Week 5 Topic 3

Question 1

Which three parts of the brain are included in the “Reward Cluster”?

Answer 1

1. Caudate
2. Putamen
3. Nucleus Accumbens

Question 2

Where is dopamine primarily produced in the brain?

Answer 2

Ventral Tegmental Area (VTA)

Dopamine neurons in the ventral tegmental area project to the nucleus accumbens where they release dopamine when activated.

What is also important is to know that VTA neurons are under the inhibitory control of local GABAergic interneurons. So activation of those GABAergic VTA neurons would prevent release of dopamine in the nucleus accumbens by inhibiting VTA dopamine neurons.

Question 3

How does the reward system shape behaviour?

Answer 3

Humans, as well as other organisms, engage spontaneously in behaviours that are rewarding. And they do so because the pleasurable feelings that are associated with the reward provide positive reinforcement, which means that the behaviour is repeated. So we can say that a reward is an appetitive stimulus, that when given to a human or another animal, alters its behaviour by producing positive reinforcement.

Question 4

What are the two categories of rewards?

Answer 4

1. natural (food, water, sex, and nurturing)

2. artificial (drugs of abuse)

Question 5

What are the two primary reward system networks?

Answer 5

1. The ascending mesolimbic dopamine pathway, which connects the ventral tegmental area, VTA, one of the principal dopamine-producing areas in the brain, with the nucleus accumbens. That is an area found in the ventral striatum, which is strongly associated with motivation and reward.
2. The mesocortical pathway, which travels from the VTA to the prefrontal cortex, and is also considered part of the reward system.

Because this pathway is a key detector of a rewarding stimulus, it is an important determinant of motivation and incentive drive. Activation of the pathways tells the individual to repeat what it did to get that reward.

Question 6

What are the primary components of the reward system?

Answer 6

1. The main dopamine pathways (especially the mesolimbic pathway)
2. Structures like the VTA and the nucleus accumbens which are connected by the pathways
3. Neurotransmitters, like dopamine.

Question 7

Evolutionarily speaking, how old is the brain’s rewards system?

Answer 7

It is a very old pathway from an evolutionary point of view. For example, the use of
dopamine neurons to mediate behavioural responses to natural rewards is seen in worms and flies
which have evolved one to two billion years ago.

Question 8

How and when was the brain’s reward pathway discovered?

Answer 8

Its discovery came from pioneering experiences by two scientists, James Olds and Peter Milner, who performed intracranial self-simulation experiments in rats, in 1954. These experiments consisted in implanting electrodes in the brains of rats and allowing the animals to self-stimulate by pressing a lever that delivered a mild burst of electrical current to stimulate the neurons.

What they discovered is that electrical stimulation in certain parts of the brain, particularly in
the septal area, which lies close to the nucleus accumbens, would produce the strongest effects,
making rats to self-stimulate repeatedly. Olds and Milner’s experiments were significant, because
they appeared to verify the existence of brain structures that were responsible for rewarding
experiences. Because if the rats pressed the lever repeatedly to receive stimulation to these areas,
it suggested that the experience was rewarding.

Question 9

Which areas in the brain are the most sensitive to reward stimulus?

Answer 9

It was discovered that some of the most sensitive areas are situated along the length of the medial
forebrain bundle. That is a large collection of nerve fibres that travels between the VTA and the
lateral hypothalamus, and towards the nucleus accumbens.

Some areas of a medial forebrain bundle were found to be so sensitive, that rats would choose
receiving stimulation to them over food or sex. Eventually, it was recognised that dopamine neurons
are activated during this type of rewarding brain stimulation, and researchers found that they could
cause rats to stop press a lever by administering a dopamine antagonist, that is a drug that blocks
the effect of dopamine.

In other words, without the activity of dopamine, the rats were less likely to
find brain stimulation reinforcing, and so they stopped pressing the lever altogether.

Question 10

What do drugs of abuse have to do with the reward system?

Answer 10

As with self-stimulation, the reward pathway is strongly activated by drugs of abuse, who all induce release of dopamine at dopamine terminals, including the nucleus accumbens.

Most drugs abused by humans, which include opiates, ethanol, nicotine, amphetamine, and cocaine, can activate the reward pathway by inducing the release of dopamine in the nucleus accumbens, and have the same dose dependent effect.

The very strong effect of drugs on dopamine release explains why drugs are more addictive than
natural rewards. When some drugs are taken, they can release 2 to 10 times the amount of dopamine
than natural rewards do. This can occur almost immediately, when drugs are smoked or injected. And
the effects can last much longer than those produced by natural rewards.

The resulting effects on the brain’s reward pathway dwarf those produced by natural rewards,
and the effect of such a powerful reward strongly motivates people to take drugs again and again.

Moreover, this deregulated dopamine release affects all the brain circuits, alerting all the brain
regions of novel rewarding experience, and recruiting other neurotransmitter systems.

Question 11

How does simulation of the brain’s reward circuits can teach one to keep taking drugs?

Answer 11

Our brains are wired to ensure that we will repeat life sustaining activities by associating those activities with pleasure or reward. So whenever the reward circuit is activated, the brain notes that something important is happening that needs to be remembered, and teaches us to do it again and again and again without thinking about it.

Because drugs of abuse stimulate the same circuit, we learn to abuse drugs in the same way, and this
is why scientists sometimes say that drug abuse is something we learn to do very, very well.

Question 12

What happens if the reward pathway becomes persistently activated?

Answer 12

Such persistent activation of the reward pathway occurs in the case of chronic drug abusers or even in individuals consuming unusually large quantity of food. To answer this question, scientists have quantified dopamine neurotransmission in the brains of addicted or obese individuals, using positron emission tomography– PET.

They have found that compared to non-addicted or non-obese control subjects, individuals that
were addicted or obese had reduced levels of dopamine D2 and D3 receptors in their striatum.

This shows that new adaptations occur in the brain following over activation with a reward pathway,
and that the brain adjusts to the overwhelming surges in dopamine and other neurotransmitters by
producing less dopamine, or by reducing the number of receptors that can receive signals.

Question 13

What could be the consequences of the neural adaptations of addiction?

Answer 13

A current hypothesis is that dopamine’s impact on the reward circuit could become abnormally low, considerably reducing that person’s ability to experience any pleasure. This would then explain why the chronic drug abuser eventually feels flat, depressed, and unable to enjoy things that previously brought pleasure. So such drug abusers need to take drugs just to try and bring their dopamine function back up to normal. This could also explain why tolerance develop, requiring large amounts of the drug to create the dopamine high.

Question 14

Do ALL reinforcing drugs induce the release of dopamine in the nucleus accumbens?

Answer 14

Yes, but they use distinct mechanisms to do so.

Question 15

How does nicotine act on the reward system?

Answer 15

Nicotine activates VTA dopamine cells directly by banding to nicotinic
acetylcholine receptors that are expressed on their surface, which causes dopamine to be released
in the nucleus accumbens.

Question 16

How do psychomotor stimulants like cocaine and amphetamine act on the reward system?

Answer 16

They increase the concentration of dopamine in
the synaptic cleft in the nucleus accumbens, through direct actions on dopamine transporters at
dopamine terminals.

Question 17

How do opiates act on the reward system?

Answer 17

The rewarding properties of opiates are mediated by their binding to mu-opioid receptors that
are found in two locations in the brain reward circuits. Mu-opioid receptors are expressed on the
GABAergic VTA interneurons, and opioids accurately inhibit these interneurons, causing disinhibition
of the dopamine VTA neurons, and consequently release of dopamine in the nucleus accumbens and
other terminal fields.
Mu-opioid receptors are also expressed on the nucleus accumbens and on dorsal striatal neurons.
Opiates can stimulate these receptors directly, and therefore, produce reward in a dopamine
independent manner.

Question 18

How does alcohol act on the reward system?

Answer 18

It facilitates the release of dopamine in the nucleus accumbens by indirectly activating
dopamine neurons. Alcohol inhibits GABAergic VTA interneurons by binding to gamma aminobutyric
acid A receptors on those neurons, and by facilitating the release of opioid peptides in the VTA. In
addition, alcohol-induced release of opioid peptides in the nucleus accumbens could also produce
reward in a dopamine independent manner.

Question 19

What is the OLD view of dopamine in the reward system?

Answer 19

At one time, dopamine was considered to be the neurotransmitter responsible for causing the experience of pleasure.

Question 20

What are the NEW views of dopamine on the reward system?

Answer 20

Dopamine is now thought to be involved in aspects of reward other than the direct experience of pleasure.

There is experimental evidence that suggests that dopamine is not a hedonic signal, which
means not a pleasure signal, but a signal for motivated behaviour.

A more current view, either dopamine does not cause hedonic reactions or pleasure, but rather
more specifically increases the motivation components of reward, such as incentive salients,
producing wanting or seeking without causing liking or show hedonic impact.

Another major alternative hypothesis is that dopamine causes learning about rewards.

Question 21

What does the cortical basal ganglia circuit, which is at the center of the rewards network, involve?

Answer 21

This circuit involves cortical areas, such as the orbital frontal cortex and the interior cingulate cortex,
that work in concert with basal ganglia structures like the ventral striatum, the ventral pallidum, and
the mid-brain dopamine neurons, to execute motivated, well-planned behaviours.

For example, the ventral striatum receives major cortical input for the orbital frontal cortex and the interior single cortex, and substantial dopaminergic input from the ventral tegmental area and the substantia nigra.

On the other hand, the ventral striatum sends projections through the ventral tegmental area and
substantia nigra, and to the ventral pallidum, which in turn, via the medial dorsal nucleus of the
thalamus, project back to the prefrontal cortex.

Question 22

Which circuits work in tandem with elements of the reward system to develop appropriate goal directed
actions?

Answer 22

The combined interplay of sensory inputs, emotional informations,
and memories of prior outcomes.

For example, a reward pathway tells the memory centres in the
brain, which involve the hippocampus and the amygdala, to pay particular attention to all features of
this rewarding experience so that it can be repeated in the future.

In this respect, the amygdala, which is particularly important for conditioned forms of learning,
interacts with the VTA nucleus accumbens pathway to determine the rewarding or aversive value
of an environmental stimulus. By doing so, it helps an organism establish associations between
environmental cues and whether or not that particular experience was rewarding or aversive– for
example, remembering what was associated with finding food or fleeing a predator.

On the other hand, the hippocampus is critical for declarative memory– the memory of persons,
places, or things. Along with the amygdala, it establishes memories of drug experiences, for example,
which are important mediators of relapse.

Question 23

What is the monitory incentive

delay task, or MID task?

Answer 23

It is a functional neuroimaging task that can be used to measure brain activation patterns that are associated with specific aspects of reward in humans. In this test, subject lay under an MRI scanner that will cause brain activation patterns, while they play repeated trials in which they win or lose money, or any equivalent incentive, depending on their ability to pay attention and react quickly.

This task is the reaction time task, which means that it tests how quickly the subject can react and
pull the trigger to hit a target that only appears for a short time on the screen. If the subject can hit
the target, they will score points. Subject can tell where the target will appear and how many points it
can win by the symbol they see on the screen before each trial. For example, a circle with three lines,
as in this picture, means 10 points. Responding too early or too late will result in a loss.

The subjects receive one incentive– money or equivalent– for points to enhance motivation during
the task. Patterns of brain activity are recorded when a reward is anticipated, that is, after the cue
is given, but before the subject hits the target, or when receiving the outcome. In this task, regions of
the reward system, such as the nucleus accumbens, are activated when a reward is anticipated.

Question 24

How is the MID task to study the reward system at King’s?

Answer 24

One of our aims is to understand how deficits in reward processing is implicated in mental disorders, such as attention deficit hyperactivity disorder, ADHD, and addictions.

First, we have analysed a large sample of 13-year-old adolescents, trying to define clusters of brain
activation patterns in their whole brain, while they anticipated a reward in the MID task. In this way,
we found that not only structure that are associated with the reward pathway were activated during
a reward anticipation in this task, but several of the clusters were also identified. You can see on this
figure the location of these clusters.

One cluster consisted of the caudate, putamen, and nucleus accumbens, that all form part of the
striatum. And this is a cluster that we named the Reward Cluster.

Another cluster that we labelled the Attention Cluster, included areas of the occipital cortex involved
in early visual processing.

Third cluster, the Response Preparation Cluster, including cortical somatosensory and motor areas.

We then explored the relation of these ephemeral clusters with behavioural outcomes that are
relevant for ADHD and addictive behaviours.

We observed that a low activation in the reward cluster is associated with high ADHD related hyperactivity in boys. On the other hand, the Attention Cluster and the Response Preparation cluster, showed significant negative association with lifetime alcohol consumption.

Overall, our results indicate that specific reward-related brain processes relate to distinct and
clinically relevant behaviours. They also indicate that functional collections related to reward
anticipation, such as reward processing, attention processing, and response preparation, are
differentially associated with adolescent ADHD symptoms and alcohol consumption.

Question 25

Which psychiatric disorders were described in the lecture, with regards to the reward system?

Answer 25

Drug addiction, ADHD, and depression.

Question 26

Is dopamine the only neurotransmitter involved in the rewards system?

Answer 26

No. Dopamine is not the only neurotransmitter involved. In fact, we have seen
that the actual network dedicated to creating the feelings we associate with rewarding or aversive
experiences is more complex.

Question 27

What is the rewards system?

Answer 27

The Reward System refers to a group of structures that is involved
in mediating rewarding experiences.

But while it is evident that the mesolimbic dopamine pathway
is implicated in pleasurable and potentially addictive behaviours, the substrates of pleasure are not
confined to this system.