Although many people engage in occasional drug use, few become drug-dependent. The mechanisms by which addiction vulnerability and drug-induced pathological factors interact to increase the likelihood of drug dependence remain unknown. Mounting evidence suggests that drug dependence is strongly associated with dysfunctional impulsive decision-making processes in which individuals with cocaine-use disorder (CUD) undervalue (Le., discount) future rewards in favor of smaller, immediate rewards to a greater extent than their non-addicted peers. Thus, temporal discounting of reward, as measured by various intertemporal choice tasks, has been proposed as a behavioral marker of addiction, which may be due to aberrant dopamine (DA) and serotonin (5HT) signaling within midbrain regions and corticostriatal circuits including the ventromedial prefrontal cortex (vmPFC) and striatum. Studies in CUD show elevated D3 receptor availability in the midbrain, decreased 5HT1B availability in the vmPFC and heightened levels of impulsive choice. Furthermore, our pilot rat positron emission tomography (PET) data demonstrate increased striatal l1C-PHNO binding is positively correlated with subsequent cocaine self-administration and individual differences in choice behavior, which highlights the impact of vulnerability factors on cocaine use. We have also shown that D2I3 receptors modulate flexible decision-making but it is not known how these receptors impact impulsive choice or cocaine self- administration. Here we will use a delay discounting across various randomly presented delays procedure, which yields robust individual differences in rat temporal discounting, in combination with two PET tracers (11C- PHNO for D3 and 11C-P943 for 5HT18 receptors), receptor-specific pharmacology and cocaine self- administration to investigate these proposed biobehavioral markers of addiction.
In Aim 1, we will investigate the relationship between individual differences in corticostriatal D3 and 5HT1B receptors and impulsive choice and cocaine self-administration.
In Aim 2, we will assess the impact of cocaine self-administration on corticostriatal D3 and 5HT18 receptors and impulsive choice using longitudinal PET/behavioral analyses and ex vivo analyses. Finally, in Aim 3, we will determine the role of midbrain D3 and vmPFC 5HT18 receptor regulated signaling in cocaine-induced enhancements in impulsive choice. In accordance with pre-clinical and clinical research, we predict that individual differences in impulsive choice are mediated by vmPFC 5HT1Band that cocaine induced-changes of midbrain D3 receptors modulates this signaling, yielding enhancements in impulsivity. Our studies in rats will complement studies in CUD individuals through the use of longitudinal neuroimaging, pharmacological manipulation of brain targets, and ex vivo validation of PET imaging results, while maintaining the common behavioral metric of impulsive choice.
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