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Evidence for striatal dopamine release during avideo game

January 1998
Nature 383

Authors:

Matthias Koepp

University College London

Roger N Gunn

Imperial College London

Andrew David Lawrence

Cardiff University

Vincent J Cunningham

University of Aberdeen

Show all 9 authorsHide

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.)

Mean time-activity 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.

…

[ 11 C]RAC-binding potential, relative tracer delivery and size of the region of interest in striatal regions

…

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Nature © Macmillan Publishers Ltd 1998

letters to nature

266 NATURE

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21 MAY 1998

26. Tanksley, S. D., Zamir, D. & Rick, C. M. Evidence for extensive overlap of sporophytic and

gametophytic gene expression in Lycopersicon esculentum. Science 213, 453–455 (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

C-labelled raclopride

to dopamine D

receptors is sensitive to levels of endogenous

dopamine, which can be released by pharmacological challenge

3–8

Here we use

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

C-labelled raclopride (RAC) to detect changes in levels

of extracellular dopamine induced by a behavioural task. During the

ﬁrst 50 minutes of a [

C]RAC–PET 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

2,9–11

. During a second [

C]RAC–

PET scan, subjects looked at an empty screen. The scanning order

was randomized for each subject. Differences in [

C]RAC-binding

potential between scans were used to infer changes in levels of

extracellular dopamine

12,13

. Binding of [

C]RAC to dopamine D

receptors was measured in the ventral and dorsal striata, which are

areas involved in goal-directed motor behaviour

2,14–16

Striatal [

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

-receptor sites avail-

able for binding to [

C]RAC. The magnitude of change of

[

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 [

C]RAC-binding potential

(mean, 4–6%)

17,18

, and was similar to that observed following

intravenous injection of amphetamine

(striatum mean, −16%;

range, −3to−24%) or methylphenidate

(striatum mean, −23%;

range, +3 to −46%). Microdialysis studies of non-human primates

Table 1 [

C]RAC-binding potential, relative tracer delivery and size of the region of interest in striatal regions

DLD

(%)

DRD

(%)

D LV

(%)

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)

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, [

C]RAC-binding potential; R

, relative tracer delivery; ROI, region of interest (mm

); s.d., standard deviation; L, left; R, right; D, dorsal; V, ventral; B, baseline conditions; T, task conditions.

Changes in BP, R

and ROI size between conditions (D) are given as a percentage change from the baseline, calculated as: ðT 2 BÞ=B 3 100. R

was signiﬁcantly decreased during the video

game (F ¼ 11:3, P ¼ 0:001), but reductions in R

were not correlated with reductions in BP (r

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

¼ 0:02, P ¼ 0:45), indicating that head movement probably did not contribute signiﬁcantly to our results.

Figure 1 Mean time–activity curves for [

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

letters to nature

NATURE

VOL 393

21 MAY 1998 267

indicate that a 1% decrease in striatal [

C]RAC binding reﬂects at

least an 8% increase in extracellular endogenous dopamine levels

Thus, the 13% reduction in [

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 [

C]RAC–

PET

After 50 min, the game ended, but the time–activity curves

(TACs) for [

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 [

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

, providing a biological explanation for the

continued separation of the TACs for [

C]RAC binding after the

video game ended.

There was a signiﬁcant correlation between performance level

achieved and reduced [

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)

. 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 [

C]RAC displacement within the

striatum might correlate with the role of dopamine in the dorsal and

ventral striata

. 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 [

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

. 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’.

. . . .. . . . . . . .. .. . . . . .. .. . . .. .. . . . . . . .. . . . . . . .. .. . . .. .. . . . . . . .. . . . . . . .. .. . . .. .. .. . . .. .. . . .. . . .. . . . . .. . . . . . . .. .. . . . . . . .. . . . .

Methods

PET-scan acquisition. Eight healthy, male, right-handed volunteers (range

36–46 years of age) took part in the study (approved by the local Ethics

Committee). Informed consent was obtained for all subjects. Each received two

[

]RAC–PET scans (total injected dose of 16–20 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

[

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 [

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

) in the striatum

L ventral

-50

-40

-30

-20

-10

Change in binding potential (%)

L dorsal

R ventral

Level of performance

R dorsal

-50

-40

-30

-20

-10

-50

-40

-30

-20

-10

-50

-40

-30

-20

-10

01234567

0123456701234567

Figure 2 Percentage change in [

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 [

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 [

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

letters to nature

268 NATURE

VOL 393

21 MAY 1998

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

max

Tracer

1 þ

where B

max

is the total concentration of speciﬁc binding sites, K

Tracer

the

equilibrium dissociation constant of the ligand, f

is the ‘free fraction’ of

unbound ligand in the tissue, and F

and K

are the concentrations and

equilibrium dissociation constants, respectively, of i competing endogenous

ligands. Changes in BP are attributed to changes in F

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

. BP and R

values were calculated for the striatal ROIs using the

TACs for [

C]RAC binding up to 50 min after injection

. Differences in

[

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

[

C]RAC-BP and the highest performance level during the game for each ROI.

SPM analysis. Parametric images of [

C]RAC-BP

were analysed using

SPM96 (ref. 21). The [

C]RAC-R

images were used to deﬁne the stereotactic

transformation parameters for the [

C]RAC-BP images. Contrasts of the

condition effects at each voxel of the [

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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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 10–100 ms (refs 3–6). 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

. Despite

intensive efforts to decipher this role

10–16

, 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.

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Marija Stojanović

Violent video games, as a modern digital media, have attracted increasing attention of children and adolescents in recent decades, causing many detrimental consequences, most notably aggressive behavior. Therefore, the goals of the paper are: presentation of research findings that testify to the influence of playing violent video games on aggressive cognition, aggressive feelings, physiological arousal, desensitization to violent scenes, as processes that play a significant role in the expression of aggressive behavior; review of research indicating significant effects of playing violent video games on aggressive behavior; summarizing and displaying the factors that mediate and moderate the link between violent video game play and aggressive behavior. Based on the findings of meta-analytic, longitudinal, experimental and correlational studies, it is clear that playing violent video games is positively related to aggressive behavior and underlying processes.

Diminished Frontal Theta Activity During Gaming in Young Adults With Internet Gaming Disorder

Article

Full-text available

Nov 2019

Cognitive control is essential for flexible, top-down, goal-directed behavior. Individuals with Internet gaming disorder (IGD) are characterized by impaired prefrontal cortex function and cognitive control. This results in an increase in stimulus-driven habitual behavior, particularly related to pathological gaming. In the present study, we investigated the electroencephalographic (EEG) activity in individuals with IGD. Twenty-four individuals with IGD and 35 healthy control (HC) subjects were recruited. We analyzed their EEG activity while the subjects played their favorite game (30–40 min duration). We compared the band power between the two groups. During gaming, the left frontal theta, alpha, and beta band activities were lower in subjects with IGD than in HCs. Moreover, the left frontal theta power negatively correlated with IGD severity. These results indicate that left frontal theta power could be used as a neurophysiological biomarker for the detection of diminished cognitive control patterns in individuals with IGD.

Changes in Magnitude and Variability of Corticospinal Excitability During Rewarded Time-Sensitive Behavior

Article

Full-text available

Jul 2019

Reward expectation and time estimation are important for behavior and affectcorticospinal excitability. This study investigated changes in corticospinal excitabilityduring rewarded time-sensitive behavioral tasks. The rewarded time-sensitive taskcomprised three fixed-ratio (FR) schedules: FRAcontained a reward stimulus after everyresponse, FRBafter every two responses, and FRCafter every four responses. Theparticipants were instructed to press a left button with the index finger as quickly aspossible in response to the appearance of a red circle. Just after the left button press,the word “10-yen” (approximately $0.1) or “no pay” was presented as feedback. Then,the participant had to mentally estimate/wait for 2.5 s from pressing the left button topressing the right button. One second after the reward stimulus, transcranial magneticstimulation (TMS) was delivered to the primary motor cortex at the hotspot of the firstdorsal interosseous (FDI) muscle. Each participant received items corresponding to thetotal monetary reward accumulated at the end of the experiment. The variability ofmotor evoked potential (MEP) amplitudes transformed from a random process duringthe resting state into an autoregressive process during the rewarded time-sensitivebehavioral task. Additionally, the random variation of MEP amplitudes in the FRC, FRB,and FRAschedules increased in a stepwise fashion. However, the magnitude of MEPamplitudes significantly increased for the FRBand FRCschedules compared to the FRAschedule. The time estimation lag was negative for the three FR schedules but there wasno difference among the three FR schedules. The magnitude of corticospinal excitabilityincreased in low reward probability, whereas the variability of corticospinal excitabilitytransformed into an autoregressive process in high reward probability. These resultsimply that the magnitude and variability of expectation-related corticospinal excitabilitiescan be differentially altered by reward probability.

Impaired reinforcement learning and behavioral activation/inhibition systems in internet addiction

Preprint

Full-text available

Aug 2023

Background The goal of this study is to examine whether goal-directed control and learning rate are more closely associated with internet addiction (IA) and analyze maladaptive behavior in IA through reinforcement learning processes and personality traits by looking at the personality traits of people with IA, thereby validating its alternative for diagnosing and measuring IA. Methods A total of sixty-one participants with IA and sixty-one healthy participants completed the Internet Addiction Test (IAT), the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scale, and the two-step Markov decision task. Through hybrid modeling and multivariate regression, the relationship between reinforcement learning parameters, personality traits, and IA scores was analyzed. Results Significant impairment in goal-directed system was observed in the IA group, although this impairment did not correlate with the degree of IA. In comparison to the healthy control group, the IA group exhibited a significantly higher learning rate, which was positively correlated with the severity of IA and reward sensitivity. Furthermore, the BIS score and learning rate were predictive of IAT scores. Conclusions Maladaptive behavior in IA can be attributed partially to deficits in goal-directed system and an elevated learning rate. Individuals with a higher BIS sensitivity are more likely to experience IA. Incorporating behavioral modeling parameters and personality factors might aid in IA diagnosis.

PET imaging of neurotransmission using direct parametric reconstruction

Article

Full-text available

Jul 2020

Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the conventional method of estimating changes in neurotransmitter levels relies on fitting a pharmacokinetic model to activity concentration histories extracted after PET image reconstruction. However, due to the statistical fluctuations of activity concentration data at the voxel scale, parametric images computed using this approach often exhibit low signal-to-noise ratio, impeding characterization of neurotransmitter release. Numerous studies have shown that direct parametric reconstruction (DPR) approaches, which combine image reconstruction and kinetic analysis in a unified framework, can improve the signal-to-noise ratio of parametric mapping. However, there is little experience with DPR in imaging of neurotransmission and the performance of the approach in this application has not been evaluated before in humans. In this report, we present and evaluate a DPR methodology that computes 3-D distributions of ligand transport, binding potential (BPND) and neurotransmitter release magnitude (γ) from a dynamic sequence of PET sinograms. The technique employs the linear simplified reference region model (LSRRM) of Alpert et al (2003), which represents an extension of the simplified reference region model that incorporates time-varying binding parameters due to radioligand displacement by release of neurotransmitter. Estimation of parametric images is performed by gradient-based optimization of a Poisson log-likelihood function incorporating LSRRM kinetics and accounting for the effects of head movement, attenuation, detector sensitivity, random and scattered coincidences. A ¹¹C-raclopride simulation study showed that the proposed approach substantially reduces the bias and variance of voxel-wise γ estimates as compared to standard methods. Moreover, simulations showed that detection of release could be made more reliable and/or conducted using a smaller sample size using the proposed DPR estimator. Likewise, images of BPND computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using ¹¹C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach.

Correlations of Internet Addiction Severity With Reinforcement Sensitivity and Frustration Intolerance in Adolescents With Attention-Deficit/Hyperactivity Disorder: The Moderating Effect of Medications

Article

Full-text available

Apr 2019

Background: Deviations in reinforcement sensitivity and frustration-related reactions have been proposed as components of the biopsychosocial mechanisms, which explained the high vulnerability to internet addiction (IA) among individuals with attention-deficit/hyperactivity disorder (ADHD). There is currently limited knowledge on the relationship of IA symptoms with reinforcement sensitivity and frustration intolerance, as well as factors moderating those correlations in this population. Objective: The aims of this study were (1) to examine the associations of IA symptoms severity with reinforcement sensitivity and frustration intolerance and (2) identify the moderators of these associations among adolescents diagnosed with ADHD in Taiwan. Methods: A total of 300 adolescents aged between 11 and 18 years who had been diagnosed with ADHD participated in this study. Their levels of IA severity, reinforcement sensitivity, and frustration intolerance were assessed using the Chen Internet Addiction Scale, behavioral inhibition system (BIS) and behavioral approach system (BAS), and Frustration Discomfort Scale, respectively. The associations of IA severity with reinforcement sensitivity and frustration intolerance were examined using multiple regression analysis. Possible moderators, including medications for ADHD, were tested using the standard criteria. Results: Higher fun seeking on the BAS (p = .003) and higher frustration intolerance (p = .003) were associated with more severe IA symptoms. Receiving medication for treating ADHD moderated the association between fun seeking on the BAS and severity of IA symptoms. Conclusion: Fun seeking on the BAS and frustration intolerance should be considered as targets in prevention and intervention programs for IA among adolescents with ADHD.

A simplified reference tissue model for PET receptor studies

Article

Jan 1996

In vivo imaging of neuromodulatory synaptic transmission using PET: A review of relevant neurophysiology

Article

Jan 1995

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.

In vivo imaging of neuromodulation using positron emission tomography: Optimal ligand characteristics and task length for detection of activation

Article

Jan 1995

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.

Positron Emission Tomographic Analysis of Central D1 and D2 Dopamine Receptor Occupancy in Patients Treated With Classical Neuroleptics and Clozapine

Article

Jul 1992
ARCH GEN PSYCHIAT

Lars Farde

• Positron emission tomography and selective radioligands were used to determine D, and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D, occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D, occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

The dopamine synapse and the notion of ‘pleasure centers’ in the brain

Article

Apr 1980
TRENDS NEUROSCI

Roy Alfred Wise

Animals will work for a reward consisting of electrical stimulation at certain specific sites within the brain. James Olds termed these ‘pleasure centers’, but both the ‘pleasure’ and the ‘center’ aspects of the hypothesis were subsequently criticised, even by Olds himself. However, as Roy Wise describes here, recent work suggests that, with some minor modifications, the concept still provides a useful experimental paradigm.

The dopamine synapse and the notion of ‘pleasure centres’ in the brain

Article

Aug 1980
TRENDS NEUROSCI

Gordon Arbuthnott

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The relationship between learning performance and dopamine in the prefrontal cortex of the rat

Article

Sep 1994
NEUROSCI LETT

To clarify the relationship between dopamine (DA) release in the prefrontal cortex and learning performance, extracellular DA was measured by an in vivo microdialysis method during a discrimination learning task. Rats were trained to discriminate between lamp-on and -off states under an operant-type learning procedure. After stable discriminative behavior was established, a microdialysis experiment was conducted. Inverse relationships were seen between the relative ratio of DA after the beginning of a learning session to the basal level and the responses (total, correct and error responses) during a session. The results indicate that the degree of DA release in the prefrontal cortex is involve in the inhibitory mechanism of the response during discrimination learning performance.

Functions of dopamine in the dorsal and ventral striatum

Article

Apr 1992

Manipulations of dopamine levels in the dorsal and ventral striatum are shown to affect the activation of behaviour in distinct, yet parallel ways, which depend upon the nature of the neocortical and limbic input to these structures. Whereas dopamine in the dorsal striatum contributes to the sensorimotor co-ordination of consummatory behaviour and the development of a ‘response set’ in motor preparatory processes for skilled responses, dopamine in the ventral striatum influences the impact of reward-related stimuli on appetitive aspects of behaviour. The circumstances under which the striatal dopamine projections are normally active to effect these functions are defined by studies which attempt to correlate firing in single units or neurochemical indices of dopamine activity with environmental conditions, internal states and behaviour.

Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model

Article

Dec 1997

A method is presented for the generation of parametric images of radioligand–receptor binding using PET. The method is based on a simplified reference region compartmental model, which requires no arterial blood sampling, and gives parametric images of both the binding potential of the radioligand and its local rate of delivery relative to the reference region. The technique presented for the estimation of parameters in the model employs a set of basis functions which enables the incorporation of parameter bounds. This basis function method (BFM) is compared with conventional nonlinear least squares estimation of parameters (NLM), using both simulated and real data. BFM is shown to be more stable than NLM at the voxel level and is computationally much faster. Application of the technique is illustrated for three radiotracers: [11C]raclopride (a marker of the D2 receptor), [11C]SCH 23390 (a marker of the D1 receptor) in human studies, and [11C]CFT (a marker of the dopamine transporter) in rats. The assumptions implicit in the model and its implementation using BFM are discussed.

Selective activation of mesocortial DA system by stress

Article

Oct 1976

IT is now well established that an important system of dopaminergic (DA) neurones innervates various parts of the cerebral cortex in the rat and other species1-3. In contrast to noradrenergic (NA) terminals which are widely distributed in this structure, the DA terminals are mainly confined to deep layers, particularly in the frontal, the cingular and the entorhinal areas4,5. The results of lesion studies demonstrated that the terminal endings in the frontal cortex originate from the A10 group of DA cell bodies localised in the mesencephalon6-8. This group also contains the cell bodies of the classical mesolimbic DA system projecting to the tuberculum olfactorium, the nucleus accumbens, the nucleus of the stria terminalis, and the amydgala9. The DA terminals found in the cingulate and entorhinal areas of cortex may originate mainly from the A9 group of DA neurones6-8. This group gives rise to the well known nigrostriatal DA system which is implicated in extrapyramidal processes. Its degeneration is in part responsible for some of the symptoms seen in Parkinsonian patients. Little is yet known about the functions of the mesocortical and mesolimbic DA pathways. Electrocoagulation or 6-hydroxydopamine (6-OHDA)-induced lesions of the ventral tegmental area, containing the A10 group, produce a syndrome characterised by ``locomotor hyperactivity, serious impairment in tests requiring inhibition of a previously learned response, facilitation of approach learning and of active avoidance and hypoemotivity''10,11. Various workers have suggested that the antipsychotic effects of neuroleptics are in part related to the blockade of postsynaptic DA receptors localised in areas innervated by the mesolimbic and mesocortical DA systems12,13. It seems important to establish whether neurones of these two DA systems correspond to an homogeneous population of cells with similar functional characteristics. We have therefore explored this problem in the rat by examining the reactivity of the mesocortical and mesolimbic DA pathways as well as that of nigrostriatal DA system to stress induced by electric foot shocks. Our results suggest that the mesocortical DA system is selectively activated by this stress.

Evidence for striatal dopamine release during avideo game

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