This grant seeks to evaluate striatal dopaminergic functioning during reward processing in autism spectrumdisorder (ASD) through the use of simultaneous positron emission tomography (PET) and functional magneticresonance imaging (fMRI). Preclinical research strongly implicates impaired mesolimbic dopamine functioningin the etiology of ASD. Additionally, fMRI evidence suggests that ASD is characterized by striatalhypoactivation during reward processing. However, since fMRI is sensitive only to blood oxygen leveldependent signals, it is not known whether striatal hypoactivation during reward processing in ASD observedwith fMRI is associated with impaired striatal dopamine functioning. Additionally, it is not known whetherstriatal hypoactivation during reward processing in ASD is linked to reduced phasic dopamine release or toreduced background dopamine tone that inhibits phasic dopamine release. Finally, whether impaireddopamine functioning in ASD is related to ASD symptom severity is poorly understood. These are critical gapsin our understanding of ASD pathophysiology given that studies of ASD model organisms are starting topinpoint the specific molecular mechanisms that are implicated in ASD, whereas not a single molecularimaging study to date has targeted the mesolimbic dopamine system in ASD. PET imaging is ideally suited tobridge this gap between preclinical ASD research and clinical neuroimaging studies of reward processing inASD. We propose to collect simultaneous PET and fMRI from a cohort of young adults with ASD and matchedtypically developing young adults during a reward processing task using the D2/D3 dopamine receptorantagonist [11C]raclopride. The use of a bolus+infusion radiotracer administration protocol will provideincreased sensitivity towards measuring dopamine release, a critical feature of this project. We will evaluatebackground dopaminergic tone and phasic dopaminergic release in response to incentives in ASD (Aim 1),correlations between PET-derived measures of D2/D3 striatal receptor occupancy and fMRI-derived measuresof striatal activation (Aim 2), and relationships between PET-derived measures of D2/D3 striatal receptoroccupancy and symptom severity in the ASD group (Aim 3). This project represents the first step of our long-term goal to establish a program of PET ASD research that is positioned to translate findings of novelcompounds that rescue receptor binding potentials in preclinical ASD models to clinical ASD studies of targetengagament by these same compounds. This pipeline of preclinical drug discovery to clinical drug evaluationis ideally suited to PET neuroimaging because of its capacity to measure classes of receptors targeted byspecific ligands.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
