Abstract
Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HT2AR) agonist radioligand [11C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [11C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HT1AR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [11C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HT2AR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [11C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HT2AR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI.
Highlights
Serotonergic neurotransmission is implicated in cognitive and emotional processes, and altered serotonin signalling is thought to contribute to a variety of disorders such as depression, addiction, schizophrenia, and anxiety
We observed large within-group variation in [11C]Center for Integrated Molecular Brain Imaging (Cimbi)-36 binding after intervention with citalopram and pindolol as compared to placebo and acute tryptophan depletion (ATD)
Using microdialysis and [11C]Cimbi-36 Positron emission tomography (PET) in pigs, the potent serotonin releaser fenfluramine produced an increase in extracellular serotonin levels of
Summary
Serotonergic neurotransmission is implicated in cognitive and emotional processes, and altered serotonin signalling is thought to contribute to a variety of disorders such as depression, addiction, schizophrenia, and anxiety. It has been reported that D2/D3 receptor agonist radioligands are more sensitive to endogenous changes in dopamine than antagonist radioligands[3]. This difference has been explained by agonist radioligands binding to the high affinity state receptor only, inducing competition with endogenous neurotransmitters[2]. It was recently shown in non-human primates that the serotonin 2A (5-HT2A) receptor agonist radioligand [11C[Cimbi-36 is more sensitive to serotonin release than the antagonist 5-HT2A receptor radioligand [11C]MDL 1009074
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