L7 - Drugs Targetting Amine Neurotransmitters

Question 1

What are the symptoms of schizophrenia?

Answer 1

Disturbances in the brain areas associated with thought, perception, attention, motor behaviour and emotion

Question 2

What is the prevalence rate of schizophrenia?

Answer 2

1.1% over the age of 18

51 million people worldwide

Question 3

What are the negative symptoms of schizophrenia?

Answer 3

More prevalent in old people 
Blunting of emotions
Withdrawal from social contacts
Flattening of emotional responses
Anhedonia – inability to take pleasure

Question 4

What are the positive symptoms of schizophrenia?

Answer 4

More prevalent in young people
Hallucinations
Delusions
Thought disorders - irrational, delusions of grandeur, garbaled sentences
Bizarre behaviour - stereotyped movement, aggression, defect in selective attention, catatonia

Question 5

What is 50% of diagnosed schizophrenia associated with?

Answer 5

Cognitive deficits
Anxiety
Depression
Self punishment

Question 6

What are the genetic causes of schizophrenia?

Answer 6

Imbalance of dopaminergic signalling
Hereditary - result of abnormalities which arise early and disrupt normal brain development
No single gene responsible
Structural differences between schizophrenic brain and healthy brain
- Schizophrenic - larger lateral ventricles and smaller volumes of tissue in left temporal lobe

Question 7

What are the environmental causes of schizophrenia?

Answer 7

Cannabis
Drugs that enhance dopaminergic signalling increase positive schizophrenia-like symptoms
Drugs that are antagonists of dopamine receptors (D2) reduce schizophrenia-like symptoms
Role for glutamate signalling - NMDA antagonists and 5 HT2A receptor agonists produce some psychotic symptoms

Question 8

What body functions is dopamine important for?

Answer 8

Movement
Attention
Learning
Reward and reinforcement of addictive drugs

Question 9

What is dopamine affected by?

Answer 9

Primary neurotransmitter affected by cocaine, amphetamines and opiates
Dopamine has actions in schizophrenia and amphetamine-induced psychosis

Question 10

What are the 4 dopaminergic pathways in the CNS?

Answer 10

Nigrostriatal pathway
Mesocortical and mesolimbic pathway
Tuberohypophyseal pathway
Medullary chemoreceptor trigger zone

Question 11

What does the nigrostriatal pathway control?

Answer 11

Fine motor control

Lost in Parkinson’s

Question 12

What does the mesocortical and mesolimbic pathway control?

Answer 12

Behavioural effects, stereotypical, perseverance, pleasure-euphoria-reward, compulsion
Most important pathway for Schizophrenia

Question 13

What does the tuberohypophyseal pathway control?

Answer 13

Pituitary hormone secretion

E.g. Prolactin

Question 14

What does the medullary chemoreceptor trigger zone control?

Answer 14

Nausea and vomiting

D1 receptors play a role here

Question 15

What is excess activity of dopaminergic system associated with?

Answer 15

Schizophrenia
Attention deficit disorder
Drug dependence

Question 16

How is dopamine synthesised?

Answer 16

1. Tyrosine – amino acid in food
2. DOPA – precursor to dopamine
3. Dopamine – precursor to other amine neurotransmitters
   - Very similar structure to the other neurotransmitters
   - Receptors for these neurotransmitters are similar in their ligand binding domain
   
   • Hard to find a drug that will act specifically

Question 17

How is dopamine released?

Answer 17

By exocytosis
Acts on post-synaptic and pre-synaptic receptors
- Pre-synaptic mainly D2

Question 18

How is dopamine destroyed/terminated?

Answer 18

Enzymes (COMT and MAO) found extracellularly and intracellularly
Action of re-uptake transporters – then broken down enzymatically

Question 19

What symptoms do D2 receptors contribute to?

Answer 19

Increased activity in mesolimbic system contributes to positive symptoms

Question 20

What symptoms do D1 receptors contribute to?

Answer 20

Decreased activity in mesocortical contributes to negative symptoms

Question 21

What are some examples of antagonists of dopamine?

Answer 21

Chlorpromazine
Haloperidol
Clozapine
All used to treat schizophrenia
All act at d2 receptors and other influences side effects

Question 22

What are the side effects of giving L-DOPA to a Parkinsons patient?

Answer 22

Can increase hallucinations

Backing up fact increased dopaminergic signalling leads to schizophrenia

Question 23

What is the role of amphetamines?

Answer 23

Stimulate secretion of dopamine
Inhibit MAO and metabolism of dopamine - accumulation of dopamine in nerve terminals
Displace dopamine from vesicles
Cause re-uptake transporters to work in reverse - dopamine pumped into extracellular space

Question 24

What are the symptoms of amphetamine and cocaine use?

Answer 24

Activation of reward pathways -->  positive symptoms of schizophrenia
Euphoric state 
Stimulation of locomotor activity 
Insomnia 
Increased stamina 
Suppresses appetite 
Increased sympathetic drive 
Neurotoxicity - metabolism of dopamine creates a reactive intermediate 
Physiologically addivtive

Question 25

What are the role of amphetamines and cocaine in terms of dopamine?

Answer 25

Increase dopaminergic transmission

Question 26

Amphetamine-like drugs are used to treat?

Answer 26

Narcolepsy

Attention deficit hyperactivity disorder (ADHD)

Question 27

What is the importance of NMDA antagonists?

Answer 27

Phencyclidine and ketamine

Produce positive and negative psychotic symptoms

Question 28

Dopamine D2 receptors

Answer 28

Antagonists used in the treatment of schizophrenia

80% occupancy to decrease positive symptoms associated with mesolimbic overactivity

Question 29

What are the side effects associated with first generation antipsychotics?

Answer 29

Motor disturbances
Prolactin secretion
Sedation

Question 30

What do antipsychotic drugs target?

Answer 30

Target Dopamine receptors and their signalling pathways

Question 31

What is an example of a group of antipsychotic drugs?

Answer 31

Phenothiazines – e.g. chlorpromazine
Block the effect of D2
Side effects - acute dystonias – reversible
- Chronic drug administration for this leads to tardive dyskinesia
- Muscular twitches - irreversible

Question 32

What are atypical antipsychotic drugs?

Answer 32

Have reduced extrapyramidal side effects

• Sulpiride
• Clozapine
• Rispiridione
• Also effect other types of transmitter systems
  
  • D1, D2, 5HT2a, alpha1, mACh