Abstract
To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. Here, we present a method that relates minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride directly to subsecond dopamine release events. We show theoretically that synaptic dopamine release induces low frequency temporal variations of extrasynaptic extracellular dopamine levels, at time scales of one minute, that can evoke detectable temporal variations in the [11C]raclopride signal. Hence, dopaminergic activity can be monitored via temporal fluctuations in the [11C]raclopride PET signal. We validate this theory using fast-scan cyclic voltammetry and [11C]raclopride PET in mice during chemogenetic activation of dopaminergic neurons. We then apply the method to data from human subjects given a palatable milkshake and discover immediate and—for the first time—delayed food-induced dopamine release. This method enables time-dependent regional monitoring of stimulus-evoked dopamine release at physiological levels.
Highlights
To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected
Using positron emission tomography (PET) and the radiotracer [11C]raclopride, we introduce here a method for the in vivo assessment of time-dependent regional dopamine release that makes use of the relation between different time scales in the dopaminergic system and that is—as we demonstrate here— readily applicable to humans. [11C]raclopride is a well-known antagonist for dopamine type 2 receptors (D2Rs) and to lesser extent dopamine type 3 receptors[6]
We demonstrate that (i) chemogenetic activation of DA neurons in mice increases the rate of spontaneous DA transients detected by fast-scan cyclic voltammetry (FSCV) and that (ii) the number of transients is significantly correlated with the logarithm of the power in the frequency band of 0.5 Hz, as calculated by wavelet transform of continuously recorded FSCV data
Summary
The spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. We show theoretically that synaptic dopamine release induces low frequency temporal variations of extrasynaptic extracellular dopamine levels, at time scales of one minute, that can evoke detectable temporal variations in the [11C] raclopride signal. We apply the method to data from human subjects given a palatable milkshake and discover immediate and—for the first time—delayed food-induced dopamine release This method enables time-dependent regional monitoring of stimulus-evoked dopamine release at physiological levels. We performed [11C]raclopride PET in mice that carry the chemogenetically activatable modified muscarinic receptor (hM3DGq) exclusively in DA neurons We compared these [11C]raclopride PET data with sub-second recordings of DA concentrations in the ventral striatum measured in situ using fast-scan cyclic voltammetry (FSCV). With the mouse data supporting our theory we conclude that temporal variations of the [11C]raclopride PET signal can be used as a measure of dopaminergic activity
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