Molecular fMRI of Serotonin Transport

Reuptake of neurotransmitters from the brain interstitium shapes chemical signaling processes and is disrupted in several pathologies. Serotonin reuptake in particular is important for mood regulation and is inhibited by first-line drugs for treatment of depression. Here we introduce a molecular-level fMRI technique for micron-scale mapping of serotonin transport in live animals. Intracranial injection of an MRI-detectable serotonin sensor complexed with serotonin, together with serial imaging and compartmental analysis, permits neurotransmitter transport to be quantified as serotonin dissociates from the probe. Application of this strategy to much of the striatum and surrounding areas reveals widespread nonsaturating serotonin removal with maximal rates in the lateral septum. The serotonin reuptake inhibitor fluoxetine selectively suppresses serotonin removal in septal subregions, whereas both fluoxetine and a dopamine transporter blocker depress reuptake in striatum. These results highlight promiscuous pharmacological influences on the serotonergic system and demonstrate the utility of molecular fMRI for characterization of neurochemical dynamics. •Molecular imaging technology enables mapping of serotonin uptake dynamics•Kinetic parameters of serotonin transport are obtained by compartmental modeling•Serotonin transporter-dependent and -independent mechanisms are differentiated•Inhibition of dopamine transporters blocks serotonin transport in some regions Molecular-level MRI produces unprecedented three-dimensional profiles of serotonin clearance and its manipulation by drugs. Data indicate areas of peak clearance and quantify regional contributions of serotonin transporter-dependent and -independent mechanisms to neurotransmitter removal.