Stimulant-induced excitatory and inhibitory dopamine receptor signaling and trafficking

Project Summary The dopamine system plays a major role in the pathogenesis of substance use disorders. Stimulant drug use and abuse lead to several dopaminergic alterations that contribute to the complex behavior associated with the formation of addiction. A single acute exposure to a stimulant drug can trigger receptor internalization as an early synaptic adaptation mechanism to high dopamine concentrations. These mechanisms have been shown to affect neuroimaging outcomes, specifically positron emission tomography (PET), which has revealed paradoxically long reductions in dopamine D2/D3 receptor availability after stimulant-induced dopamine release. To date, we still have a limited understanding of the timeline of dopamine receptor internalization and recovery with repeated drug exposure and how these adaptation mechanisms affect whole-brain signaling of both excitatory D1 and inhibitory D2-type receptors. This study aims to address this knowledge gap by characterizing how two classes of stimulant drugs (amphetamine and methylphenidate) modulate dopamine receptor subtype signaling and receptor trafficking over time. Using state-of-the-art simultaneous PET and functional magnetic resonance imaging (fMRI) methodology in non-human primates, the timescales of amphetamine-induced receptor internalization and recycling will be established using repeated amphetamine administrations. Targeted dopaminergic blocking drugs will be paired with amphetamine to determine how the balance between excitatory D1 and inhibitory D2 receptor signaling and trafficking is modulated over time. The effects of repeated amphetamine will then be compared to those of methylphenidate to assess varying levels of dopamine surges and differential mechanisms of action across these two stimulant drugs. Overall, this study will unravel brain- wide molecular and functional changes due to repeated stimulant drug exposure by imaging the timescales of dopamine receptor trafficking in the living brain in a translational animal model. The results will elucidate the role of dopamine D1 and D2-type receptor adaptations, thereby providing important insight into the neurobiological mechanisms involved in repeated stimulant drug use relevant for initiating and eventually preventing drug sensitization and addiction.