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Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.
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266 NATURE
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26. Tanksley, S. D., Zamir, D. & Rick, C. M. Evidence for extensive overlap of sporophytic and
gametophytic gene expression in Lycopersicon esculentum. Science 213, 453455 (1981).
Acknowledgements. We thank B. Charlesworth for input, counsel and support, and J. Greenberg,
T. Morton and J. Mach for assistance with the manuscript. This work was supported by a grant from the
NIH (to D.C. and B. Charlesworth).
Correspondence and requests for materials should be addressed to D.S.G. (e-mail: dguttman@midway.
uchicago.edu).
Evidence for striatal dopamine
release during a video game
M. J. Koepp, R. N. Gunn, A. D. Lawrence, V. J. Cunningham,
A. Dagher, T. Jones, D. J. Brooks, C. J. Bench & P. M. Grasby
MRC Cyclotron Unit, Hammersmith Hospital, DuCane Road, London W12 0NN,
UK, and Division of Neuroscience and Psychological Medicine, Imperial College
School of Medicine, St Dunstan’s Road, London W6 8RP, UK
.........................................................................................................................
Dopaminergic neurotransmission may be involved in learning,
reinforcement of behaviour, attention, and sensorimotor
integration
1,2
. Binding of the radioligand
11
C-labelled raclopride
to dopamine D
2
receptors is sensitive to levels of endogenous
dopamine, which can be released by pharmacological challenge
3–8
.
Here we use
11
C-labelled raclopride and positron emission tomo-
graphy scans to provide evidence that endogenous dopamine is
released in the human striatum during a goal-directed motor task,
namely a video game. Binding of raclopride to dopamine recep-
tors in the striatum was significantly reduced during the video
game compared with baseline levels of binding, consistent with
increased release and binding of dopamine to its receptors. The
reduction in binding of raclopride in the striatum positively
correlated with the performance level during the task and was
greatest in the ventral striatum. These results show, to our
knowledge for the first time, behavioural conditions under
which dopamine is released in humans, and illustrate the ability
of positron emission tomography to detect neurotransmitter
fluxes in vivo during manipulations of behaviour.
We used
11
C-labelled raclopride (RAC) to detect changes in levels
of extracellular dopamine induced by a behavioural task. During the
first 50 minutes of a [
11
C]RACPET scan, eight male volunteers
played a video game, which involved learning to navigate a tank for a
monetary incentive. This task is comparable to tasks in animal
studies in which dopamine is released during the anticipatory or
appetitive phase of motivated behaviour, where dopamine is
involved in learning which environmental stimuli or actions predict
rewarding or aversive outcomes
2,911
. During a second [
11
C]RAC
PET scan, subjects looked at an empty screen. The scanning order
was randomized for each subject. Differences in [
11
C]RAC-binding
potential between scans were used to infer changes in levels of
extracellular dopamine
12,13
. Binding of [
11
C]RAC to dopamine D
2
receptors was measured in the ventral and dorsal striata, which are
areas involved in goal-directed motor behaviour
2,1416
.
Striatal [
11
C]RAC-binding potential was reduced (analysis of
variance (ANOVA) F ¼ 7:72, P , 0:01) during the video
game, particularly in the ventral striatum (Table 1). Our results
are compatible with a task-related increase in levels of extra-
cellular dopamine reducing the number of D
2
-receptor sites avail-
able for binding to [
11
C]RAC. The magnitude of change of
[
11
C]RAC-binding potential (ventral striatum mean, 13%; range,
+8 to 42%) was considerably greater than the reported ‘within
subject test/retest variation in striatal [
11
C]RAC-binding potential
(mean, 46%)
17,18
, and was similar to that observed following
intravenous injection of amphetamine
8
(striatum mean, 16%;
range, 3to24%) or methylphenidate
6
(striatum mean, 23%;
range, +3 to 46%). Microdialysis studies of non-human primates
Table 1 [
11
C]RAC-binding potential, relative tracer delivery and size of the region of interest in striatal regions
LD
B
LD
T
DLD
(%)
RD
B
RD
T
DRD
(%)
LV
B
LV
T
D LV
(%)
RV
B
RV
T
DRV
(%)
...................................................................................................................................................................................................................................................................................................................................................................
BP 2.47 2.23 8.9 2.38 2.22 6.1 2.22 1.93 11.8 2.27 1.92 13.9
(s.d.) (0.36) (0.42) (16.4) (0.34) (0.41) (16.1) (0.28) (0.33) (18.8) (0.31) (0.35) (20.5)
...................................................................................................................................................................................................................................................................................................................................................................
R
I
0.98 0.88 8.5 0.94 0.87 6.5 0.98 0.89 8.5 1.03 0.91 10.5
(s.d.) (0.13) (0.08) (13.8) (0.12) (0.07) (12.1) (0.12) (0.13) (14.4) (0.11) (0.12) (14.7)
...................................................................................................................................................................................................................................................................................................................................................................
ROI size 8,151 8,300 1.9 7,600 8,188 7.9 4,747 4,280 8.7 4,692 4,215 9.3
(s.d.) (711) (846) (8.2) (567) (574) (7.2) (628) (612) (16.2) (680) (691) (15.7)
...................................................................................................................................................................................................................................................................................................................................................................
BP, [
11
C]RAC-binding potential; R
I
, relative tracer delivery; ROI, region of interest (mm
3
); s.d., standard deviation; L, left; R, right; D, dorsal; V, ventral; B, baseline conditions; T, task conditions.
Changes in BP, R
I
and ROI size between conditions (D) are given as a percentage change from the baseline, calculated as: ðT 2 BÞ=B 3 100. R
I
was significantly decreased during the video
game (F ¼ 11:3, P ¼ 0:001), but reductions in R
I
were not correlated with reductions in BP (r
2
¼ 0:05, P ¼ 0:24). There was no difference in striatal ROI size across conditions (P ¼ 0:64) and no
correlation between changes of BP and ROI size (r
2
¼ 0:02, P ¼ 0:45), indicating that head movement probably did not contribute significantly to our results.
Figure 1 Mean timeactivity curves for [
11
C]RAC uptake, normalized for
radioactivity injected, for the four striatal ROIs and the reference region
(cerebellum). Data are given from time of radioligand injection to the end of
scanning period (up to 90 min). R, right; L, left.
Nature © Macmillan Publishers Ltd 1998
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NATURE
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indicate that a 1% decrease in striatal [
11
C]RAC binding reflects at
least an 8% increase in extracellular endogenous dopamine levels
8
.
Thus, the 13% reduction in [
11
C]RAC-binding potential in the
ventral striatum reported here suggests at least a twofold increase in
levels of extracellular dopamine. Computer simulations have shown
that this magnitude of change should be detectable with [
11
C]RAC
PET
13
.
After 50 min, the game ended, but the timeactivity curves
(TACs) for [
11
C]RAC binding remained below the baseline curves
without convergence (Fig. 1). A similar effect has been reported
following pharmacological challenges
4,19
, and may simply reflect the
kinetic properties of [
11
C]RAC and the diffusion and re-uptake
kinetics of dopamine. Sustained alterations in dopamine concen-
trations after a period of behavioural manipulation have been
described in the rat
20
, providing a biological explanation for the
continued separation of the TACs for [
11
C]RAC binding after the
video game ended.
There was a significant correlation between performance level
achieved and reduced [
11
C]RAC-binding potential in all striatal
regions (Fig. 2); the significance of this correlation was confirmed by
an independent analysis using statistical parametric mapping
(SPM)
21
. SPM revealed that this significant correlation mainly
encompassed the ventral striatum, predominantly the left side
(Fig. 3). These results further validate the putative link between
the behavioural manipulation and dopamine release, and comple-
ment electrophysiological studies of behaviour in awake animals, in
which dopaminergic neurotransmission was associated with sen-
sorimotor functions related to rewarding, aversive and stressful
stimuli
1,22,23
. In monkeys, most dopaminergic neurons in the ventral
tegmental area and pars compacta are activated by unexpected
primary appetitive rewards and reward-predicting cues
1,9,15
.
Here, regional differences in [
11
C]RAC displacement within the
striatum might correlate with the role of dopamine in the dorsal and
ventral striata
2
. The dorsal striatum receives inputs from motor,
sensory, premotor, and dorsal prefrontal cortices
14,16
, whereas the
ventral striatum receives afferent inputs from orbitofrontal cortex,
amygdala, hippocampus, and anterior cingulate
14,16
. On the basis of
these anatomical connections, we interpret changes in ventral
striatal [
11
C]RAC binding to be related to affective components of
the task, whereas dorsal striatal dopamine release may be related to
sensorimotor coordination and response selection
2
. This new
method of detecting neurotransmitter release during behavioural
manipulation extends the success of brain-perfusion mapping in
humans to the study of a true cognitive neurochemistry of
behaviour’.
M
. . . .. . . . . . . .. .. . . . . .. .. . . .. .. . . . . . . .. . . . . . . .. .. . . .. .. . . . . . . .. . . . . . . .. .. . . .. .. .. . . .. .. . . .. . . .. . . . . .. . . . . . . .. .. . . . . . . .. . . . .
Methods
PET-scan acquisition. Eight healthy, male, right-handed volunteers (range
3646 years of age) took part in the study (approved by the local Ethics
Committee). Informed consent was obtained for all subjects. Each received two
[
11
]RAC–PET scans (total injected dose of 1620 mCi), one during the
behavioural task (video game) and one under baseline conditions (blank
screen). Subjects played the video game from 10 min before to 50 min after
[
11
C]RAC injection. PET scans were acquired on separate days using a 953B-
Siemens/CTI PET camera in three-dimensional mode. Head movement during
scanning was minimized by the use of a moulded head rest and external head
markings.
Behavioural task. The video game involved moving a ‘tank’ through a
‘battlefield’ on a screen using a mouse with the right hand. Subjects had to
collect ‘flags’ with the tank while destroying ‘enemy tanks’. Enemy tanks could
destroy the three ‘lives’ of the subjects’ tank. If subjects collected all flags, they
progressed to the next game level, which required more flags to be collected. A
reward of £7 was given per game level achieved.
Region-of-interest (ROI) analysis. TACs of [
11
C]RAC binding were derived
for ventral and dorsal striata and cerebellum. From these TACs, binding
potential (BP), and the relative rate of ligand delivery (R
I
) in the striatum
L ventral
-50
-40
-30
-20
-10
0
10
20
Change in binding potential (%)
L dorsal
R ventral
Level of performance
R dorsal
-50
-40
-30
-20
-10
0
10
20
-50
-40
-30
-20
-10
0
10
20
-50
-40
-30
-20
-10
0
10
20
01234567
01234567
0123456701234567
Figure 2 Percentage change in [
11
C]RAC-binding potential between task and
baseline conditions, plotted against performance level. A significant inverse
correlation is seen in all striatal regions (Spearman rank correlation coefficients
for left and right ventral and left dorsal striatum: r ¼ 2 0:86, P ¼ 0:017; right dorsal
striatum: r ¼ 2 0:83, P ¼ 0:020).
Figure 3 Regions of the brain in which there was a statistically significant
correlation between reduced [
11
C]RAC-BP and task performance; such a
correlation was more pronounced in the ventral striatum. Upper row, the
transverse and coronal glass brain views show those voxels with a significant
inverse correlation of [
11
C]RAC-BP with the highest performance level reached
(threshold for display, P , 0:05). Lower row, three-dimensional SPM projections
superimposed on representative transaxial and coronal magnetic resonance
image brain slices (threshold for display, P , 0:05).
Nature © Macmillan Publishers Ltd 1998
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268 NATURE
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compared to the cerebellum were estimated using a simplified reference region
model
24,25
. The model derives BP from the ratio of the volumes of distribution
of the ligand in the striatum relative to the cerebellum. BP is a composite
function of parameters, as follows:
BP ¼
f
2
B
max
K
D
Tracer
1 þ
^
i
F
i
K
D
i
where B
max
is the total concentration of specific binding sites, K
D
Tracer
the
equilibrium dissociation constant of the ligand, f
2
is the ‘free fraction of
unbound ligand in the tissue, and F
i
and K
D
i
are the concentrations and
equilibrium dissociation constants, respectively, of i competing endogenous
ligands. Changes in BP are attributed to changes in F
i
for endogenous
dopamine. Striatal ROIs were outlined on an add-image of summated time
frames, using an edge-fitting algorithm set at a fixed threshold (40%) of the
image maximum. The ventral (comprising the ventral half of the putamen) and
dorsal (comprising the dorsal half of the putamen and the body of the caudate
nucleus) striata were operationally defined. The cerebellum was defined by
cluster analysis
26
. BP and R
I
values were calculated for the striatal ROIs using the
TACs for [
11
C]RAC binding up to 50 min after injection
25
. Differences in
[
11
C]RAC-BP at baseline and during the task were tested with repeated-
measure ANOVA, with three ‘within-subject’ factors (task versus baseline,
left versus right hemisphere and dorsal versus ventral striatum). Spearman rank
correlation coefficients were calculated for the relationship between changes in
[
11
C]RAC-BP and the highest performance level during the game for each ROI.
SPM analysis. Parametric images of [
11
C]RAC-BP
24
were analysed using
SPM96 (ref. 21). The [
11
C]RAC-R
I
images were used to define the stereotactic
transformation parameters for the [
11
C]RAC-BP images. Contrasts of the
condition effects at each voxel of the [
11
C]RAC-BP images were assessed
using the t-value, with the highest performance level entered as a covariate of
interest, giving a statistical image for each contrast.
Received 23 September 1997; accepted 20 March 1998.
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Acknowledgements. M.J.K. was supported by a grant from the Theodore and Vada Stanley Foundation
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Theroleofdendritesinauditory
coincidence detection
Hagai Agmon-Snir*, Catherine E. Carr
& John Rinzel*
* Mathematical Research Branch, NIDDK, National Institutes of Health,
Bethesda, Maryland 20892, USA
Department of Zoology, University of Maryland, College Park,
Maryland 20742, USA
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Coincidence-detector neurons in the auditory brainstem of mam-
mals and birds use interaural time differences to localize
sounds
1,2
. Each neuron receives many narrow-band inputs from
both ears and compares the time of arrival of the inputs with an
accuracy of 10100 ms (refs 36). Neurons that receive low-
frequency auditory inputs (up to about 2 kHz) have bipolar
dendrites, and each dendrite receives inputs from only one
ear
7,8
. Using a simple model that mimics the essence of the
known electrophysiology and geometry of these cells, we show
here that dendrites improve the coincidence-detection properties
of the cells. The biophysical mechanism for this improvement is
based on the nonlinear summation of excitatory inputs in each of
the dendrites and the use of each dendrite as a current sink for
inputs to the other dendrite. This is a rare case in which the
contribution of dendrites to the known computation of a neuron
may be understood. Our results show that, in these neurons, the
cell morphology and the spatial distribution of the inputs enrich
the computational power of these neurons beyond that expected
from point neurons (model neurons lacking dendrites).
Over the past 40 years it has become widely accepted that
dendrites play a major role in neuronal computation
9
. Despite
intensive efforts to decipher this role
1016
, however, the contribution
of the dendrites to the function of the single neuron remains elusive.
Nevertheless, the existence of different dendritic geometries and
their plausible effect on computation have been used as evidence for
dendritic computation
11,12,17
. As analysis of dendritic computation is
most powerful when the role of the neuron is understood, we used
brainstem auditory coincidence detectors to demonstrate the com-
putational advantages of having synaptic inputs on the dendrites
rather than on the cell body.
Coincidence detectors of the auditory brainstem are binaural
neurons that respond maximally when they receive simultaneous
inputs from the two ears. This condition is met when delay line
inputs from each ear exactly compensate for a delay introduced by
an interaural time difference (ITD, the time difference between the
Present address: New York University, Center for Neural Science and Courant Institute of Mathematical
Sciences, New York 10003, USA.
... The administered [ 11 C]raclopride competes with endogenous dopamine for binding to the dopamine D 2 receptors, and an increase in the concentration of endogenous dopamine is supposed to result in a decrease in the binding of administered [ 11 C]raclopride, as measured by PET. Using this competition paradigm, some PET studies measured the BP before and after the stimulations and reported that the BP decreased after stimulation, such as an amphetamine challenge and behavioral or cognitive tasks (12)(13)(14)(15)(16)(17)(18)(19)(20). ...
... In PET studies with [ 11 C]raclopride, the measurement of changes in the BP due to pharmacological or neuropsychological stimulations has been attempted using various approaches, such as a scan with bolus-plus-continuous infusion, two separate PET scans with a bolus injection, and a single session of PET scan with extended simplified reference tissue model including timedependent parameters (12)(13)(14)(15)(16)(18)(19)(20). In the conventional bolusplus-continuous infusion approach, the BP can be estimated by the ratio of radioactivity concentration between the striatum and cerebellum at equilibrium, and the calculation process is easy and stable. ...
... Unlike dopamine elevation by pharmacological challenge, the amount of dopamine release as a result of cognitive performance is supposed to be smaller. However, some studies with behavioral or cognitive tasks have reported a reduction in striatal BP (16,18); for example, about 13% BP reduction in the ventral striatum was observed during a video game (16), demonstrating the possibility of measuring the dopamine release induced by neuropsychological stimulation as well as the pharmacological challenge using [ 11 C]raclopride-PET. On the other hand, our study did not detect any changes in BP by both injection methods, which suggests the difficulty of measuring the changes in BP due to psychological stimulation reproducibly by [ 11 C]raclopride-PET. ...
Article
Full-text available
Objectives Positron emission tomography (PET) with [11C]raclopride has been applied to measure changes in the concentration of endogenous dopamine induced by pharmacological challenge or neuropsychological stimulation by evaluating the binding potential (BP) between the baseline and activated state. Recently, to reliably estimate BP in the activated state, a new approach with dual-bolus injections in a single PET scan was developed. In this study, we investigated the feasibility of applying this dual-bolus injection approach to measure changes in endogenous dopamine levels induced by cognitive tasks in humans.Methods First, the reproducibility of BP estimation using the dual-bolus injection approach was evaluated using PET scans without stimulation in nine healthy volunteers. A 90-min scan was performed with bolus injections of [11C]raclopride administered at the beginning of the scan and 45 min after the first injection. BPs in the striatum for the first injection (BP1) and second injection (BP2) were estimated using an extended simplified reference tissue model, and the mean absolute difference (MAD) between the two BPs was calculated. The MAD was also compared with the conventional bolus-plus-continuous infusion approach. Next, PET studies with a cognitive reinforcement learning task were performed on 10 healthy volunteers using the dual-bolus injection approach. The BP1 at baseline and BP2 at the activated state were estimated, and the reduction in BP was evaluated.ResultsIn the PET scans without stimulation, the dual-bolus injection approach showed a smaller MAD (<2%) between BP1 and BP2 than the bolus-plus-continuous infusion approach, demonstrating good reproducibility of this approach. In the PET scans with the cognitive task performance, the reduction in BP was not observed in the striatum by either approach, showing that the changes in dopamine level induced by the cognitive tasks performed in this study were not sufficient to be detected by PET.Conclusion Our results indicate that the cognitive task-induced changes in dopamine-related systems may be complex and difficult to measure accurately using PET scans. However, the proposed dual-bolus injection approach provided reliable BP estimates with high reproducibility, suggesting that it has the potential to improve the accuracy of PET scans for measuring changes in dopamine concentrations.
... Dopaminergic neurotransmission consistent with dopamine release has been reported in a number of situations, the most common being the effect of amphetamine administration and non-drug intervention in experiments of exposure of individuals to neuropsychological stimuli (Koepp et al., 1998;Gjedde et al., 2010). The evidence includes former cocaine addicts who re-expose themselves to cocaine-related cues (Wong et al., 2006), as illustrated in Figure 2. Some reported changes differ in healthy volunteers and patients with neuropsychiatric disorders (Laruelle and Abi-Dargham, 1999;Wong et al., 2008). ...
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... Exsmokers or never-smokers who work overtime are more likely to become smokers because of increased stress and exhaustion 7,8 . Gambling and playing video games are two environmental motivational stimuli which, combined with smoking or other addictive substances, may increase dopamine in the nucleus accumbens 6,9,10 . It is customary in China for people to attend mental activities on weekends or during the evening hours after dinner. ...
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... There are different conditions under which human beings release dopamine, including playing video games [12]. Thus, passing a level, obtaining a high score, competing with others, and facing a new challenge can generate pleasurable sensations that contribute to therapeutic adherence and increase the user's effort to obtain superior results during the therapeutic intervention process. ...
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... We are talking about immediate feedback and active participation, although fun is undoubtedly one of the key elements for this type of technological resources to generate the desired effect. From the perspective of neuroscience, the biochemical mechanisms that support motivation when using video games were proven by [3] and are closely related to the rapid achievement of rewards, which increases the levels of dopamine in the nucleus accumbens. ...
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... We are talking about immediate feedback and active participation, although fun is undoubtedly one of the key elements for this type of technological resources to generate the desired effect. From the perspective of neuroscience, the biochemical mechanisms that support motivation when using video games were proven by [3] and are closely related to the rapid achievement of rewards, which increases the levels of dopamine in the nucleus accumbens. ...
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Considerable evidence suggests that cognitive state affects local levels of neurotransmitter in the brain. We introduce a compartment model of neuroreceptor ligand kinetics to describe the effect of change in cognitive state on positron emission tomography (PET) signal dynamics. The model is used to establish optimal experimental conditions, timing of activation, and ligand characteristics, for detecting cognitive activation. The model, which follows free and bound endogenous neurotransmitter, describes the PET curve predicted for a single injection of radioligand in the presence or absence of activation. Activation was conceptualized as the performance of a task that raises the level of neurotransmitter that competes for receptor sites with the radioligand. Simulating the dopamine system, for example, required making assumptions regarding the kinetic rate constants for binding/dissociation of endogenous dopamine to/from the receptor and dopamine concentrations in the synapse. Simulations suggest that activation of dopamine should be detectable with PET and the D2 receptor ligand [11C]raclopride, although this ligand might not be optimal. Aspects of experimental design can be modified to optimize the likelihood of detecting neurotransmitter changes. The ideal radioligand for these studies should bind irreversibly to its receptor. Furthermore, the task should commence at injection time and last for at least 7 minutes. Optimal task duration depends on the dynamics of free radioligand in the tissue and can be determined via model simulations for any well‐characterized receptor ligand. Flow effects were shown to be distinguishable from those of neurotransmitter activation. General principles regarding desirable ligand characteristics and activation timing held for both the D2 receptor and the dopamine transporter site. © 1995 Wiley‐Liss, Inc.
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Recent data from positron emission tomography (PET) imaging studies suggest the possibility of studying synaptic transmission in vivo in humans. The approach will require a synthesis of two established techniques: brain activation studies (conventionally performed by measuring regional cerebral blood flow or metabolism) and neurotransmitter receptor imaging (using radiolabelled ligands that bind to specific neuroreceptors). By comparing neuroreceptor binding in subjects at rest and while performing an activation task, it may be possible to determine whether a particular neurotransmitter is involved in performance of the task. The underlying principle is that endogenous neurotransmitter competes with the injected radioligand for the same receptors, thereby inhibiting ligand binding. This effect will be even more pronounced during activation, as the synaptic concentration of transmitter rises. Thus, activation of a specific neurotransmitter will be detected as a decrease in specific binding of the radioligand. In this paper we review neurophysiological and biochemical literature to estimate the endogenous neurotransmitter concentration changes that will be expected to occur during an activation task, using the dopamine system as an example. We calculate that the average synaptic dopamine concentration is ≈ 100 nM and that it approximately doubles during activation. This, along with consideration of the concentration of radioligand and affinities of the ligand and dopamine for dopamine receptors, suggests that physiological activation of a specific neurotransmitter system is likely to be detectable with PET. © 1995 Wiley‐Liss, Inc.