Effects of Sustained D2 Receptors Blockade on Brain Structure and Function in Healthy Volunteers

TBackground The effect of D2 Receptor (D2R) blockade, exerted by antipsychotics, on brain structure and function is still under debate. Studies in patients reported mixed results with difficulties in separating disease and treatment effects. Single-dose studies in healthy volunteers (HV) have shown no change or reduction in striatal volumes, increased striatal cerebral blood flow (CBF) and reduced cortico-striatal functional connectivity (FC). However, it remains unclear whether these effects are stable after prolonged D2R blockade and how do they relate to extrapyramidal symptoms (EPS). Methods A total of 37 HV (15 females) entered a double-blinded, randomized, crossover, placebo-controlled study. Participants received either amisulpride 400mg or placebo daily for seven days. T1-maps and brain volume estimation were derived from MP2RAGE sequence. PCASL and resting-state multi-echo fMRI sequences were used to assess CBF and FC respectively. Voxel-wise permutation-based paired t-test as in FSL randomise was used to test drug effects (TFCE correction). We tested the association between drug effects and EPS (ESRS scale) using Spearman correlation. Analyses were performed on all subjects with available data. Results We did not find voxel-wise differences between amisulpride and placebo in both T1-maps and brain volumes. Amisulpride increased CBF in the striatum and reduced FC between its sensorimotor subdivision and the primary motor cortex as compared with placebo. Greater reduction in functional connectivity was associated with greater EPS (R2= 0.33, p= 0.018). Conclusions Our results indicate that functional alteration in the striatum persist after sustained D2R blockade without structural changes and could potentially serve as a biomarker for EPS.