Lecture 12 - Drug action in the CNS - antipsychotics Flashcards
What do amine transmitters in the CNS do?
Found in small populations in specific brain regions
Emotions, cognition & awareness
- Noradrenaline
- Dopamine
- 5-hydroxtryptamine
- Acetylcholine
- Localised to small populations of neurons with cell bodies in the brain stem & basal forebrain
- associated with ‘high level behaviours’ e.g. emotions, cognition and awareness
- many anti-psychotics, known as known ‘neuroleptics’, used in the treatment of schizophrenia
- anti-depressant drugs exert their actions interfering the amine transmission.
What are 3 functional aspects of dopamine?
- Nigrostriatal pathway - fine motor control
- Mesocortical and mesolimbic pathways - behavioural effects, stereotypical, perseverance, pleasure-euphoria-rewards (motivation), compulsion
- Tuberohypophyseal pathway - pituitary hormone secretion - e.g. Prolactin
Describe features of noradrenaline
- A1 receptors widely distributed, involved in motor control, cognition, fear
- A2 involved in regulation of blood pressure, sedation and analgesia
- B1 in cortex, striatum and hippocampus contribute to long term effects of antidepressants
- LC (locus coeruleus) neuronal activity is increased with behavioural arousal, controls wakefulness and alertness, control of mood (deficiency linked to depression)
Describe the process of the creation of adrenaline
Tyrosine (tyrosine hydroxylase) –> DOPA (DOPA decarboxylase) –> Dopamine (dopamine B-hydroxylase) –> noradrenaline (Phenylethanolamine N-methyltransferase) –> Adrenaline
What is dopamine a precursor for?
- Dopamine is precursor to noradrenaline.
- Made in cytosol, then transporters found on vesicle membrane is involved in dopamine transportation.
- Enzymes found inside neurons
What type of receptors does dopamine bind to?
only binds to G-protein receptors
How can measurements of dopamine metabolic products can used to monitor dopamine release in patients
Breakdown products found in the urine, so this can be measured
What are the 2 families of dopamine receptors?
D1 & D5 - Gs coupled receptors, stimulate adenylyl cyclase. Increase cAMP, PKA and protein phosphorylation
D2, D3 & D4 - Gi coupled receptors, inhibit adenylyl cyclase. Activate potassium channels, inhibit VGCC (voltage-gated calcium channels). Oppose effects of D1 receptor activation.
Where are DA (dopamine) receptors in brain?
- dopamine receptors in brain in distinct but overlapping areas
- D2 receptors found in pituitary and on dopamine neurons (inhibitory autoreceptors)
What is associated with unwanted side effects?
Lack of selectivity with dopamine receptor agonists and antagonists
- drugs will increase dopamine release will affect all pathways
What type of transmission does amphetamines and cocaine increase?
- dopamine
- noradrenaline
What do amphetamines do?
Amphetamines stimulate secretion of dopamine and noradrenaline, displace dopamine & noradrenaline, cause re-uptake transporters to work in reverse
What does cocaine do?
Cocaine inhibits dopamine
What does increase dopamine signalling lead to?
increased motor activity
What are amphetamine-like drugs used to treat?
narcolepsy (stimulate wakefulness) and attention deficit hyperactivity disorder (ADHD) - increase concentration
What occurs in animals in the presence of cocaine?
animals’ stereotypical behaviours activation of reward pathways & feelings of euphoria (in the limbic system)
What are symptoms of schizophrenia?
- characterized by disturbances in the area of the brain associated with thought, perception, attention, motor behaviour & emotion
What is the prevalence rate for schizophrenia?
approximately 1.1% of the population over the age of 18 –> at any one time as many as 51 million people worldwide suffer from schizophrenia
- over 250,000 diagnosed cases in the UK
Describe the positive symptoms of schizophrenia
- hallucinations (voices)
- delusions (paranoid)
- thought disorders (irrational/wild delusions of grandeur. garbled sentences)
- Defects in selective attention
- BIzarre behaviour
- Aggression
- Stereotyped movements
- Catatonia (affects movement)
What are the negative symptoms of schizophrenia?
- blunting of emotions
- withdrawal from social contacts
- flattening of emotional responses
- anhedonia (reduced motivation to feel pleasure)
- reluctance to perform everyday tasks
What may happen to ventricles of people with schizophrenia?
Enlarged ventricles
What accompanies schizophrenia?
- cognitive defects (attention, memory)
- anxiety
- depression
- self-punishment
Describe the suicide figures associated with schizophrenia
50% cases - 10% successful
What are the causes of schizophrenia?
environmental &
- found to be hereditary and a result of abnormalities which arise early in life and disrupt the normal development of the brain
- no single gene is responsible
- consumption of cannabis in adolescence is one of the environmental factors
- increase in D2 agonist = schizophrenia (increase in positive symptoms) - antagonist = opposite
What are the structural differences between a healthy brain and a schizophrenia brain?
Schizophrenic brains tend to have larger lateral ventricles and a small volume of tissue in the left temporal lobe. At a microscopic level, see decreased dendritic arborization and spines. Synaptic dysfunction implicated
What do drugs that enhance dopamine signalling lead to?
increase positive schizophrenia-like symptoms, D2 blocking drugs reduce them
What effect can glutamate signalling lead to?
A role for glutamate signalling increase positive schizophrenia-like symptoms, D2 blocking reduces reduce them
What is the neuroanatomical & neurochemical basis of schizophrenia?
- overactivity of mesolimbic pathway associated with positive symptoms - increased D2 activity
- decreased activity in mesocortical pathway associated with negative symptoms - D1 receptors implicated
What is the dopamine theory of schizophrenia?
- amphetamine produces behaviors similar to acute schizophrenic episode
- Hallucinations are side effect of treating Parkinson’s patient with levodopa
- DA release in animals produce stereotypic behaviours
- D2 receptor agonists induce stereotypical behaviours in animals AND like amphetamines exacerbate symptoms of schizophrenia patients
- Dopamine antagonists and drugs that block dopamine storage (reserpine) controls positive symptoms of schizophrenia and amphetamine-induced behaviours
What is the effect of dopamine antagonists on NMDA glutamate receptors?
reduced function of NMDA glutamate receptors
What is produced by drugs which inhibit NMDA receptors?
- e.g. ketmine & phencyclidine - produce positive, negative and cognitive symptoms
Describe animal models used to study schizophrenia
Transgenic mice with reduced NMDA receptor expression show stereotypical behaviours
Animal models used to study schizophrenia and test drugs - used to be amphetamines, but now increasingly use NMDA inhibitors and mutants in gene like DISC-1, which is ONE of the genes implicated.
Describe antipsychotic drugs
- Dopamine D2 antagonists used in the treatment of schizophrenia (80% occupancy of receptors in the brain, is needed to decrease POSITIVE symptoms)
- More than 80 anti-psychotic drugs available for clinical use
- First generation anti-psychotics - referred to as typical, classic or conventional - e.g. chlorpromazine, haloperidol
- Side effects include motor disturbances (Parkinson’s like)(extrapyramidal effects) and prolactin secretion
- Second Generation Antipsychotics - referred to as atypical - e.g. clozapine, risperidone (less extrapyramidal side effects - movement disorders)
What are unwanted effects of antipsychotic drugs?
Parkinson’s like symptoms, acute reversible dystonias, slowly developing irreversible tardive dyskinesia (involuntary movements). Increased prolactin release, sedation, hypotension, weight gain, dry mouth, blurred vision
What is new research surrounding antipsychotic drugs?
allosteric modulators - work on ligand-gated ion channels. Also new research on muscarinic receptors
