My overarching career goal to be achieved through this K23 award is to learn how to integrate pharmacological, molecular genetic, and neuroimaging techniques in the development and assessment of medications for the treatment of alcoholism. To accomplish my goal of becoming an independent physician scientist at the conclusion of the K23 award period, it is important for me to gain proficiency as a general academician and to obtain specific sub-specialty training. My sub-specialty training will be organized under the umbrella of an integrated neuroscience project organized as three experiments requiring knowledge and expertise with the disciplines of pharmacology, neuroimaging, and molecular genetics. My project is based upon understanding the role of serotonergic function as a determinant of drinking behavior in heavy social drinkers. Predicated on the hypothesis that serotonergic function is under genetic control at the 5'-flanking regulatory region (5'-HTTPLR) of the serotonin transporter (SERT), I will study how individuals with the long (LL) form, with up to three times greater uptake of intrasynaptic serotonin (5-HT) and therefore a relative hyposerotonergic state than those with the short or heterozygous form (SS/SL), differ in their ability to appreciate the hedonic effects of alcohol or crave for it when provoked by experimenter generated cues in the human laboratory. I will pharmacologically provoke the serotonergic system, using the tryptophan depletion paradigm, to determine whether alterations in 5-HT availability exacerbates the functional and behavioral differences due to genotypic variation at the SERT. I will use Single Photon Emission Computerized tomography (SPECT) to demonstrate that individuals with the LL form compared with the SS/SL variants have increased SERT density, an index of the functional capacity of the 5-HT system in individuals with these respective genotypes. If these experiments are successful, I may be able to show that genotypic differences between heavy social drinkers can be associated with differential risks of developing the alcoholism disease. This study therefore has the potential to identify a method for delineating heavy social drinkers with the greatest risk for developing the alcoholism disease, and should guide the rational development of specific serotonergic agents for the treatment of alcoholism.
| Seneviratne, Chamindi; Franklin, Jason; Beckett, Katherine et al. (2013) Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence. Hum Genet 132:1165-76 |
| Johnson, Bankole A; Ait-Daoud, Nassima; Seneviratne, Chamindi et al. (2011) Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry 168:265-75 |
| Johnson, Bankole A; Ait-Daoud, Nassima (2010) Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. Curr Pharm Des 16:2103-12 |
| Seneviratne, Chamindi; Ait-Daoud, Nassima; Ma, Jennie Z et al. (2009) Susceptibility locus in neurokinin-1 receptor gene associated with alcohol dependence. Neuropsychopharmacology 34:2442-9 |
| Seneviratne, Chamindi; Huang, Weihua; Ait-Daoud, Nassima et al. (2009) Characterization of a functional polymorphism in the 3' UTR of SLC6A4 and its association with drinking intensity. Alcohol Clin Exp Res 33:332-9 |
| Ait-Daoud, Nassima; Roache, John D; Dawes, Michael A et al. (2009) Can serotonin transporter genotype predict craving in alcoholism? Alcohol Clin Exp Res 33:1329-35 |
| LoCastro, Joseph S; Youngblood, Marston; Cisler, Ron A et al. (2009) Alcohol treatment effects on secondary nondrinking outcomes and quality of life: the COMBINE study. J Stud Alcohol Drugs 70:186-96 |
| Johnson, Bankole A; Javors, Martin A; Roache, John D et al. (2008) Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking? Prog Neuropsychopharmacol Biol Psychiatry 32:209-16 |
| Zweben, Allen; Pettinati, Helen M; Weiss, Roger D et al. (2008) Relationship between medication adherence and treatment outcomes: the COMBINE study. Alcohol Clin Exp Res 32:1661-9 |
| Johnson, Bankole A; Koob, George F; Schuckit, Marc A et al. (2006) Understanding and treating alcohol dependence. Alcohol Clin Exp Res 30:567-84 |
Showing the most recent 10 out of 18 publications
