Inverse changes in raphe and cortical 5-HT_1B receptor availability after acute tryptophan depletion in healthy human...

Serotonergic neurotransmission plays a key role in the pathophysiology and treatment of various neuropsychiatric diseases. The purpose of this study was to investigate changes in serotonergic neurotransmission after acute tryptophan depletion (ATD) using positron emission tomography (PET) with [¹¹ C]P943, a 5-HT_1B receptor radioligand previously shown to be sensitive to changes in 5-HT. Five healthy subjects were scanned on a high resolution PET scanner twice on the same day, before and approximately 5 hours after ingesting capsules containing an amino acid mixture that lacks tryptophan. For each scan, emission data were acquired for 120 min after intravenous bolus injection of [¹¹ C]P943. Binding potential (BP_ND ) values were estimated from parametric images using the second version of the multilinear reference tissue model (MRTM2, t* = 20 min) with cerebellar grey matter used as a reference region. The change in [¹¹ C]P943 binding (ΔBP_ND , %) was calculated as (BP_ND,post  - BP_ND,pre )/(BP_ND,pre ) × 100, and correlation analysis was performed to measure linear associations of ΔBP_ND between raphe and other regions of interest (ROIs). ΔBP_ND ranged from -6% to 45% in the raphe, with positive values indicating reduced competition from 5-HT. In cortical regions, ΔBP_ND ranged from -28% to 7%. While these changes did not reach significance, there were significant negative correlations of ΔBP_ND of the raphe with those of cerebral cortical regions and the thalamus (e.g., r = -.96, p = .011 for average cortex). These findings support the hypothesis that raphe serotonin is a critical modulator of cortical serotonin release via projecting neurons in healthy human subjects.