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.

1 INTRODUCTION

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

465

(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

addiction.

2 MATERIALS AND METHODS

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

466

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 RESULTS

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

467

Table 1: Estimated time difference.

eriment set u

Time

(

minutes

)

1. Standar

2. DBS 32

3. Dru

(

SCH23390

)

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

uenc

1. Standar

2. DBS 21

3. Dru

(

SCH23390

)

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.

4 DISCUSSION

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

468

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

expected.

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.

5 CONCLUSIONS AND FUTURE

DIRECTION

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

addiction.

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