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Effect of fenfluramine-induced increases in serotonin release on [18F]MPPF binding: a continuous infusion PET study
Joanna I Udo de Haes1, Norihiro Harada, Philip H Elsinga
1Department of Biological Psychiatry, University Medical Center Groningen, The Netherlands. j.i.udo.de.haes@psy.umcg.nl
Abstract:
[(18)F]MPPF is a selective and reversible antagonist to the serotonin-1A (5-HT(1A)) receptor. The aim of the present study was to investigate whether the binding of [(18)F]MPPF is sensitive to increases in 5-HT levels. We used the 5-HT releasing agent and reuptake inhibitor fenfluramine (FEN) to increase the concentration of 5-HT. [(18)F]MPPF binding was assessed using positron emission tomography (PET) in conscious monkeys. Possible effects of blood flow on ligand binding were excluded by using a bolus-infusion paradigm. Control scans were obtained to assess the state of ligand equilibrium. FEN (5 or 10 mg/kg, i.v.) was administered between 90 and 130 min after the start of the [(18)F]MPPF infusion. The binding potential (BP) was calculated for an early interval (30 min preceding FEN administration) and late interval (20-50 min after administration of FEN). Microdialyses results showed a 20- and 35-fold increase in extracellular 5-HT levels in the prefrontal cortex after injection of FEN at a dose of 5 mg/kg and 10 mg/kg respectively. However, despite these large increases in 5-HT levels, no differences in BP were found between the control and FEN scans. These results may imply that the majority of 5-HT(1A) receptors is in the low affinity state in the living brain.
Insights
[(18)F]MPPF binding to serotonin-1A receptors remained stable despite significant serotonin level increases induced by fenfluramine. This suggests most 5-HT(1A) receptors may exist in a low-affinity state in the living brain.
Area of Science:
- Neuroscience
- Radiochemistry
- Pharmacology
Background:
- [(18)F]MPPF is a selective serotonin-1A (5-HT(1A)) receptor antagonist.
- Understanding 5-HT(1A) receptor dynamics is crucial for neurological research.
Purpose of the Study:
- To determine if [(18)F]MPPF binding is affected by elevated serotonin (5-HT) levels.
- To investigate the affinity state of 5-HT(1A) receptors in vivo.
Main Methods:
- Positron emission tomography (PET) was used to assess [(18)F]MPPF binding in conscious monkeys.
- Fenfluramine (FEN) was administered to increase extracellular 5-HT levels.
- Binding potential (BP) was calculated before and after FEN administration.
Main Results:
- Fenfluramine significantly increased extracellular 5-HT levels (20- and 35-fold).
- Despite increased 5-HT, no significant changes in [(18)F]MPPF binding potential were observed.
- Blood flow effects were controlled using a bolus-infusion paradigm.
Conclusions:
- [(18)F]MPPF binding is not sensitive to acute increases in 5-HT levels.
- Findings suggest that the majority of 5-HT(1A) receptors may be in a low-affinity state in the living brain.
- This has implications for interpreting PET imaging studies of the 5-HT(1A) system.
