Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits

Abstract

Structural remodeling has been observed in the human brain over periods of weeks to months, but the molecular mechanisms governing this process remain incompletely characterized. Using multimodal pharmaco-neuroimaging, we found that acute D2 receptor blockade induced reversible striatal volume changes and structural-functional decoupling in motor circuits within hours; these alterations predicted acute extrapyramidal motor symptoms with high precision. Our findings suggest a role for D2 receptors in short-term neural plasticity and identify a potential biomarker for neuroleptic side effects in humans.

Antipsychotic Drug Effects in Schizophrenia: A Review of Longitudinal fMRI Investigations and Neural Interpretations

“…fMRI investigations on visual-acoustic [25], reward [26][27][28], and motor [29] tasks all show reduced activation or diminished negative modulation with D 2 antagonism. Dopaminergic antagonism also appears to alter the temporal coherence or functional connectivity in HC [30,31]. The data suggests that, if D 2 antagonists affect the BOLD signal via vascular effects, the BOLD signal would increase.…”

Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density

“…54 Clinically, D2 blockade is suspected to contribute to striatal volume enlargement in schizophrenia 55 and has been shown to have shortterm reversible structural effects. 56 Given these structural changes, it is important to point out that any inference from measured DAT to structural parameters, such as density of dopaminergic terminals, is limited by the fact that the measurement will be affected both by the amount of synapses and the average amount of transporter protein in the synaptic membrane, and therefore remains indirect. In particular, a downregulation of DAT could in principle be counterbalanced or obscured by a concomitant rise in synaptic abundance.…”

“…Barring this possibility, based on these results, we conclude that neither D2 receptor blockade or the increases in presynaptic striatal dopamine release reliably found in schizophrenia 12 appear to cause appreciable changes in DAT density, making a role of this molecule, and the integrity of the presynaptic terminals that it labels, in either the pathogenesis or the currently practiced treatment of schizophrenia unlikely. 55,56 Conversely, DAT alterations may represent a core feature of other neuropsychiatric disorders such as ADHD and seem sensible to the effect of psychostimulants such as methylphenidate. 19 The present study, and the literature it surveys, has several limitations.…”

Oscillations and Neuronal Dynamics in Schizophrenia: The Search for Basic Symptoms and Translational Opportunities

“…This is because the modifications of neuronal circuits through ongoing developmental processes, the adaptive changes in large-scale networks as well as the effects of antipsychotic medication on brain structure [104] and function [105] are likely to impede the identification of those pathophysiological processes that are at the origin of the disorder.…”