Genetic influences on the human mesolimbic dopamine reward system

Abstract

Current estimates suggest that as many as 9% of Americans meet the DSM-IV criteria for substance use disorders, and the annual economic burden of substance abuse has been assessed at approximately half a trillion dollars. Thus, addiction is a highly prevalent social problem that rivals almost any other public health issue in terms of social and personal costs. However, despite the fact that addiction is significantly heritable, very few specific genetic susceptibility factors have been reliably identified. Moreover, even for the most promising risk genes, the systems-level neural mechanisms that mediate their impact on risk are largely unknown. In this dissertation, I use a dual-scan dopamine receptor imaging approach with the stimulant drug amphetamine to probe the neurogenetic architecture of addiction. Motivated by the key role played by dopamine in drug addiction, I test the hypothesis that genetic variability in three distinct brain signaling systems with conceptual links to addiction converge to exert a sensitizing effect on striatal dopamine responses to drugs of abuse. First, I examine variation at a locus in the CSNK1E gene, which encodes a protein kinase that regulates the function of the dopamine signaling integrator DARPP-32. Second, I study an allelic variant in the gene encoding an hypothalamic-pituitary-adrenal (HPA) stress axis factor (CRH) that has been previously associated with stress-induced alcohol consumption in non-human primates. Finally, given the prominent psychopathological and neurobiological parallels between obesity and addiction, I investigate the novel hypothesis that obesity-linked genetic variability in leptin signaling (LEPR) may predispose risk for substance abuse by affecting striatal dopamine responses to stimulants. In all cases, individuals who carried the putative risk allele at each of these loci demonstrated marked sensitization of striatal dopamine responses to amphetamine. In turn, the magnitude of striatal dopamine release was positively associated with subjective responses to amphetamine and with individual differences in impulsivity. Taken together, these findings support the involvement of two genes (CSNK1E and CRH) in risk for addiction, nominate a third (LEPR) for enhanced phenotypic investigation, and offer a common neurobiological mechanism – sensitization of striatal dopaminergic function – that may be involved in the conferral of susceptibility by diverse genetic risk factors.