The Role of D1 Receptor Medium Spiny Neuron Pathway in Video
Gaming Addiction Relapse
Nuo Chen
Shanghai Pinghe School, Shanghai, China
Keywords: Video Game Addiction, D1R-MSN, Long Term Depression, Deep Brain Stimulation.
Abstract: Video game addiction has gained increasing amount of attention as the problem keeps prevailing, especially
among adolescents. Inspired by mechanism of cocaine induced substance addiction (D1R-MSN direct
pathway) and a potential treatment protocol proposed in previous literature, experiments are done in 40 human
subjects to test the mechanism of video game addiction relapse and craving. The results show that low
frequency deep brain stimulation of 12 Hz combined with an infusion of drug SCH23390 (D1 receptor
antagonist) causes an increase in self-control time, indicating a reversal effect of video game addiction relapse
and craving. The same combination of treatment is shown to reduce firing frequency of video game cue
induced D1R-MSNs, providing neuroscientific basis for the mechanism of the addiction and the treatment.
The combination also proves the role of synaptic change in D1R-MSNs direct pathway in the cause of video
game addiction relapse and craving. The mGluR1 dependent long-term depression (LTD) reducing total
glutamate release and surface expression of AMPA receptors might be the mechanism behind the treatment.
Addiction is the inability to quit using a substance or
taking part in a behavior, regardless of the harm they
might bring. Common types of addictions include
cocaine addiction, gambling addiction, heroin
addiction etc (Medical News Today, 2021). The
mechanism of addiction is complex and involves
multiple brain areas. Nucleus Accumbens (NAc) has
been proven to play an important role in the addiction
(Scofield et Al, 2016). According to the type of
dopamine receptors that the neuron express, medium
spiny neurons (MSN) are divided into two classes: D1
receptor MSNs and D2 receptor MSNs (Reinius et al,
2015). D1R-MSNs mainly build up the direct
pathway. In the pathway, Nucleus Accumbens
receives input from prefrontal cortex, then project to
SN and VTA, which in turn project to thalamus and
to the cortex to direct behavior. Activation and
potentiation of these D1R-MSNs ultimately disinhibit
the thalamus projection to the motor cortex and
enhances movement and execution of movements
(Smith, Lobo, Spencer, Kalivas 2013). The direct
pathway is also found to be related to craving
behavior (Scofield et Al, 2016). D1 receptors are
shown to be responsible for LTP mechanism which
increases the strength of potentiation between the
connection of cortex neurons and MSN (Smith, Lobo,
Spencer, Kalivas 2013).
Few papers have regarded the role of NAc in
behavioral addiction such as video game addiction,
but studies on cocaine have revealed an important
role of NAc in drug relapse and craving behavior. It
has been shown that cocaine selectively potentiates
cortical afferents onto D1 MSNs (Creed, Lüscher
2013). It is a mechanism that is possibly triggered by
the activation of ERK kinase by D1 receptor binding
with dopamine. The activation of ERK kinase is
correlated with the insertion of AMPA receptor and
locomotor sensitization (Pascoli, Turiault, Lüscher
2012). Since the dopaminergic neurons are also
glutamate releasing, the drug cue causing a firing of
these cotransimission neurons will release Glutamate
as well (Broussard 2012), stimulating D1R MSN for
drug seeking behavior. A protocol proposed that gives
D1 receptor antagonist SCH23390 and low frequency
deep brain electrical stimulation of 10-15Hz to the
Nucleus Accumbens Shell area can reverse the
enhanced motor behavior caused by a LTP that is
caused by repeated exposure of cocaine (Creed,
Pascoli, Lüscher 2015).
In recent years, gaming addiction, sometimes
referred to as Internet and video gaming addiction
Chen, N.
The Role of D1 Receptor Medium Spiny Neuron Pathway in Video Gaming Addiction Relapse.
DOI: 10.5220/0011372200003438
In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 465-470
ISBN: 978-989-758-596-8
2022 by SCITEPRESS Science and Technology Publications, Lda. All rights reserved
(IGVD) or Internet gaming addiction (IGD), has
garnered attention. According to GAS scale of criteria
for gaming addiction, relapse is among the 7 criteria,
suggesting a potential similarity with some of the
substance addiction like the cocaine addiction as
mentioned before (Lemmens, Valkenburg, Peter
2009). Besides, previous papers have shown that NAc
is increasingly active in the subjects with internet or
gaming addiction (Kuss, Griffiths 2012), and it has
been reported to be activated in cue-induced gaming
urge (Ko et al 2009). Considering the similarity in
nucleus activity and symptoms, we hypothesize that
the D1R MSN pathway also plays a role in video
gaming addiction and its relapse behavior. The goal is
to use the protocol from Creed et al paper on humans
and test whether the treatment causes both
electrophysiological and behavioral changes that are
aligned with a reversed effect of video game
2.1 Subjects
All the 40 participants have gone through the Game
Addiction Scale (GAS), validated to be a standard
measure of gaming addiction. According to the
modification done by (Khazaal et al, 2018), we adjust
the questionnaire to fit internet gaming and video
gaming investigation. We include questions like “Do
you play video games on the Internet or off line to
escape from real life situations?” Each question
begins with “During the last 6 months, how often do
you…”, and the answer is given in a 1-5 point scale
(Khazaal et al, 2018).
Each question is in accordance to the seven
criteria of addiction: salience, tolerance, mood
modification, relapse, withdrawal, conflict and
problems. With the point of scale, 40 subjects with
similar high score of severe addiction problem is
chosen for better control.
2.2 Electrode Implantation
In this experiment, multi-electrode array (MEA)
consisting of 64 platinum microelectrode is implanted
into the human brain Nucleus Accumbens Shell area
to perform both functions of recording and deep brain
stimulating (DBS). This requires an MR imaging on
a 1.5 T scanner to identify brain area (Horn et al,
2017). During the implantation of the electrode, the
patients are generally under anesthesia but were
awake when electrode testing is performed (Horn et
al, 2017). The participants are given the video game
cues (their favorite video game according to the
questionnaire presented on the TV screen in front
when doing surgery), and the signals of action
potential rate is recorded. The electrodes are planted
at the spot where the rate is the highest. The rate can
be visualized by oscilloscope that is connected to the
array and heard by the loudspeaker connected.
(Carter, Shieh 2015).
In this way, the specific D1R-MSNs that are
responsive to video game cues are detected. They are
thus prepared to be recorded and stimulated by
electrodes of MEA. The electrode used are also
modified with drug infusion capability (Vanegas et al
2019), which will be used later to inject SCH23390,
the D1 receptor antagonist (Faedda, Kula,
Baldessarini 1989).
2.3 Self-control Tasks
The participants with the electrodes implanted will
undergo several blocks of treatments and tasks. It is
shown in an abbreviated scheme in fig.1. The self-
control task aims to gather data of whether certain
patterns of treatments can reverse the behavioral
aspects of video game addiction: relapse and craving.
The participants are placed in a vacant room with only
one TV screen and a joystick connected, through
which they can play the games they are addicted to.
However, they are asked to control their impulse as
long as possible. We are thus recording the self-
control time before and after giving certain patterns
of treatments. Electrophysiology data regarding D1R-
MSN activity are also recorded in the process.
Figure 1> Experiment procedure and scheme.
An interval of 24 hours is given between each task
and treatment. It aims to give adaptation time to
participants. More importantly, it aims to test the
long-term effect of the treatment. In similar
experiments executed on rats, the protocol that
successfully reverse the effect of addiction in the long
term shows consistency in the data after 24 hours.
ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare
Considering ethical issue and the tediousness of the
experiment, we set no longer interval than 24 hours
which could have been a better measurement for long
term effect.
The same patch of 40 subjects goes through 4
treatment and task blocks in sequence. Considering
the uneasiness when it comes to the approval of
human participants, the different combinations of
treatments are done on the same person. However,
adjustments can be done if any preceding tasks evoke
a long-term effect in data. For instance, if significant
difference is found in both behavioral and
electrophysiological data in the second task, the
preceding treatment (only DBS) will switch position
with the following treatment (only SCH23390).
Besides that, SCH23390 is a short-lived drug with
elimination time of around 25 minutes (Faedda, Kula,
Baldessarini 1989), and the DBS stimulation is only
12 Hz for 10 minutes. Thus, the treatments
themselves, if not evoking a chemical change, will
not have impact on the following treatment.
2.4 Electrophysiology Recording
Using Multielectrode assay, we can gather the signals
of the potential around the recording probe. The raw
signal will need to be processed in a sequence of steps
for analysis. First, by applying a band pass filter with
a typical narrow band of 300-3000Hz, the noises are
largely filtered out, leaving only the information of
action potential of all the recorded neurons (Obien,
Deligkaris, Bullmann, Bakkum, Frey 2015).
The next step would be to detect time of spikes
using amplitude thresholding. Finally, each neuron
recorded has a particular firing pattern and shape, so
we can sort all the spikes into different individual
neurons. This will require some sophisticated
technology like PCA and wavelet transformation
(Obien, Deligkaris, Bullmann, Bakkum, Frey 2015).
With the spike pattern of both individual neurons
and the aggregate of all neurons, we can count the
spikes and reckon the spike rate. It is calculated by
the number of spikes divided by the same time
interval (Gerstner, Kistler, Naud, Paninski 2014). It
can act an indicator of synaptic strength.
3.1 Behavioral
In testing the reversal effect of three different
treatments (only DBS, only SCH23390, DBS +
SCH23390), we used self-control time as a
benchmark. In the first task where no treatment is
given, we expect a low self-control time, which we
proposed as about 30 minutes. In the ideal situation,
the second and third task will yield similar results,
with no significant increase in self-control time. It is
only in the last treatment that a significant increase in
self-control time is recorded, indicating a successful
impact of the final treatment on video game addiction
relapse in most subjects. The pattern can be visualized
in Fig.2 with the estimated and expected data shown
in Table 1.
Figure 2: Self-control time after different treatment.
The Role of D1 Receptor Medium Spiny Neuron Pathway in Video Gaming Addiction Relapse
Table 1: Estimated time difference.
eriment set u
1. Standar
2. DBS 32
3. Dru
4. DBS+SCH23390 90
If the result is not as expected, a significant
increase in self-control time would be observed in
either second or third task. If the effect is long term,
the rest of the task is likely to be affected and show
same pattern of increase in self-control time.
3.2 Electrophysiology
In determining the effect of different treatment on the
D1R-MSNs, we gathered data regarding spike
frequencies for individual neurons (gone through
spike sorting) and the whole patch of neurons (before
spike sorting). A higher spike frequency indicates a
stronger synaptic connection. We expect the spike
frequency to be high in the first task when no
treatment is given, which explains the corresponding
low self-control time, since the impulse is generated
through frequent firing of neurons that builds up the
direct pathway that contribute to craving and
relapsing. We also expect the firing pattern to be
similar in both second and third task, indicating an
ineffectiveness of treatment on the long-term synaptic
structure of D1R-MSNs. It is only in the final
treatment that is reported to induce LTD (Creed,
Pascoli, Lüscher 2015) can lower the firing frequency
in the recording after 24 hours. This can explain the
corresponding increased self-controlled time. The
pattern is shown in Fig.3 with the estimated data in
Table 2.
Figure 3: Spike frequency (Hz) after different treatments.
Table 2. Estimated spike frequency data.
eriment set u
ike fre
1. Standar
2. DBS 21
3. Dru
4. DBS+SCH23390 7
If the results go unexpected, a decrease in spike
frequency is likely going to be recorded in either
second or third task and is likely to last for the
following tasks. If either situation occurs, it would
invalidate our hypothesis to certain extent. If DBS
alone can cause a long-term effect, we cannot prove
how without D1 receptor antagonist, LTP induced by
D1 receptor is offset. If SCH23390 alone can cause a
long-term effect, we cannot prove how the short-lived
drug can have an impact alone on the long-term
structure of the synapse. Only together with low
frequency DBS that can induce LTD, and SCH23390
that can prevent the effect of LTP, can we explain the
mechanism of video game addiction relapse and
craving, and the mechanism of how to solve it.
The reversal effect that only occurs when low
frequency DBS and SCH23390 is given together is
likely caused by a specific type of LTD: mGluR1-
dependent LTD. It is reported that frequency of 10-15
Hz stimulation is associated with mGluR1-dependent
LTD (Creed, Pascoli, Lüscher 2015). There are two
pathways of mGluR-dependent LTD. The first
pathway: Low frequency electrical stimulation
excites the afferent cortex neuron and promotes the
release of enough Glutamate neurotransmitter from
pre synaptic region to the synaptic cleft for mGluR
receptor to accept. Group 1 mGluR receptor generates
endocannabinoids by activation of phospholipase C,
which generates diacylglycerol, which in turn in the
ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare
end revert by the lipid precurson to endocannabinoids
(Wilson & Nicoll 2002). The DBS also likely causes
a post synaptic excitability, opening the L-type
voltage-gated calcium channels, which positively
modulate the mobilization of the endocannabinoids
(Lüscher, Huber 2010).
Endocannabinoids are released by exocytosis
back to reach to the presynaptic membrane and more
specifically, the CB1 receptor on it. The CB1 receptor
in turn inhibit the Calcium channel, which is
important for the release of neurotransmitter
(Lüscher, Huber 2010). A long-term decrease in
EPSC recorded in the post synaptic region is
Another pathway shows that Stimulation of
Group I mGluR activates phospholipase C (PLC),
inositol triphosphate (IP3) pathway to release Ca2+
from intracellular stores and protein kinase C (PKC).
PKCα phosphorylates ser880 of GluA2 to trigger
endocytosis of α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor (AMPAR) and
reduce the level of surface expression (Kang, Kaang
2016). Both pathways act to decrease the amplitude
of currents passing to post synaptic region (Scheyer,
Christian, Wolf, Tseng 2018). In either way, it can
help explain our data that there is a decrease in the
spike counts, since weaker currents passing through
the AMPA receptors is less likely to induce a negative
55mV potential that results in an action potential.
The expected results indicate the availability of
treatment protocol of 12Hz low frequency Deep Brain
Stimulation combined with infusion of SCH23390
D1 receptor antagonist targeting Nucleus Accumbens
shell area in relieving symptoms of video game
addiction relapse and craving. It is visualized by a
decrease in self-control time in video game addicts
when asked to control impulses. The
electrophysiology results also prove the role of D1R-
MSNs and the mechanism of video game addiction as
well as the mechanism of LTD in solving the problem.
Internet gaming and video game addiction is a
problem that is exclusively investigated in human.
However, there is problem in figuring out mechanism
if human are used as subjects. It is hard to isolate the
effect of D1R-MSNs in the addiction (what we tested
in this paper is a reverse way of thinking that proves
the significance by blocking the effect), and it is
unethical to develop a video game addiction in human
from zero to test the effect. In vitro studies have been
done in epilepsy patients(Jones 2016). Similar studies
can be done in the future from patients suffering from
comorbidity in different types of addictions. In vitro
investigation will be more precise and controllable.
The technology currently applicable on human is
still immature. Some technology that is current under
development will help constitute a more complete
experiment. MIT researchers are currently
developing an Ultrathin needle that will allow more
specific targeting of infusion into the brain (Trafton
2018). SEEG is a technology that is currently used to
more precisely spot the sources of epilepsy (Isnard et
al 2018). Similar approach might be used in video
game addiction cause source in the future. These
technologies can provide an even more accurate and
controlled environment for studying the video game
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