Effect of 5-HT on binding of [11C] WAY 100635 to 5-HT1A receptors in rat brain, assessed using in vivo microdialysis and PET after fenfluramine

By using a combination of positron emission tomography (PET) and postmortem tissue dissection, the effect of increased endogenous serotonin on specific binding of [C-11]WAY 100635 to the 5-HT1A receptor was investigated in rat brain in vivo. The binding studies were complemented by in vivo microdialysis to monitor 5-HT levels in similarly treated isoflurane-anaesthetised rats, with the dialysis probe locations corresponding to two of the tissues sampled for specific binding of the radioligand. Fenfluramine treatment (10 mg/kg i.p.) resulted in a similar to5-fold increase in extracellular 5-HT in medial prefrontal cortex and a similar to 15-fold increase in lateral hippocampus, maximal at similar to 40 min after injection. PET scan duration was either 60 or 90 min, beginning 30 min after fenfluramine injection. The specific binding of [C-11]WAY 100635 was reduced by 10-20% in hippocampus, which showed highest binding in control animals. Specific binding, however, was unaffected in both prefrontal cortex and midbrain raphe, each additional high binding regions. The minimal effects are consistent with a low baseline occupancy of the 5-HT1A receptor by 5-HT in vivo, so that only a large change in endogenous agonist concentration will affect radioligand binding. This implies that utilisation of [11C]WAY 100635 in human PET to quantify 5-HT1A receptor expression can be extended to pathology where synaptic 5-HT levels are altered as a consequence of the disease state. (C) 2001 Wiley-Liss, Inc.