Frontolimbic Circuits, Dopamine, and Attentional Bias to Alcohol Cues

The excess allocation of attention toward addiction-related stimuli has been widely reported across a wide variety of addictions, including alcohol use disorders (AUDs). This phenomenon is defined as addiction attentional bias (AB) and is thought to reflect Pavlovian conditioning processes associated with the repeated pairing of sensory stimuli with the rewarding properties of reinforcing substances. AB to alcohol related stimuli has been reported in alcohol addicted and heavy social drinking populations. The presence of addiction AB is of clinical importance as it has been reported to correlate with drug craving, addiction severity, and treatment outcomes. A more recent study found that another form of AB, generalized reward (non-drug related), AB was also heightened in addicted individuals. In a population of substance abuse users (SUDs) generalized AB reflected an increase allocation of attention to a monetary reward. This phenomenon of generalized reward AB is true for healthy young adults with no SUD history. The presence of heightened addiction and generalized AB in addicted and healthy populations may suggest individual differences in susceptibility to reward conditioning. Preclinical models of addiction have reported marked individual differences in the responses to reward conditioned stimuli and that a tendency toward greater sensitivity to reward conditioning is a risk factor for addiction. However, these individual differences have not been greatly explored in humans, and not been investigated in at-risk social drinking populations. Moreover, very few studies to date have investigated the neural mechanisms of addiction and generalized reward AB. Thus the overall goal of this dissertation was to characterize alcohol and generalized reward attentional bias in a social drinking sample and the neural mechanisms that contributes to the expression of these behavioral phenomena. Specifically, we investigated two distinct forms of alcohol AB in heavy, binge and moderate social drinkers and assessed the role of current and past binge drinking behavior on alcohol AB. To probe the underlying mechanisms of alcohol AB, we assessed sensitivity to reward conditioning, a process that may potentially underlie AB and investigated the role of adolescent binge alcohol exposure on sensitivity to reward conditioning. To further explore the neural mechanisms of AB, we probed the role of dopamine (DA) in alcohol AB and reward conditioning. Using a phenylalanine/ tyrosine (P/T) depleted amino acid (AA) beverage to pharmacologically manipulate DA levels, we assessed changes in AB and functional connectivity of the frontolimbic network, a key network for reward conditioning in heavy, binge and moderate social drinking males. Our investigations of AB revealed a significant difference in alcohol AB on one of our tasks, but with moderate drinkers showing greater AB than our hypothesized heavy, binge drinkers. Current and adolescent binge drinking measures negatively correlated with alcohol AB on this task as well. We also found that alcohol AB was inversely related to the magnitude of AB toward a reward-conditioned cue in a reward conditioning task. Furthermore, in a subset of female participants, we detected a significant relationship between frequency of adolescence binge drinking and reward conditioning. Specifically, a greater frequency of binge drinking before age 18 predicted significantly greater expression of reward conditioning, independent of current binge alcohol use. Finally, our investigations of the role of DA and the frontolimbic network revealed that frequency of binge drinking prior to age 18 negatively correlated with changes in alcohol AB after dopamine depletion. Current and past binge drinking significantly predicted changes in alcohol AB but only in heavy drinkers. Furthermore, current binge drinking was directly related to alcohol AB while adolescent binge drinking was inversely related. Our neuroimaging analysis revealed a significant relationship between the change in functional connectivity and alcohol AB. Specifically, increased AB was positively correlated with increased functional connectivity of the VTA and executive region of the Striatum and the VTA and DLPFC. Taken together, these studies contribute to our understanding of alcohol related attentional bias, generalized reward conditioning and the role of dopamine and frontolimbic neurocircuitry in these behavioral phenomenon and emphasis the importance of investigating individual differences to AB and reward conditioning in humans.Doctor of Philosoph