Anissa Abi-Dargham - Dopamine in schizophrenia: from molecules to behavior

ViDA 2021 - Wed June 23rd 2021
Anissa Abi-Dargham
Department of Psychiatry, Stony Brook University
Dopamine in schizophrenia: from molecules to behavior
This lecture will integrate findings from molecular and functional imaging studies in patients with schizophrenia aimed at understanding the topography of dopamine dysregulation in this disease as well as its functional impact on circuitry and behavior. We have used Positron Emission Tomography (PET) imaging of D2 radiotracers combined with pharmacological manipulations of the dopaminergic system, to examine indices of pre and post synaptic dopamine function and, in the same subjects, we used functional imaging to assess the significance of the molecular alterations. These studies have revealed topographical perturbations in presynaptic dopamine function where the associative striatum shows excess storage and release and extrastriatal regions, including cortex and midbrain, show a deficit in dopamine release. To understand the localized striatal enhancement in dopamine, in presence of low midbrain dopamine availability, we examined local striatal mechanisms that may dysregulate dopamine. One important such mechanism is the cholinergic modulation of dopamine release, via the striatal cholinergic interneurons. For this purpose, we measured the vesicular cholinergic transporter, using PET and a radiotracer specific for this target, which relates to the storage capacity for acetylcholine (ACH) in a small cohort of patients and controls. The molecular alterations described are linked to abnormal connectivity of the rostral caudate to the rest of the brain, particularly to cortical regions, and to measures of auditory perceptual bias and hallucinations. In addition, cortical dopamine deficit has implications for the role of cortical D1 receptors in modulating activity and cognitive processes. Understanding these molecular and functional abnormalities is a critical step in developing novel and targeted therapeutics for the various symptom domains of the disease. We will conclude by highlighting a new multisite trial of a D1 agonist in schizophrenia based in part on these findings and an overall model for the role of dopamine in the development and staging of the disease.​