L7 - Drugs Targetting Amine Neurotransmitters Flashcards
What are the symptoms of schizophrenia?
Disturbances in the brain areas associated with thought, perception, attention, motor behaviour and emotion
What is the prevalence rate of schizophrenia?
1.1% over the age of 18
51 million people worldwide
What are the negative symptoms of schizophrenia?
More prevalent in old people Blunting of emotions Withdrawal from social contacts Flattening of emotional responses Anhedonia – inability to take pleasure
What are the positive symptoms of schizophrenia?
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
What is 50% of diagnosed schizophrenia associated with?
Cognitive deficits
Anxiety
Depression
Self punishment
What are the genetic causes of schizophrenia?
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
What are the environmental causes of schizophrenia?
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
What body functions is dopamine important for?
Movement
Attention
Learning
Reward and reinforcement of addictive drugs
What is dopamine affected by?
Primary neurotransmitter affected by cocaine, amphetamines and opiates
Dopamine has actions in schizophrenia and amphetamine-induced psychosis
What are the 4 dopaminergic pathways in the CNS?
Nigrostriatal pathway
Mesocortical and mesolimbic pathway
Tuberohypophyseal pathway
Medullary chemoreceptor trigger zone
What does the nigrostriatal pathway control?
Fine motor control
Lost in Parkinson’s
What does the mesocortical and mesolimbic pathway control?
Behavioural effects, stereotypical, perseverance, pleasure-euphoria-reward, compulsion
Most important pathway for Schizophrenia
What does the tuberohypophyseal pathway control?
Pituitary hormone secretion
E.g. Prolactin
What does the medullary chemoreceptor trigger zone control?
Nausea and vomiting
D1 receptors play a role here
What is excess activity of dopaminergic system associated with?
Schizophrenia
Attention deficit disorder
Drug dependence
How is dopamine synthesised?
- Tyrosine – amino acid in food
- DOPA – precursor to dopamine
- 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
How is dopamine released?
By exocytosis
Acts on post-synaptic and pre-synaptic receptors
- Pre-synaptic mainly D2
How is dopamine destroyed/terminated?
Enzymes (COMT and MAO) found extracellularly and intracellularly
Action of re-uptake transporters – then broken down enzymatically
What symptoms do D2 receptors contribute to?
Increased activity in mesolimbic system contributes to positive symptoms
What symptoms do D1 receptors contribute to?
Decreased activity in mesocortical contributes to negative symptoms
What are some examples of antagonists of dopamine?
Chlorpromazine Haloperidol Clozapine All used to treat schizophrenia All act at d2 receptors and other influences side effects
What are the side effects of giving L-DOPA to a Parkinsons patient?
Can increase hallucinations
Backing up fact increased dopaminergic signalling leads to schizophrenia
What is the role of amphetamines?
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
What are the symptoms of amphetamine and cocaine use?
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
What are the role of amphetamines and cocaine in terms of dopamine?
Increase dopaminergic transmission
Amphetamine-like drugs are used to treat?
Narcolepsy
Attention deficit hyperactivity disorder (ADHD)
What is the importance of NMDA antagonists?
Phencyclidine and ketamine
Produce positive and negative psychotic symptoms
Dopamine D2 receptors
Antagonists used in the treatment of schizophrenia
80% occupancy to decrease positive symptoms associated with mesolimbic overactivity
What are the side effects associated with first generation antipsychotics?
Motor disturbances
Prolactin secretion
Sedation
What do antipsychotic drugs target?
Target Dopamine receptors and their signalling pathways
What is an example of a group of antipsychotic drugs?
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
What are atypical antipsychotic drugs?
Have reduced extrapyramidal side effects
- Sulpiride
- Clozapine
- Rispiridione
- Also effect other types of transmitter systems
- D1, D2, 5HT2a, alpha1, mACh
