The preludes to this project are two successful prior collaborations with Bulgarian colleagues in which we conducted comprehensive characterization of impulsivity in relatively pure users of opiates and stimulants and collected and stored genetic material from many of these participants. The overall aim of this competing renewal is to investigate the role of impulsivity as an endophenotype for drug addiction. Although impulsivity is considered one of the strongest candidate endophenotypes for addiction, progress in the field is hampered by: (1) the heterogeneity of impulsivity, characterized by multiple personality, psychiatric, and neurocognitive dimensions; (2) the heterogeneity of addiction phenotypes, due in part to the high rates of polysubstance dependence; and (3) the limited number of studies following the full endophenotype criteria and related lack of objective quantitative methods for optimal endophenotype selection. To address these challenges, we have developed a program of addiction research in Bulgaria, a key transit country for heroin trafficking and a major European center for production of synthetic amphetamine-type stimulants. This has allowed us to access rare populations of predominantly monosubstance-dependent heroin and amphetamine users, many in protracted abstinence. Our preliminary results reveal a complex relationship between trait and neurocognitive (state) dimensions of impulsivity, often manifested in opposite directions in heroin and amphetamine dependent individuals. Pilot computational modeling analyses of decision-making, a central neurocognitive aspect of impulsivity, proved particularly informative by indicating that different mechanisms underlie the impaired decision-making of opiate and stimulant users. Our findings underscore the utility of examining multiple and more narrowly-defined dimensions of impulsivity and contribute significantly to a growing body of literature that reveals important differences between chronic users of different classes of drugs. With this competing renewal application, we propose to continue our collaboration to build sustainable infrastructure for neurogenetic addiction research in Bulgaria and address the following specific aims: (1) Assess the utility of various personality, psychiatric, and neurocognitive indices of impulsivity (either individually or in combination) as candidate endophenotype(s) for drug addiction in general and for opiate and stimulant addictions in particular. We propose to compare the traditional method for endophenotype selection to a novel, empirically-derived quantitative method for optimal endophenotype selection in approaching this aim. To replicate and validate our previous findings, we will use the same comprehensive impulsivity battery in a new cohort of 100 heroin users and 100 siblings; 100 amphetamine users and 100 siblings; and 100 healthy non-related controls (N=500), for a total N=800 across the two studies; (2) Evaluate the viability of computational model parameters modeling various neurocognitive dimensions of impulsivity as novel endophenotype(s) for addiction; and (3) Test the external validity of the optimal endophenotype(s) by evaluating their associations with HIV and other risk behaviors in opiate and stimulant users in protracted abstinence, a question of critical importance for prevention and intervention efforts in this much less-well understood stage of the addiction cycle.
Heroin and amphetamine addiction remain significant public health problems worldwide. Much remains to be uncovered regarding their etiology, despite years of research that show a strong genetic basis for substance use disorders. We have identified a unique cohort of drug users characterized by predominantly monosubstance-dependent patterns of drug use and by protracted abstinence, which may help decipher some of the neurocognitive and genetic risk factors associated with drug addiction and their relation to HIV and other risk behaviors.
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