Common Reward Pathway

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Stellenbosch University Shaun Shelly|076-511-0863

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Addictions Care Course 1 Page 1 of 7

The common reward pathway for substances of abuse,

specifically relating to neuroanatomy and

neurophysiology.

Shaun Shelly

Although substances of abuse have varied and diverse primary targets and acute

effects neurochemically, research has shown that almost all substances of abuse lead

to an increase in dopamine in the mesocorticolimbic dopaminergic system. The

understanding of this common reward pathway is important as it could (i) lead to the

development of a single medication that works for various classes of substances of

abuse in addiction treatment; and (ii) give a better understanding as to why all those

suffering from addiction experience similar psycho-social devastation in spite of the

variety of drugs of choice.

The Reward System

As humans we are prepared to allocate time, effort and energy in the acquisition of the

things that are essential for our survival. These things can be considered the fruit,

or reward, of our labour.

The human brain has a complex system of reward that has evolved to assist in the

mediation of pleasurable behaviour (Esch & Stefano, 2004). Primary reward is

designed to ensure human survival by directing us toward beneficial behaviours such

as eating and procreating and then reinforcing such essential behaviours (Goldstein,

2002) (Nestler E. , 2005) (World Health Organisation, 2004). Secondary reward deals

with more abstract concepts such as achieving life goals (Taber, Black, Porrino, &Hurley, 2012).

Box 1:

Brief description of main areas involved in the reward system

Ventral

Tegmental Area

(VTA)

The VTA is situated in the evolutionary old area called the

midbrain. It consists of a group of neurons and is the origin

of the dopaminergic cell bodies. Although there are relatively

few neurons (about 5000) these dopaminergic neurons can

have an axonal length of 74cm and 500,000 terminals per

individual neuron. As a result the dopaminergic neuronshave an extensive reach to multiple areas and modulate

diverse brain functions (Arias-Carrion et al, 2010).


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At the centre of the reward

(World Health Organisation,

projects from the ventral t

prefrontal cortex and is t

mesolimbic pathway links th

Nucleus

Accumbens

(NAc)

The N

consist

these c

neural

amino

the N

neuron

striato-

Limbic System The li

linepart of

closely

the link

the Ma

Prefrontal

Cortex

(PFC)

This is

cortex

ability

predict

other t

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system are the mesolimbic and mesocortical

2004) (Esch & Stefano, 2004). The mesocorti

egmental area (VTA) to the perirhinal, cin

ought to be important for reward proce

VTA with the limbic system via the nucleus

FMRi Image Source: Princeton University

c forms the main portion of the ventral striat

of two bodies, one for each hemisphere, and

onsists of two structures, the core and the sh

cells produce the neurotransmitter

utyric acid (GABA), and these neurons proje

c. Projecting into the NAc are the dopa

s from the VTA. The VTA is a part of the

thalamo-cortical loop.

CMRi Image Source: Wikimedia

bic system consists of the set of brain structu

he cortex. In some literature the NAc is conthe limbic system. The areas of the limbic

linked to reward are the Amygdala and, bec

between memory and reward, the Hippocam

mmillary body.

the anterior part of the frontal lobes. The pr

is primarily credited with executive functi

to make decisions, determine good fro

ion of consequences, salience and inhibition a

ings.

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pathways

c pathway

ulate and

ssing. The

ccumbens

m and

each of

ell. The

amma-

t from

inergic

ortico-

es that

sideredsystem

use of

us and

frontal

n: the

bad,

mongst


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(NAcc) and is thought to be i

Porrino, & Hurley, 2012). See

In response to a motivationa

excited and they send an elec

This causes dopamine to be r

on the NAcc neurons. The a

slight mood elevation to eu

response in the case recurrin

It is important in terms of adstages is the actual receipt of

to the reward that triggers t

relevant event. Should the

result in further dopamine re

process.

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mportant for the reinforcement of reward (Ta

Figure 1

lly relevant event, the VTA is stimulated. Ner

tronic impulse along the axons that project int

eleased into the synapse and then latches ont

ctivation of this system produces changes ra

phoria. In this way we develop an adaptive

events or stimuli (Kalivas & Volkow, 2005).

diction that the motivationally relevant eventhe reward, while after time it is the repeate

he release of dopamine and acts as the mo

reward exceed the anticipated level of rewar

lease and even further enhance the learning a

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ber, Black,

e cells are

the NAcc.

receptors

ging from

behaviour

t in initialprecursor

ivationally

d, this can

nd reward


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It is believed that it is this reward system, along with the serotonin systems, that is co-

opted and eventually modified by substances of abuse (Dackis & C, 2005).

Box 2:

The discovery and evidence of the reward system

During the 1950s a number of experiments were conducted by stimulating

various brain areas in a variety of rats (Olds & Milner, 1954). It was discovered

that by stimulating the various areas the rats would seek to repeat the

experience through self-stimulation, even to the point of physical exhaustion

and in spite of physical discomfort.

In further animal experiments, if dopamine was blocked they stopped

partaking in rewarding activities (Wise, 1998). Paradoxically the elimination of

dopamine does not seem to affect the ability to like certain things, such as

sweetness. (Pecina et al,1997). This would imply that other systems are

involved in the wanting of things, as per Koob, 1992.

In a series of very controversial experiments during the 1960s Heath inserted

an electrode into the NAc of patient B-19. He then continuously self-

stimulated even though he was left frustrated and had a nervous feeling

(Heath, 1964).

These, and further experiments, have certainly strengthened the case for the

existence of a reward pathway as described in this essay. It is, however,

unfortunate that this has sometimes been erroneously labelled the pleasure

centre or pathway, which has had some unfortunate implications in the

understanding of the development of addiction in those that use substances

of abuse.

The effects of substances of abuse

When a substance of abuse is administered it starts a cascade of complex reactions in

the brain. The chemistry of substances of abuse is as diverse as there are names, and

each one has a specific protein target in the brain.

As discussed, dopamine is central to the reward system and forms the basis of all

current models of instrumental responding. Therefore, if there is a common reward

pathway for substances of abuse, it would seem logical that all these substances of

abuse would have an effect on dopamine.

If we consider the varied acute effects of the multitude of substances of abuse the

likelihood of a common reward pathway may seem remote, however, if we examine

the actions of many of these substances we find this to be the case. The following table

gives a simplified overview:


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Substance PMA Main Effect Other

Cocaine Blocks DA uptake Inc Dopamine Directly increase

doperminergic

transmission in the

NAcLSD Inc Serotonin

Heroin Activates Mu &

delta receptors

Inc Dopamine through

disinhibition in the VTA

of dopamine neurons

and direct effects on DA

terminals

Amphetamines Inc Dopamine &

blocks DA uptake

Inc Dopamine

Nicotine Acetylcholine Inc Dopamine

Alcohol GABA &

Substance P

Inc GABA Increased MDP

activityMarijuana Activates

Endocannabinoid

receptors

Inc Dopamine in

MDP

MDMA Inc Serotonin

and block 5-HT

uptake

Inc Serotonin Inc Dopamine

I have highlighted the instances where dopamine release is stimulated, and indeed we

see that the substances of abuse listed here all seem to have an effect on dopamine

levels, which will in turn activate the natural reward pathway. This evidence is further

enhanced by the observation that substances of abuse can lead to cross-tolerance andcross-sensatization (Nestler E. , 2005).

Having said this and pointed out the importance of the dopaminergic pathways and

the increased levels of dopamine during drug administration, there is evidence that the

reward system may collapse under the constant artificial stimulation by drugs of choice

and natural dopamine levels may drop significantly causing a variety of negative

affective states (Esch & Stefano, 2004) (Nestler E. , 2005). It is at this point that other

systems take over.

Conclusion

While all the current evidence seems to demonstrate that there is indeed a commonreward pathway, its not the only place that substances of abuse are active, and it is

doubtful that the effects on the reward pathway are identical. It also seems that while

this reward pathway is responsible for the development of addiction, the chronic state

of addiction probably lies in other systems.

The value in understanding the common reward pathway for substances of abuse and

natural rewards is not so that we can block that reward pathway this would raise


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serious bio-ethical issues but rather so we can prevent the hi-jacking and

modification of this system that moves an individual from the state of being a

substance user or activity partaker to being addicted to it.

Further research in this direction would possibly lead to the development of a

medication that could be used to treat all compulsions and addictive behaviours,

natural or substance induced, possibly developing an addiction vaccine. The big

question is: if such a vaccine were to be developed, who would want to take it?

BIBLIOGRAPHY

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Taber, K., Black, D., Porrino, L., & Hurley, R. (2012). Neuroanatomy of dopamine:

Reward and Addiction.Journal of Neuropsychiatry Clinical Neuroscience .

Volkow, N., Baler, R., & Goldstein, R. (2011). Addiction: Pulling at the Neural Threads of

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