For alcohol-dependent individuals who are fortunate enough to become abstinent, 45% to 75% will relapse at least once. One way to potentially decrease the occurrence of relapse is to investigate the neurobiology of behavioral traits that may contribute to relapse. One such trait is the tendency to choose smaller immediate rewards ("Now") over larger delayed rewards ("Later"), which is more common among individuals with a history of alcohol dependence than among those without. This preference for Now versus Later, or immediate reward bias, is thus an intermediate behavioral phenotype for alcohol use disorders. Such intermediate phenotypes are thought to be more amenable to investigation, as they are relatively less complex and are likely to be less etiologically heterogeneous compared to alcohol use disorders. While recent studies have begun to establish the neural circuitry underlying immediate reward bias, the neurobiological mechanisms that contribute to this clinically significant behavioral trait remain to be fully investigated. In addition to alcohol abuse history, a variation in the catechol-O-methyltransferase (COMT) gene predicts both Now versus Later preference and underlying brain activity in the prefrontal and posterior parietal cortex. COMT is an enzyme responsible for the breakdown of dopamine and is the primary regulator of dopamine levels in the cortex. A common functional variation in the COMT gene results in an enzyme with either high or low activity. The COMT genotype that leads to high levels of COMT activity, and therefore low levels of dopamine, is associated with greater immediate reward bias relative to the other two genotypes. These data suggest there is an inverse relationship between baseline cortical dopamine and an individual's preference for Now versus Later. However, it is unknown whether baseline dopamine levels interact with transient fluctuations in dopamine to alter immediate reward bias and underlying brain activity. We predict that transient fluctuations in dopamine will affect immediate reward bias and fronto-parietal activity in a COMT genotype-dependent fashion in both control subjects and alcohol-dependent individuals. We will test this hypothesis with two complementary experiments that entail different transient manipulations of dopamine.
In Aim 1, we will acutely deplete dopamine using an amino acid beverage deficient in the precursors required for dopamine synthesis.
In Aim 2, we will transiently elevate dopamine by administering a COMT inhibitor. In both studies, participants will complete a Now/Later decision making task during functional magnetic resonance imaging to test whether acute dopaminergic manipulations change immediate reward bias and the underlying brain activity and whether such effects are moderated by COMT genotype or alcohol use history. This is one of the first studies to examine the neurobiological bases of pharmacological manipulation of impulsive decision making. Because immediate reward bias is a characteristic of alcohol-dependent individuals, these results could lead to the development of novel supportive therapies and improved treatment outcomes for people seeking abstinence.
These studies will provide the scientific community with information on the neurobiological mechanisms that contribute to impulsive decision making and the relationship between impulsive decision making and alcohol use disorders. Understanding the neural mechanisms of impulsive decision making may provide key insights into the neurobiology of alcohol use disorders and aid in the development of novel supportive therapies for these and related disorders.
|Kelm, Mary Katherine; Boettiger, Charlotte A (2013) Effects of acute dopamine precusor depletion on immediate reward selection bias and working memory depend on catechol-O-methyltransferase genotype. J Cogn Neurosci 25:2061-71|