interdisiplinary research career in this field. Risk for smoking behaviors in adolescents, including earlier age of initiation and likelihood of regular smoking, has been associated with both a clinical diagnosis of ADHD and non-clinical levels of ADHD symptoms. Several converging lines of work suggest that the high rates of smoking in the presence of ADHD symptoms may be related to common genetic vulnerabilities that increase risk for both ND and ADHD. In addition, increased risk for smoking in this population may be related to the effects of nicotine and nicotine abstinence on ADHD-related deficits in executive function (EF) and delay discounting (DD). The research plan focuses on elucidating a neurobiological pathway to ND by examining the genetic and cognitive correlates of smoking in adolescents with ADHD. First, secondary analysis of extant geneticially-informative samples will be conducted to address gaps in the literature related to 1) the latent genetic, environmental, and gene by environmental influences on the overlap between smoking/ND and ADHD and 2) associations with measured genetic variation related to the neuropharmacology of nicotine (i.e. dopaminergic, nicotinic acetylcholinergic, and nicotine metabolism genes) and the ND/ADHD comorbidity. Few genetic studies have examined ADHD and smoking concurrently and this work will assist in characterizing phenotypes and selecting measured genes most relevant to this etiological pathway, that is, adolescent smoking in the presence of ADHD symptoms. Second, new data will be collected using laboratory pharmacology methods to probe the cognitive and genetic mechanisms underlying increased risk for smoking in adolescents with ADHD by assessing the effects of nicotine abstinence on EF and DD in adolescent smokers with and without ADHD. EF and DD performance will be compared in adolescent smokers with (n=32) and without (n=32) ADHD after 24-hour biochemically verified smoking abstinence in the following conditions: 1) placebo patch (nicotine abstinence) and 2) 14 mg nicotine patch (nicotine replacement). DNA will also be collected in order to test the moderating role of genetic variation related to nicotine neuropharmacology on EF and DD processes. Results will inform a critical vulnerability for nicotine use in a high risk population, i.e. adolescents with ADHD, and advance the understanding of etiological factors in ND more broadly. This research will lead to subsequent grant applications to further probe genetic and neuropharmacological mechanisms associated with smoking risk in the presence of ADHD as well as clinical projects to develop more effective interventions for ND in this high- risk group. To enable the PI to pursue this long-term research agenda, she will work with experienced mentors to build upon her current expertise in neurocognitive phenotypes of ADHD with five areas of training: (1) nicotine psychopharmacology, 2) laboratory methods in behavioral pharmacology, 3) special issues in adolescent smoking research, 4) behavioral genetic analytic approaches, and 5) synthesizing these training experiences into a long-term pharmacogenetics of ND research program. Taken together, the proposed research and training plans address a key priority of integrating genetic and pharmacological methodologies to advance the understanding of etiological and treatment factors in ND, and it will fully prepare the PI for an independent clinical research career in the field.
Public Health Relevancy This project is of considerable public health significance. Smoking is the leading cause of preventable death in the US and adolescents with attention-deficit hyperactivity disorder (ADHD) start smoking earlier and smoke much more than those without ADHD. This project will improve our understanding of the genetic risk factors for smoking in these adolescents and help identify some of the reasons why adolescents with ADHD smoke more, potentially leading to better prevention and treatment programs.
|Karoly, Hollis C; Bidwell, L Cinnamon; Mueller, Raeghan L et al. (2018) Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis. Alcohol Clin Exp Res 42:531-539|
|Knopik, Valerie S; Marceau, Kristine; Bidwell, L Cinnamon et al. (2018) Prenatal substance exposure and offspring development: Does DNA methylation play a role? Neurotoxicol Teratol :|
|Bidwell, L Cinnamon; Karoly, Hollis C; Thayer, Rachel E et al. (2018) DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity. Addict Biol :|
|Bidwell, L Cinnamon; Balestrieri, Sara G; Colby, Suzanne M et al. (2018) Abstinence-induced withdrawal severity among adolescent smokers with and without ADHD: disentangling effects of nicotine and smoking reinstatement. Psychopharmacology (Berl) 235:169-178|
|Marceau, Kristine; Cinnamon Bidwell, L; Karoly, Hollis C et al. (2018) Within-Family Effects of Smoking during Pregnancy on ADHD: the Importance of Phenotype. J Abnorm Child Psychol 46:685-699|
|Bidwell, L Cinnamon; Marceau, Kristine; Brick, Leslie A et al. (2017) Prenatal Exposure Effects on Early Adolescent Substance Use: Preliminary Evidence From a Genetically Informed Bayesian Approach. J Stud Alcohol Drugs 78:789-794|
|Vergara, Daniela; Bidwell, L Cinnamon; Gaudino, Reggie et al. (2017) Compromised External Validity: Federally Produced Cannabis Does Not Reflect Legal Markets. Sci Rep 7:46528|
|Bidwell, L Cinnamon; Karoly, Hollis C; Hutchison, Kent E et al. (2017) ADHD symptoms impact smoking outcomes and withdrawal in response to Varenicline treatment for smoking cessation. Drug Alcohol Depend 179:18-24|
|Bidwell, L Cinnamon; Gray, Joshua C; Weafer, Jessica et al. (2017) Genetic influences on ADHD symptom dimensions: Examination of a priori candidates, gene-based tests, genome-wide variation, and SNP heritability. Am J Med Genet B Neuropsychiatr Genet 174:458-466|
|Bidwell, L Cinnamon; Palmer, Rohan H C; Brick, Leslie et al. (2016) A Propensity Scoring Approach to Characterizing the Effects of Maternal Smoking During Pregnancy on Offspring's Initial Responses to Cigarettes and Alcohol. Behav Genet 46:416-30|
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