Internalization of serotonin 5‐HT _1A autoreceptors as an imaging biomarker of antidepressant response

Immunocytochemical and brain imaging of 5‐HT_1A autoreceptor internalization. (a) Schematic representation of [¹⁸F]MPPF binding to 5‐HT_1A autoreceptors in 5‐HT neurons. Under basal conditions (upper image), 5‐HT_1A autoreceptors are mostly located on the somatodendritic plasma membrane of 5‐HT neurons and available for [¹⁸F]MPPF binding (blue shapes). After indirect activation of 5‐HT_1A autoreceptors by acute administration of fluoxetine (which increases the extracellular concentration of 5‐HT), 5‐HT_1A receptors are internalized in the cytoplasm (lower image) and no longer available for [¹⁸F]MPPF binding in vivo. (b) Electron micrographs illustrating the subcellular localization of 5‐HT_1A receptors in DRN dendrites, as revealed by immuno‐electron microscopy (immunogold labeling). In a control rat (upper image), the immunogold particles are mostly found on the plasma membrane, whereas 1 h after fluoxetine administration (10 mg/kg i.p.), there is a 30–40% reduction in the density of this plasmalemmal labeling and a corresponding increase in the cytoplasmic labeling (lower image). (Reprinted with permission from Ref 26. Copyright 2004 Elsevier) (c) Color‐coded PET images of a cat brain showing the summed distribution of [¹⁸F]MPPF, before (upper image) and 1 h after (lower image) the acute administration of fluoxetine (10 mg/kg i.p.). White arrowheads point at the DRN, in which a selective decrease in [¹⁸F]MPPF binding is observed after the treatment. (Reprinted with permission from Ref 32. Copyright 2006 Elsevier) (d) Color‐coded PET images of the summed distribution of [¹⁸F]MPPF in the brain of eight subjects who received placebo (upper image) or a unique oral dose of fluoxetine (20 mg), 5 h before the scan (lower image). White arrowheads point at the DRN, in which [¹⁸F]MPPF binding is selectively decreased after fluoxetine. Empty arrowheads point at the hippocampus in which [¹⁸F]MPPF binding is unchanged. (Reprinted with permission from Ref 33. Copyright 2008 Elsevier)