“…2 ). Note that the dynamics of ΔSUVr(t), assessed with simulations using a gamma variate function for h ( t ) 15 , which has been successfully used to model preclinical dynamic PET data with a serotoninergic challenge 30 , did not correspond with the dynamics of the experimental ΔSUVr(t) data with MP in the present study. Fig.…”
Section: Resultscontrasting
confidence: 60%
“… 31 ); K 1 r = 0.092 mL/min g, k 2 r = 0.45 min −1 , and R 1 = 1.154, k 2 = 0.45 min −1 , and k 2 a = 0.065 min −1 (see ref. 30 ); β = 0.02 min −1 . Fig.…”
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride’s binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of “high”. We show for the first time that the “high” is associated with the fast dopamine increases induced by methylphenidate.
“…2 ). Note that the dynamics of ΔSUVr(t), assessed with simulations using a gamma variate function for h ( t ) 15 , which has been successfully used to model preclinical dynamic PET data with a serotoninergic challenge 30 , did not correspond with the dynamics of the experimental ΔSUVr(t) data with MP in the present study. Fig.…”
Section: Resultscontrasting
confidence: 60%
“… 31 ); K 1 r = 0.092 mL/min g, k 2 r = 0.45 min −1 , and R 1 = 1.154, k 2 = 0.45 min −1 , and k 2 a = 0.065 min −1 (see ref. 30 ); β = 0.02 min −1 . Fig.…”
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride’s binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of “high”. We show for the first time that the “high” is associated with the fast dopamine increases induced by methylphenidate.
“…The variability observed is mainly driven by the maximal amplitude of each curve and corresponds to 8–15% across individuals, which can be considered as a low inter-subject variability and is in the same range as the variability obtained with binding ratios in the challenge study. Considering the variability of lp-ntPET model described in Irace et al (2020) , the results of discharge modeling in the article are very close between the four cats and could probably be reduced even more by using the robust b-ntPET algorithm presented by Irace et al (2020) . Finally, the kinetic modeling results suggest an apparent slow 5-HT release after d-fenfluramine injection, which is unexpected given its fast kinetics observed using microdialysis experiments.…”
IntroductionSerotonin is involved in a variety of physiological functions and brain disorders. In this context, efforts have been made to investigate the in vivo fluctuations of this neurotransmitter using positron emission tomography (PET) imaging paradigms. Since serotonin is a full agonist, it binds preferentially to G-protein coupled receptors. In contrast, antagonist PET ligands additionally interact with uncoupled receptors. This could explain the lack of sensitivity to serotonin fluctuations of current 5-HT1A radiopharmaceuticals which are mainly antagonists and suggests that agonist radiotracers would be more appropriate to measure changes in neurotransmitter release. The present study evaluated the sensitivity to endogenous serotonin release of a recently developed, selective 5-HT1A receptor PET radiopharmaceutical, the agonist [18F]F13640 (a.k.a. befiradol or NLX-112).Materials and MethodsFour cats each underwent three PET scans with [18F]F13640, i.e., a control PET scan of 90 min, a PET scan preceded 30 min before by an intravenous injection 1 mg/kg of d-fenfluramine, a serotonin releaser (blocking challenge), and a PET scan comprising the intravenous injection of 1 mg/kg of d-fenfluramine 30 min after the radiotracer injection (displacement challenge). Data were analyzed with regions of interest and voxel-based approaches. A lp-ntPET model approach was implemented to determine the dynamic of serotonin release during the challenge study.ResultsD-fenfluramine pretreatment elicited a massive inhibition of [18F]F13640 labeling in regions known to express 5-HT1A receptors, e.g., raphe nuclei, hippocampus, thalamus, anterior cingulate cortex, caudate putamen, occipital, frontal and parietal cortices, and gray matter of cerebellum. Administration of d-fenfluramine during PET acquisition indicates changes in occupancy from 10% (thalamus) to 31% (gray matter of cerebellum) even though the dissociation rate of [18F]F13640 over the 90 min acquisition time was modest. The lp-ntPET simulation succeeded in differentiating the control and challenge conditions.ConclusionThe present findings demonstrate that labeling of 5-HT1A receptors with [18F]F13640 is sensitive to serotonin concentration fluctuations in vivo. Although the data underline the need to perform longer PET scan to ensure accurate measure of displacement, they support clinical development of [18F]F13640 as a tool to explore experimental paradigms involving physiological or pathological (neurological or neuropsychiatric pathologies) fluctuations of extracellular serotonin.
“…It is likely that full PET kinetic modelling, which is the gold standard in PET experiments, will not be the standard for most PET/MR protocols. Simplified PET methods have to be developed for each radioligand to provide spatially localized and quantitative information on target engagement or endogenous neurotransmitter release, to be compared with synchronized fMRI or fUS data (Irace et al, 2020).…”
Section: Hybrid Protocols For Synchronized Neuroimagingmentioning
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