CNS 3 - Antipsychotics Flashcards
What are neuroleptics?
Antipsychotics
What are the 4 main amine neurotransmitters in the CNS?
- Noradrenaline
- Dopamine
- 5HT (serotonin)
- Acetylcholine
What kind of signalling do antipsychotics target?
Dopamine
What kind of signalling do antidepressants target?
Serotonin and some noradrenaline
What kind of behaviours are the amine neurotransmitters associated with?
High level behaviours e.g. cognition, emotions, awareness
Where is the main source of noradrenergic neurons in the brain?
Locus coeruleus
What is the locus coeruleus associated with? (2)
- Wakefulness and alertness (arousal)
- Mood
Why is noradrenaline an aerosol neurotransmitter?
Presynaptic and postsynaptic terminal not closely associated so noradrenaline is released like an aerosol and have a broad influence
What are alpha 1 adrenoreceptors in the brain associated with? (3)
- Motor control
- Cognition
- Fear
Where are alpha 1 adrenoreceptors found in the brain?
Widely distributed
What are alpha 2 adrenoreceptors found in the brain associated with? (3)
- Blood pressure regulation
- Sedation
- Analgesia
Where are beta 1 adrenoreceptors found in the brain? (3)
- Cortex
- Striatum
- Hippocampus
What are beta 1 adrenoreceptors found in the brain associated with? (2)
- Initiating movement
- Learning
Which G protein are beta 1 receptors coupled to?
Gs
Which G protein are alpha 2 receptors coupled to?
Gi
Which G protein are alpha 1 receptors coupled to?
Gq
What are the 3 dopaminergic pathways in the brain?
- Nigrostriatal pathway
- Mesocortical and mesolimbic pathways
- Tuberohypophyseal pathway
Where are the cell bodies in the nigrostriatal pathway located?
Substantia nigra
Where do the neurons in the nigrostriatal pathway extend to?
Striatum
What is the nigrostriatal pathway associated with?
Fine motor control
What pathway degenerates in Parkinson’s disease?
- Nigrostriatal pathway
- Loss of dopaminergic neurons in the substantia nigra
Where are the cell bodies in the mesolimbic and mesocortical pathways located?
Ventral Tegmental Area
Where do the neurons in the mesolimbic and mesocortical pathways extend to?
Cortex
What are the mesolimbic and mesocortical pathways associated with? (3)
- Behavioural effects
- Pleasure-euphoria-reward (motivation)
- Compulsion
Which pathway is associated with addicition and attention deficit disorders?
Mesolimbic and mesocortical pathways
Where are the cell bodies in the tuberohypophyseal pathway located?
Hypothalamus
Where do the neurons in the tuberohypophyseal pathway extend to?
Pituitary
What is the tuberohypophyseal pathway associated with?
Pituitary hormone secretion e.g. prolactin
Which amino acid is dopamine synthesised from?
Tyrosine
What is the rate limiting step in dopamine synthesis?
Conversion of tyrosine to DOPA by tyrosine hydroxylase
How is dopamine synthesised?
- Tyrosine converted to DOPA by tyrosine hydroxylase
- DOPA converted to dopamine by DOPA decarboxylase
How is Parkinson’s disease treated?
L-dopa drug which can cross the blood-brain barrier and is converted into dopamine by DOPA decarboxylase to increase dopamine concentrations in the brain
Why can’t dopamine itself be given to Parkinson’s patients?
Dopamine can’t cross the blood-brain barrier but L-dopa can
What enzymes will be expressed in dopaminergic neurons? (2)
- Tyrosine hydroxylase
- DOPA decarboxylase
What enzymes will be expressed in noradrenergic neurons? (3)
- Tyrosine hydroxylase
- DOPA decarboxylase
- Dopamine beta hydroxylase
What is dopamine the precursor molecule for?
Noradrenaline
What is noradrenaline the precursor molecule for?
Adrenaline
Which enzyme do dopaminergic neurons NOT express?
Dopamine beta hydroxylase
What kind of receptors are dopamine receptors?
G protein coupled
How is dopamine action terminated?
- Dopamine reuptake transporters
- Breakdown by MAO or COMT enzymes
What are the 2 main products of dopamine metabolism?
- HVA
- DOPAC
Why are HVA and DOPAC important?
Their levels are measured in the clinic to determine if there are issues with dopaminergic transmission in a patient
Which dopamine receptors are coupled to Gs? (2)
- D1
- D5
Which dopamine receptors are coupled to Gi? (3)
- D2
- D3
- D4
Where in the brain are D1 receptors found?
Cortex
What inhibitory effects do D2 receptors have aswell as the normal Gi inhibition of adenylate cyclase? (2)
- Activate K+ channels to prevent APs
- Inhibit Ca2+ channels to prevent Ca2+ influx
How are D2 receptors autoinhibitory?
They reduce excitability of dopaminergic neurons and reduce dopamine release
Where in the brain are D2 receptors found?
Pituitary
What does inhibition of D2 receptors in the pituitary cause?
Increased prolactin secretion
How do amphetamines work?
- Taken up into neurons and displace dopamine and noradrenaline from vesicles
- Dopamine and noradrenaline build up in the cytosol which causes the reuptake transporters to work in reverse to get rid of it
- Causes increased dopaminergic and noradrenergic signalling independent of APs
How does cocaine work?
- Inhibits the reuptake transporters for dopamine and noradrenaline
- Causes increased dopaminergic and noradrenergic signalling independent of APs
What are the effects of taking amphetamines/cocaine? (3)
- Increased motor activity
- Activation of reward pathways
- Euphoria
What are therapeutic uses for amphetamines/cocaine? (2)
- Increase wakefulness in narcolepsy
- Increase focus in ADHD
What are the 2 types of schizophrenia symptoms?
- Positive
- Negative
What are the positive symptoms of schizophrenia? (8)
- Hallucinations
- Delusions
- Paranoia
- Attention deficits
- Bizarre behaviour
- Aggression
- Stereotyped movements
- Catatonia
What are the negative symptoms of schizophrenia? (4)
- Blunting of emotions
- Withdrawal from society
- Anhedonia
- Reluctance to perform everyday tasks
What kind of symptoms are seen in young schizophrenia patients?
Mainly positive symptoms, negative symptoms increase with age
What may accompany schizophrenia symptoms? (4)
- Cognitive defects (attention, memory)
- Anxiety
- Depression
- Suicide attempts
What are risk factors for developing schizophrenia? (3)
- Abnormalities which disrupt normal brain development
- Genetic predisposition
- Consumption of cannabis in adolescence
How are the positive symptoms of schizophrenia treated?
D2 antagonists
How does ketamine work?
NMDA receptor antagonist
What signalling pathways other than dopamine might be involved in schizophrenia? (2)
- Glutamate (NMDA antagonists produce psychotic symptoms e.g. ketamine)
- Serotonin (5HT2A agonists produce psychotic symptoms e.g. LSD)
How does LSD work?
5HT2A receptor agonist
Which pathway is overactive in schizophrenia? (3)
- Mesolimbic pathway
- Increased D2 activity
- Associated with positive symptoms
Which pathway has decreased activity in schizophrenia? (3)
- Mesocortical pathway
- Decreased D1 activity
- Associated with negative symptoms
What is the evidence for the dopamine theory of schizophrenia? (4)
- Amphetamines increase dopaminergic signalling and cause schizophrenic-like behaviour
- Parkinson’s patients treated with L-dopa have hallucinations as a side effect
- D2 agonists induce stereotypic behaviours in animals
- Dopamine antagonists control positive symptoms
What does reserpine do?
- Blocks dopamine storage
- Depletion of amine transmitters
How do antipsychotic drugs work?
D2 receptor antagonists
What occupancy of D2 receptors is needed to decrease positive symptoms?
80%
What are the 2 types of antipsychotics?
- First generation (typical/conventional)
- Second generation (atypical)
What are examples of first generation antipsychotics? (2)
- Haloperidol
- Chlorpromazine
What are the problematic side effects of first generation antipsychotics? (2)
- Motor disturbances (Parkinson’s like)
- Prolactin secretion
What are examples of second generation antipsychotics? (2)
- Clozapine
- Risperidone
Why are second generation antipsychotics favoured over first generation?
Fewer extrapyramidal side effects
What are some unwanted side effects of antipsychotics? (4)
- Irreversible dyskinesia
- Weight gain
- Hypotension
- Sedation
