Addiction lecture 2

Question 1

Drugs of abuse causes increased levels of ____ in the _____.

Answer 1

Dopamine in the NAcc

Question 2

Explain the relationship between memory, drive, reward and control in the addicted and non addicted brain.

Answer 2

• In the non addicted brain, the control circuit overcomes the drive
• In the addicted brain, the enhanced expectation value of the drug of abuse in reward motivation and memory circuit overcomes the control circuit.
• This is a positive feedback loop that is initiated by consumption of the drug. This lack of control results in more drive to take the drug.

Question 3

The mesolimbic pathway:
Drugs of abuse increase dopamine release in the ___. This dopamine is released from dopaminergic neurones that project from the ___. This dopamine can activate both __ and __ receptors and which each have different intracellular effects. These receptors are found on _______ medium ____ neurones of the NAcc which are involved in reward and reinforcement. They integrate _______ inputs from the cerebral cortex with dopamine inputs from the midbrain. This interaction between ______ and dopamine may underlie _____ - potentially _____ of drug seeking behaviours.

__ receptors are __ coupled and are _____ as they stimulate ____ ____ and ___ the neurone

__ receptors are __ coupled and are _____ as they _____ _____ ____ and ____ the neurone

Answer 3

NAcc
VTA
D1 and D2
GABAergic medium spiny neurones 
Glutamatergic 
Glutamate
Learning
Learning 

G1 receptors are GS coupled and are excitatory as they stimulate adenyl cyclase and excite the neurone

G2 receptors are Gi/O coupled and are inhibitory as they inhibit adenyl cyclase and inhibit the neurone

Question 4

What neurones in the DA seem to feedback on the VTA and what does this do?

Answer 4

Medium Spiny GABAergic neurones in the VTA that are stimulated by D1 receptors seem to feedback on the VTA to act as a negative feedback mechanism to decrease stimulation of dopamine neurones from the VTA that cause a release in dopamine in the NAcc

Question 5

There is a high propensity to relapse after cessation of drug use - based on George Koobs negative effect hypothesis.

Explain the differences between drug effects in drug naive, drug user and dependent users (graphs)

Answer 5

Drug naive:
Patients experience an increase in euphoria from normal baseline levels when they take the substance. When the drug effect wears off they experience a short period of dysphoria. This is where the psychological effects of withdrawal are experienced.

Drug user:
Repeat drug users experience less euphoria than drug naive people when they use drugs of abuse. This is because they have started to build up a tolerance to the drug. When the drug effects wear off they experience more dysphoria

Dependent user:
Dependent users have a reduced baseline level of mood. Thus, they have a different drive to take the drug. Rather than experiencing the positive reinforcement of the drug (taking to feel euphoric), they take the drug due to negative reinforcement (taking to relieve negative symptoms and to get back to a normal level). When they take the drug their mood returns to what used to be a ‘normal’ level. When the drug effects wear off they experience more dysphoria - psychological withdrawal.

Question 6

Psychological effects of withdrawal:

• Repeated withdrawal affects baseline mood and may lead to _____.
• This involves:
• The _______ of stress hormones
• Increased production of ______

Answer 6

Relapse
Production
Dynorphin

Question 7

What is Dynorphin?

Answer 7

• It is an endogenous ligand for the kappa opioid receptor
• It is distributed throughout the brain and spinal cord
• Dysregulation of dynorphin/kappa opioid receptor systems contribute to anhedonia and depressive symptomology
• This is associated with dependence and also drug craving and seeking that is seen in withdrawn addicts

Question 8

KOPr agonists:
They produce ____ in humans and aversive effects in animals.
Conditioned place ____ are observed in response to systemic KOPr agonists
They decrease ___ release so this is the reason for aversive and dysphoric effects.

Answer 8

Dysphoria
AVERSIONS
Dopamine

Question 9

1) stimulation of __ receptor on GABAergic neurone in the NAcc by __ (due to drugs of abuse)
2) The __ receptor is a Gs coupled ____ which activates ____ ____ to increase ____ production which then activates ____ the transcription factor to increase ______ of the protein _____
3) This increase in _____ _____ can last for a few months!
4) ______ acts at kappa opioid receptors on __ neurones and reduces __ release
5) Less __ release causes ______!

Answer 9

1) D1, DA
2) D1, GPCR, Adenyl cyclase, CAMP, CREB, transcription, Dynorphin
3) Dynorphin, transcription
4) Dynorphin, DA, DA
5) DA, Dysphoria!

Question 10

What might kappa opioid antagonists be able to do?

Answer 10

They might be effective ‘anti relapse’ therapies as they can be used to return the addicts mood to baseline. If they are not dysphoric then they will not need experience the negative reinforcement effects of needing to take the drug to alleviate their ‘dysphoric mood’.

Question 11

D2 receptors in the striatum (NAcc)

• Use ___ scanning to show the distribution of [11c] raclopride in the striatum
• [11c] raclopride competes with __ for the __ receptors so some bind __ and others the radioactive ligand
• If there is a decrease in ligand binding then their is either MORE __ competing for the __ receptors or less __ receptors available to bind to!

Answer 11

PET 
DA 
D2
DA
DA
D2
D2

Question 12

Can use PET scans to show distribution of [11c] raclopride in control and cocaine dependent subjects before and after methylphenidate:

What was seen in addicts and what was seen in controls?

Answer 12

At rest in addicts, there were fewer signals from the [11c] raclopride - this suggests that there are fewer D2 receptors in addicts for the ligand to bind. There was also less response seen to methylphenidate

In normal controls, there was more [11c] raclopride activity at rest and more activity with the MP

Question 13

Do addicts start with fewer D2 receptors?
A study in non addicts where they were given methylphenidate. Some liked the effects and others disliked the effects.

Those who liked the effects had: more/less D2 receptors in their ____
Those with more/less D2 receptors in their ____ like the effects of drugs of abuse more and are at more risk of becoming an addict as a result!

So could there be a _____ predisposition to becoming an addict?

Answer 13

LESS D2 receptors in their NAcc

Those with LESS D2 receptors in their NAcc like the effects more

So could there be agenetic predisposition to becoming an addict?

Question 14

____ JW 2007 conducted PET scans in rats. This study was to test ____.

• Some rats were ____ and others weren’t.
• PET scans showed that rats with __ __ receptors in their NAcc were more _____. They took more ____ than those with more ___ receptors.
• Rats with ____ __ receptors in their NAcc were less ____ and took less ____.

This matched the human study in which those who liked drugs of abuse more had fewer D2 receptors in their NAcc.

Answer 14

Dalley JW 2007
Impulsivity

Impulsive
Less D2 receptors 
Impulsive 
Cocaine 
D2 receptors

Less D2 receptors
Impulsive
Cocaine

Question 15

The study by ____ __ et al ____ looked that the effects of chronic _____ use on __ receptor density:

A monkey had the ability to self administer ____ for 1 year. With chronic use of ____ at 6 and 12 months the density of __ receptors in the NAcc shown by ___ scans appears to have _______. SO chronic ___ use appears to ___ __ receptor density in the NAcc. Previous studies showed that those with fewer __ receptors liked the effects of stimulants more then those with more __ receptors.

A limitation of the study is that this might only apply to psychostimulants.

Answer 15

Nader MA et al 2006
Cocaine use on D2 receptor density

Cocaine 
Cocaine 
D2 
PET 
Decreased 
Cocaine 
Decrease D2 
D2 
D2

Question 16

_____ et al ___ showed that polymorphisms (___) in human dopamine D2 receptor gene decreases expression of D2 receptor. It is known that those with ____ D2 receptors might have a greater drive to take rewarding drugs as they like the effects more. There is also some evidence that those with the ___ in their genes are more likely to become an addict.

Hence an interplay between _____ (___ in D2 receptor gene) and _____ (environmental effects on D2 levels) that can influence D2 receptor levels.

It has also been shown that prolonged cocaine intake reduces D2 receptor density.

Answer 16

Zhang et al 2007
SNPs
Fewer
SNP

Nature (SNP)
Nurture

Question 17

‘Rewarding’ environments increase D2 levels and decrease cocaine self administration.

Nader showed that _____ monkeys have higher levels of D2 receptor in their striatum than ____ monkeys. These ____ animals took less cocaine than ____ ones when allowed to self administer.

PET scans showed that putting an animal in an unrewarding cage e.g. _____, no toys, boring food resulted in a ____ in D2 receptor levels and increased cocaine self administration.

Therefore the environment can change the amount of D2 receptors in the brain and influence drug ‘____’. In other words, neurobiological effects occur with changes in rewarding/unrewarding environment.

Answer 17

Dominant
Submissive
Dominant
Submissive

Isolation
Decrease

‘Likability’

Question 18

Rewarding environments increase D2 levels and ____ cocaine self administration. This is demonstrated in the intruder test where an acute stressor is introduced.

What happens here?

Answer 18

1) Cage introduced into pack of monkeys containing a dominant/submissive monkey
2) Dom monkeys throw poo at pack and pack throws poo at monkey if it is submissive
3) In control conditions - dominant monkeys administer less cocaine as they are already rewarded

4) After the intruder test:
Dominant monkey takes even less cocaine (cocaine response curve shifts right).
In contrast, the submissive monkeys that had the poo thrown at them took even more cocaine as they had a higher drive to seek the reward as they were in a miserable, unrewarding environment. Their cocaine dose response curve shifted left and they had reduced D2 levels.

Question 19

Low D2 receptor levels:
Talk through what 2 factors contribute to low D2 receptor levels and the consequences of this. (5 main points)

What is the one slight issue?

Answer 19

1) Environmental factors such as being in unrewarding environments AND genetic factors such as SNPs in gene encoding D2 receptor lead to…
2) Low D2 receptor levels
3) This then results in a low endogenous ‘reward’ tone
4) This then results in enhanced liking of drugs of abuse as low endogenous reward means they want to seek more reward in life
5) Results in increased drug intake which then leads back to reduced D2 receptor levels!

BUT this might only be the case for psychostimulants and is only an idea!

Question 20

Give an example of two drugs that enhance natural reward which might decrease use of drugs of abuse.

Answer 20

Bupropion (NA/DA reuptake inhibitor)
Bromocriptine (partial D2 agonist)

• May be more effective in people with certain D2 SNPs?

Question 21

What do D2 receptors do? Explain.

Answer 21

Activating D2 receptors results in conscious perception of euphoria.

Decreasing the activation of/number of D2 receptors results in less euphoric effect.

These D2 receptors are on the cell body of NA output neuronesand on glutamatergic neurones.

Question 22

The ____ ____ is responsible for the perception of euphoric reward.

It receives input from _____ neurones from the ____ which receives input from GABAergic neurones from the globus ____ which receives input from GABAergic neurones from the ____ where these Gi/O coupled D2 receptors are located!

If there are fewer D2 receptors then the perception of euphoric reward is decreased as the glutamatergic input is reduced. This results in ___ seeking behaviour.

Answer 22

Frontal Cortex

Glutamatergic
Thalamus
Globus Pallidus
NAcc

Drug