Indiana University-Purdue University Indianapolis (IUPUI) / Impulsivity is associated with addiction in many human studies. Delay discounting (DD) is often used to measure impulsive choice in humans and animals. In DD testing, a small immediate reward is pitted against a larger delayed reward, and relative preference is assessed. The relative contribution of ethanol to impulsivity in alcoholism is not well-understood, therefore I will test the hypothesis that ethanol exposure will increase impulsivity in High Alcohol Preferring (HAP) mice as measured in an adjusting amount DD task. Selectively bred HAP mice were exposed to ethanol and tested in DD in 3 different experiments. Experiment 1: ad lib homecage ethanol drinking for 21 days and 17 days were used to expose mice to ethanol. Additionally, mice were tested in DD while “currently drinking” vs. “abstinent”. In experiment 2, to achieve higher blood alcohol concentrations, mice were injected with 3.5 g/kg ethanol 8 times and tested before and after in DD. In both experiments 1 and 2, mice were tested at only 2 delays (0.5 sec and 10 sec), to maximize sensitivity to detect shifts in choice behavior. In experiment 3, mice responded for 8% ethanol or 0.01% saccharin at a full range of delays: 0, 1, 2, 4, and 8 sec. Experiment 1 did not reveal any impact of ethanol drinking on impulsivity. Experiment 2 revealed a strong trend of reduced impulsivity in the 10 sec delay group after ethanol injections. Experiment 3 revealed reduced impulsivity at the 8 sec delay in the group responding for ethanol, and also revealed a significant correlation between higher ethanol drinking and reduced impulsivity. These data were unexpected, and imply that the a priori hypothesis not only should be rejected, but that the opposite hypothesis may be true: ethanol decreases impulsivity, at least with high dose exposure and in responding for it as a reinforcer. This effect was similar to the effect observed in other studies with amphetamine, which consistently decreases impulsivity. Ethanol may have been exerting an amphetamine-like effect on impulsivity at the doses tested here. There is no evidence in the data generated in these studies that ethanol increases impulsivity.

Indiana University-Purdue University Indianapolis (IUPUI) / Drug addiction is a behavioral disorder characterized by impulsive behavior and continued intake of drug in the face of adverse consequences. Millions of people suffer the financial and social consequences of addiction, and yet many of the current therapies for addiction treatment have limited efficacy. Therefore, there is a critical need to characterize the neurobiological substrates of addiction in order to formulate better treatment options. In the first chapter, the striatal dopamine system is interrogated with [11C]raclopride PET to assess differences between chronic cannabis users and healthy controls. The results of this chapter indicate that chronic cannabis use is not associated with a reduction in striatal D2/D3 receptor availability, unlike many other drugs of abuse. Additionally, recent cannabis consumption in chronic users was negatively correlated with D2/D3 receptor availability. Chapter 2 describes a retrospective analysis in which striatal D2/D3 receptor availability is compared between three groups of alcohol-drinking and tobacco-smoking subjects: nontreatment-seeking alcoholic smokers, social-drinking smokers, and social-drinking non-smokers. Results showed that smokers had reduced D2/D3 receptor availability throughout the striatum, independent of drinking status. The results of the first two chapters suggest that some combustion product of marijuana and tobacco smoke may have an effect on striatal dopamine concentration. Furthermore, they serve to highlight the effectiveness of using baseline PET imaging to characterize dopamine dysfunction in addictions. The final chapter explores the use of [18F]fallypride PET in a proof-of-concept study to determine whether changes in cortical dopamine can be detected during a response inhibition task. We were able to detect several cortical regions of significant dopamine changes in response to the task, and the amount of change in three regions was significantly associated with task performance. Overall, the results of Chapter 3 validate the use of [18F]fallypride PET to detect cortical dopamine changes during a impulse control task. In summary, the results reported in the current document demonstrate the effectiveness of PET imaging as a tool for probing resting and activated dopamine systems in addiction. Future studies will expand on these results, and incorporate additional methods to further elucidate the neurobiology of addiction.