Neurobiology and neurochemistry of reward and addictive behaviours

Question 1

Humans engage in behaviours that are rewarding. The pleasurable feelings provide positive reinforcement, so that the behaviour is repeated to ensure we get the same reward again. There are 2 types of reward, natural and artificial. What do these both mean?

Answer 1

• natural = food, sex, water, affection
• artificial = drugs, gambling, alcohol

Question 2

When we talk about substances and their misuse, there is a continuum as laid out below:

Drug Use
Drug Misuse, Abuse
Problematic / Hazardous Drug Use
Harmful Use
Dependent Use

What does drug use mean?

Answer 2

• any psychoactive recreational substance use/ experimental use
• smoking weed for example

Question 3

When we talk about substances and their misuse, there is a continuum as laid out below:

Drug Use
Drug Misuse, Abuse
Problematic / Hazardous Drug Use
Harmful Use
Dependent Use

What does drug misuse/abuse mean?

Answer 3

• any unsanctioned recreational substance use

Question 4

When we talk about substances and their misuse, there is a continuum as laid out below:

Drug Use
Drug Misuse, Abuse
Problematic / Hazardous Drug Use
Harmful Use
Dependent Use

What does Problematic / Hazardous Drug Use mean?

Answer 4

• use of a psychoactive substance at amounts or rates likely to lead to problems
• can be physical or psychological problems

Question 5

When we talk about substances and their misuse, there is a continuum as laid out below:

Drug Use
Drug Misuse, Abuse
Problematic / Hazardous Drug Use
Harmful Use
Dependent Use

What does Harmful Use mean?

Answer 5

• use of a psychoactive substance which leads to harm whether to health, psychological well being, or socially; need not be dependent use

Question 6

When we talk about substances and their misuse, there is a continuum as laid out below:

Drug Use
Drug Misuse, Abuse
Problematic / Hazardous Drug Use
Harmful Use
Dependent Use

What does Dependent Use?

Answer 6

• persistent uncontrolled drug use repeatedly leading to [multiple] harmful consequences
• drinking alcohol to stop themselves entering withdrawal

Question 7

What does addiction mean?

1 - need more of a drug/stimulus to achieve same effects as previously
2 - continue using drug/stimulus despite being aware of the negative consequences
3 - stop taking the drug/stimulus as patient is aware of the negative consequences
4 - normal function of the body is impaired if drug/stimulus is stopped

Answer 7

2 - continue using drug/stimulus despite being aware of the negative consequences
- a compulsive behaviour
- despite negative effects, patient still gets pleasure/positive reward which provides positive reinforcement and behaviour is reinforcing (compulsion)
- loss of control in limiting intake

Question 8

What is Tolerance, also referred to as a hyposensitisation syndrome?

1 - need more of a drug/stimulus to achieve same effects as previously
2 - continue using drug/stimulus despite being aware of the negative consequences
3 - stop taking the drug/stimulus as patient is aware of the negative consequences
4 - normal function of the body is impaired if drug/stimulus is stopped

Answer 8

1 - need more of a drug/stimulus to achieve same effects as previously
- patient does not respond to a substance in the same way, becoming tolerant
- patient seeks a higher dose or stronger drug for same effect

Question 9

What is Dependence?

1 - need more of a drug/stimulus to achieve same effects as previously
2 - continue using drug/stimulus despite being aware of the negative consequences
3 - stop taking the drug/stimulus as patient is aware of the negative consequences
4 - normal function of the body is impaired if drug/stimulus is stopped

Answer 9

4 - normal function of the body is impaired if drug/stimulus is stopped
- can present with physiological symptoms (alcohol withdrawal)

Question 10

When we talk about harm associated with substance abuse disorders, there are 3 main types; pain, dependence and social. What are the 3 types of pain?

1 - acute, subacute and chronic
2 - early, middle and late
3 - acute, chronic and intravenous drug user

Answer 10

3 - acute, chronic and intravenous drug user
- acute = harm following a single use of a substance/drug
- chronic = harm due to regular use of a substance/drug
- intravenous drug user =high rate of toxicity

Question 11

When we talk about harm associated with substance abuse disorders, there are 3 main types; pain, dependence and social. What are the 3 types of dependence?

1 - acute, subacute and chronic
2 - pleasure intensity, tolerance and dependence, psychological addiction
3 - acute, chronic and intravenous drug user

Answer 11

2 - pleasure intensity, tolerance and dependence, psychological addiction
- intensity of pleasure = drugs that induce immediate euphoria
- tolerance and dependence = stronger drug dose required for euphoric effects
- psychological addiction = cravings for drug

Question 12

When we talk about harm associated with substance abuse disorders, there are 3 main types; pain, dependence and social. What are the 3 types of social harm?

1 - acute, subacute and chronic
2 - pleasure intensity, tolerance and dependence, psychological addiction
3 - acute, chronic and intravenous drug user
4 - intoxication, social harms, cost to economy

Answer 12

4 - intoxication, social harms, cost to economy
- intoxication = harm to persons or property following single use
- social harms = destruction of a social circle (family, friends)
- cost to economy = unemployment, treatment in NHS

Question 13

When we talk about the life cycle of addiction, we need to consider the timescale and the effects. The scale for both of these is:

• acute drug use
• chronic drug use
• short term abstinence
• long term abstinence

When we think about time scale, how do we apply the above to a timescale for the life cycle of addiction? (for example is chronic drug use days or minutes)

Answer 13

• acute drug use = minutes/hours
• chronic drug use =days/year
• short term abstinence = hours days
• long term abstinence = days/years

Question 14

When we talk about the life cycle of addiction, we need to consider the timescale and the effects. The scale for both of these is:

• acute drug use
• chronic drug use
• short term abstinence
• long term abstinence

When we think about the effect, how do we apply the above to an effect for the life cycle of addiction?

Answer 14

• acute drug use = reward/replacement
• chronic drug use = tolerance/dependance
• short term abstinence = withdrawal (tremors, GI disorders)
• long term abstinence = cravings/relapse (synaptic re-modelling)

Question 15

What is the mesolimbic pathway, also referred to as the reward pathway?

1 - a dopaminergic pathway in the brain involved in positive reinforcement
2 - a glutaminergic pathway in the brain involved in positive reinforcement
3 - a sertoninergic pathway in the brain involved in positive reinforcement
4 - a acetylcholinergis pathway in the brain involved in positive reinforcement

Answer 15

1 - a dopaminergic pathway in the brain involved in positive reinforcement

Question 16

The Mesocorticolimbic pathway is considered to be part of the wider cortico-basal ganglia-thalamo-cortical loop [CBGTC]. What components of the brain make up the CBGTC?

1 - cortex, cerebellum, basal ganglia
2 - cortex, thalamus and brain stem
3 - cortex, brain stem and basal ganglia
4 - cortex, basal ganglia and thalamus

Answer 16

4 - cortex, basal ganglia and thalamus

Question 17

What are positive and negative valenced emotions, which is involved in the mesocorticolimbic pathway?

Answer 17

• positive = intrinsic attractiveness/goodness
• negative = averseness/badness of an event, object, or situation
• essentially positive or negative emotions

Question 18

What is the start of the mesolimbic pathway?

1 - ventral tegmental area
2 - substantia niagra
3 - pituitary gland
4 - hypothalamus

Answer 18

1 - ventral tegmental area
- nucleus accumbens (main dopamine nucleus)
- located in the midbrain

Question 19

The ventral tegmental area (VTA), located in the midbrain is the start of the mesocorticolimbic pathway. What is the VTA?

Answer 19

• a group of neurons located close to the midline on the floor of the midbrain

Question 20

The ventral tegmental area (VTA), located in the midbrain is the start of the mesocorticolimbic pathway. The VTA is a group of neurons located close to the midline on the floor of the midbrain. VTA is the start of the mesolimbic pathway, where does it travel to next?

1 - nucleus accumbens
2 - substantia niagra
3 - pituitary gland
4 - hypothalamus

Answer 20

1 - nucleus accumbens

Question 21

What is the difference between the mesolimbic and mesocortical pathways?

Answer 21

• mesolimbic = middle (midbrain) and limbic systems
• mesocortical = middle (midbrain) and cortical regions (outer brain areas)

Question 22

What is the cingulate gyrus?

Answer 22

• an arch-shaped bulging of the cerebral cortex
• located above the corpus callosum
• described as the limbic cortex (involved in emotions and memory), influences emotionally enhanced memories

Question 23

The ventral tegmental area, nucleus accumbens, prefrontal cortex and the cingulate gyrus are all involved in the mesocorticolimbic pathway. What other 2 key subcortical structures are involved in brain?

1 - amygdala and hippocampus
2 - amygdala and thalamus
3 - brain stem and hippocampus
4 - amygdala and pons

Answer 23

1 - amygdala and hippocampus

Question 24

The image below illustrates the normal pathway for reward and reinforcement based on natural reinforces, such as food and sex. Why is understanding this pathway important for addiction, tolerance and dependance?

Answer 24

• addictive drugs can hijack this system
• BUT worse they provide an even greater positive valence than natural rewards (greater positive feeling), meaning they may be more likely to increase the risk of them repeating this regularly

Question 25

The Nucleus Accumbens, which is part of the mesocorticolimbic pathway is important in processing of cognitive processing of motivation and reward, such as pleasure and re-enforcement. What are a few examples of non-natural pathways that can activate the natural pathway for reward and reinforcement seen below?

Answer 25

• cannabis/weed
• opioids
• alcohol

Question 26

The Nucleus Accumbens (NA), which is part of the mesocorticolimbic pathway is important in processing of cognitive processing of motivation and reward, such as pleasure and re-enforcement. The NA can be stimulated in the anticipation to reward, what is the size of the stimulation of the NA relative to?

1 - the size of the potential reward
2 - the duration of the potential reward
3 - the intensity of the potential reward

Answer 26

1 - the size of the potential reward
- dopamine is released in anticipation of the receiving the reward
- the bigger the reward the bigger the stimulation required

Question 27

When we think about the reinforcement system we are aware that there is direct reinforcement from a stimulus, where something good has just occurred and we learn from this experience, and we are more likely to do this again. This is then able to strengthen neural connections between neurons detecting the stimulus and the neurons that produce the instrumental response, called long term potentiation. This is called associative learning (like with the dog, food, bell and saliva). Using cocaine as an example, how does this work?

Answer 27

• patient takes cocaine in a nightclub
• patient then associated going to a nightclub with taking cocaine
• clinically important as if someone in remission from cocaine goes to a nightclub they are more likely to relapse

Question 28

Drug dependance, which is where a patients normal functioning (or at least normal for the patient) is dependent on the drug that they are taking. Drug dependence has been shown to cause homeostatic neuronal adaptations (changes in normal neuronal function due to the stimulus) to the drug. What can this then cause in the brain and result in?

Answer 28

• synaptic plasticity (changes in neuronal connections)
• associative learning processes (reward and feeling good is associated with drug use)
• for example fight or flight system switched on with the drug, but if drug stops the body is still in fight or flight mode

Question 29

Long term potentiation is when a synaptic connection is constantly stimulated, For example, NMDA and AMPA glutamate receptors are stimulated. Extended opening of NMDA receptors increases intracellular Ca2+. The increased intracellular Ca2+ signals for the increase of AMPA receptors on the membrane, More receptors on the membrane makes them more sensitive to glutamate and more likely to cause an action potential. Which dopamine receptors are involved in long term potentiation?

1 - D1 receptors
2 - D2 receptors
3 - D3 receptors
4 - D4 receptors

Answer 29

1 - D1 receptors

Question 30

Dopamine D1 receptors are involved in long term potentiation through the modification of glutamatergic transmission, which then allows long term potentiation (essentially more glutaminergic receptors are located on the cells membrane). What does this do to the synapses on dendrite spines and branches?

1 - nothing
2 - dendrite number and length increases
3 - synaptic remodelling causing increased number of dendritic spines
4 - synaptic remodelling causing a decreased number of dendritic spines

Answer 30

3 - synaptic remodelling causing increased number of dendritic spines
- more dendritic spines increase the surface area to receive information)

Question 31

Dopamine D1 receptors are involved in long term potentiation in cocaine addiction through the modification of glutamatergic transmission, which then allows long term potentiation. This causes synaptic remodelling (essentially means more dendritic spines that increase surface area to receive information). Even in abstinence do these changes just disappear and what is the importance of them remaining?

Answer 31

• dendritic spines remain for months following abstinence
• memories in these pathways can trigger relapse, hence why its so difficult to remain abstinent

Question 32

In cocaine addiction are there more D1 or D2 dopaminergic receptors?

Answer 32

• D1 receptors
• cocaine activates the reward pathway of mesolimbic system

Question 33

In cocaine addiction there are less D2 dopaminergic receptors. What can this then cause in patients for natural rewards?

Answer 33

• the same thing that may have given them a reward previously cannot compare with cocaine
• patient has to then seek cocaine to ensure the same reward is felt
• this can impact adversely on classic conditioning (memory/learning) and motivational states

Question 34

What is the locus coeruleus, which in Latin means “blue spot”?

1 - nucleus in the pons of the brainstem responsible for dopamine synthesis
2 - nucleus in the pons of the brainstem responsible for the synthesis of norepinephrine
3 - nucleus in the pons of the brainstem responsible for the synthesis of corticol
4 - nucleus in the pons of the brainstem responsible for the synthesis of serotonin

Answer 34

2 - nucleus in the pons of the brainstem responsible for the synthesis of norepinephrine
- principal site for brain synthesis of norepinephrine
- involved in stress and panic (fight or flight response)

Question 35

Opioid receptors are present throughout the mesocorticolimbic pathway, of which the locus coeruleus (LC), which in Latin means “blue spot” is part of. The LC is the principal site for brain synthesis of norepinephrine, a nucleus in the pons of the brainstem that is involved in stress and panic (fight or flight response). Opioids are able to reduce intracellular Ca2+ in the pre-synapse and increase K+ leaving the post-synapse, both of which cause hyperpolarisation. What do opioids generally do to the LC?

Answer 35

• inhibit their firing
• acute opioids = acute inhibition of LC
• chronic opioids = LC neurons return to normal, linked with withdrawal from opioids

Question 36

Opioid receptors are present throughout the mesocorticolimbic pathway, of which the locus coeruleus (LC), which in Latin means “blue spot” is part of. The LC is the principal site for brain synthesis of norepinephrine, a nucleus in the pons of the brainstem that is involved in stress and panic (fight or flight response) and pain. Acute opioid use causes acute inhibition of the LC, but chronic activation of the opioid receptors leads to compensatory functional changes, this can lead to tolerance, why?

• tolerance = desensitisation to a drug, meaning we need more of the drug for the same effects

Answer 36

• LC develops tolerance to the inhibitory effect of opioids
• LC begins firing up-regulates in an attempt to return to normal
• larger doses of opioids are required to inhibit this additional firing from the LC causing tolerance

Question 37

Opioid receptors are present throughout the mesocorticolimbic pathway, of which the locus coeruleus (LC), which in Latin means “blue spot” is part of. The LC is the principal site for brain synthesis of norepinephrine, a nucleus in the pons of the brainstem that is involved in stress and panic (fight or flight response) and pain. Acutely opioids inhibit the LC, but during chronic activation of the opioid receptors on the LC mean the LC goes into overdrive just to get back to normal levels. This can leads to compensatory functional changes and then dependance, why?

Answer 37

• when opioids are stopped the LC is still over active (increased fight of flight response)
• no inhibition of the additional firing of the LC means patient experiences excessive fight or flight
• excessive fight or flight can present physiologically and cause withdrawal symptoms
• this can lead to a disturbance in physical homeostatic when the drug is removed

Question 38

If a patient is addicted to opioids, the aim is for complete absence. However, this is generally not possible and a treatment pathway should be used. What should be the first aim of a treatment plan?

1 - stop the drug and monitor the patient
2 - motivate the patient towards change and involve them in treatment plan
3 - start on a lower dose of opioids and slowly withdraw the drug

Answer 38

2 - motivate the patient towards change and involve them in treatment plan

Question 39

If a patient is addicted to opioids, the aim is for complete absence. However, this is generally not possible and a treatment pathway should be used. The first step is to try and motivate the patient towards change and involve them in treatment plan. What should be the next phase?

Answer 39

• minimise harms related to taking substances
• improve physical and mental health
• reduce criminal activity
• reduce rate of blood-borne infections

Question 40

If a patient is addicted to opioids, the aim is for complete absence. However, this is generally not possible and a treatment pathway should be used. What should be the final phase of any treatment plan?

Answer 40

• stop substance use all together
• if not stopping, then substituting for a safer drug option
• naloxone is the opioid antagonist

Question 41

Alcohol is a suppressant, meaning it is able to reduce neuronal activity. What affected does alcohol have on GABA and glutamate receptors?

1 - GABA and glutaminergic = antagonist
2 - GABA = antagonist and Glutamine = agonist
3 - GABA = agonist and Glutamine = agonist
4 - GABA = agonist and Glutamine = antagonist

Answer 41

4 - GABA = agonist and Glutamine = antagonist
- generally large alcohol can inhibit most voltage gated channels

Question 42

Patients who associate alcohol with a positive valence (which increases dopamine release) and associate with a feeling of reward when consumed will have increased dopamine release from where?

Answer 42

• ventral tegmental area signals to the nucleus accumbens to release dopamine

Question 43

Patients who associate alcohol with a positive valence (which increases dopamine release) and associate with a feeling of reward when consumed will have increased dopamine release from the ventral tegmental area (VTA). What effect does alcohol then have on the VTA?

Answer 43

• NMDA (glutamate) antagonist of cortical inputs disinhibits VTA
• causes increased dopamine release to the nucleus accumbens
• means we continue to want alcohol to get the same effects

Question 44

In acute alcohol use what would we expect to see in GABA-A and NMDA receptors?

Answer 44

• agonist at GABA-A receptors
• antagonist at NMDA receptors
• cells inhibited from firing

Question 45

In chronic alcohol use what would we expect to see in GABA and NMDA receptors?

Answer 45

• down regulation of GABA-A receptors as alcohol is acting as an agonist so we dont need as many
• up-regulation of NMDA receptors as alcohol is an antagonist so we need more to increase sensitivity
• the increased NMDA receptors means the firing of NMDA receptors returns to a normal level as a compensatory mechanism

Question 46

In a patient who has alcohol withdrawal what could we see and why?

Answer 46

• over excitation due to increased NMDA receptors
• alcohol was acting as an antagonist to NMDA receptors, without it they go into overdrive
• physical symptoms (agitation, tremors, confusion, seizures)

Question 47

What are the 3 steps of alcohol dependance?

Answer 47

1 - assessment (history)
2 - pyschoeducation (education, SMART goals)
3 - motivation for change (brief interventions, motiavtional interviewing)

Question 48

What are the 2 initial drugs that can be administered in a patient with alcohol withdrawal?

Answer 48

1 - benzodiazepines (GABA agonist)
2 - oral thiamine

Question 49

Alcohol acts as a suppressant by acting as an agonist of GABA-A. In acute alcohol ingestion alcohol is GABA-A is agonist and an antagonist for the glutamate NMDA receptors. What does this do to the patient?

Answer 49

• increases GABA binding to GABA-A receptors, reducing neuronal activity
• decreases glutamates ability to bind with NMDA receptors and decreasing neuronal activity

Question 50

Alcohol acts as a suppressant by acting as an agonist of GABA-A. In chronic alcohol ingestion what does alcohol do to GABA-A and glutamate NMDA (bound with Mg+) receptors. What happens to the receptors and what does this do to the patient?

Answer 50

• down-regulates the number GABA-A receptors
• down regulation of GABA-A is to increase neuronal firing (leads to tolerance)
• up-regulation of glutamate NMDA receptors
• up-regulation of glutamate NMDA receptors is to increase neuronal firing above the suppression by GABA

Question 51

Alcohol is a suppressant and In chronic alcohol ingestion the following occurs:

down-regulates the number GABA-A receptors
- down regulation of GABA-A is to increase neuronal firing

• up-regulation of glutamate NMDA receptors
• up-regulation of glutamate NMDA receptors is to increase neuronal firing above the suppression by GABA

In chronic alcohol ingestion what happens when the suppressor (alcohol) is removed?

Answer 51

• bodies is primed for hypersensitivity to excitation above normal levels
• physical signs of hypersensitivity can be seen in a patients withdrawal symptoms (agitation, tremors, confusion, seizures)