Antipsychotics Flashcards
what are the 4 amine transmitters in the CNS?
- noradrenaline
- dopamine
- serotonin
- acetylcholine
what are the properties of the amine transmitters in the CNS?
Where are they found in the brain
What behavior are amines responsible for
- localised to small populations of neurons with cell bodies in the brainstem and basal forebrain
- associated with high level behaviours e.g. emotion, cognition and awareness
antipsychotics and antidepressants exert their actions by interfering with amine transmission
what are the functional aspects of noradrenaline transmission?
- alpha1 receptors (Gq) widely distributed: involved in motor control, cognition and fear
- alpha2 receptors (Gi): involved in regylation of blood pressure, sedation and analgesia
- beta1 receptors (Gs) found in cortex, striatum and hippocampus: contribute to long-term effects of antidepressants
which brain area produces noradrenaline?
locus coeruleus
- linked with behavioural arousal, wakefulness and alertness
- deficiency of NA production is linked to depression
how is noradrealine metabolised?
- recycled by neuronal reuptake transporters
- broken down by MAO, aldehyde reductase or COMT
where is noradrenaline localised?
10000 cell bodies of noradrenergic neurons found in the locus coeruleus in the pons
- axons give millions of NA terminals to the cortex, hippocampus, hypothalamus, amygdala, thalamus and cerebellum
what are the receptors for noradrenaline?
What type of receptor is it
- all GPCRs the same in CNS and PNS
- widely distributed in the brain
- involved in motor control via cerebellum, cognition via cortex and fear responses via amygdala
what are the functional aspects of dopamine transmission?
- nigrostriatal pathway: fine motor control
- degenerates in Parkinson’s in the substantia nigra - mesocortical and mesolimbic pathways (cell bodies in VTA)
- behavioural effects, stereotypical, pleasure-euphoria-reward, motivation, compulsion - tuberohypophyseal pathway: pituitary hormone secretion e.g. prolactin
what disorders is dopamine involved in?
- Parkinson’s disease
- Schizophrenia
- Attention deficit disorder
- Drug dependence
- Endocrine disorders
what is the distribution of dopamine in the CNS?
- high levels of dopamine in striatum
- forms part of extrapyramidal motor system in cerebellum
- distribution is more restricted compared to NA
how is dopamine synthesised?
- tyrosine is converted into DOPA by tyrosine hydroxylase
- L-DOPA is converted into dopamine by DOPA decarboxylase
tyrosine hydroxylase is the rate limiting amount: if its function increases, amount of dopamine produced increases
leads to production of NA via dopamine beta-hydroxylase and then adrenaline
how is dopamine metabolised?
- COMT and MAO break down dopamine
- reuptake transporters can recycle it too
what is reserpine?
it blocks dopamine storage and leads to depletion of dopamine
used to control positive symptoms of schizophrenia
how can L-DOPA be used to treat Parkinson’s?
dopaminergic neurons do not express dopamine beta-hydroylase
- in parkinson’s, dopaminergic neurons are lost
- L-DOPA can be administered to increase dopamine synthesis, but can produce hallucinations
what are the 2 families of dopamine receptors?
- D1 and D5: Gs-coupled receptors
- stimulate adenylyl cyclase, increase cAMP, PKA and protein phosphorylation
- D1: decreased activity in mesocortical contributes to negative symptoms - D2, D3 and D4: Gi coupled receptors
- inhibit adenylyl cyclse, activate K+ channels, inhibit VGCC, inhibit AP firing and decrease Ca2+ influx into neurons by closing Ca2+ channels
- less dopamine is released from synapse due to less Ca2+ = autoinhibitory receptors
- opposite effects to D1
- D2: increased activity in mesolimbic system to cause positive symptoms
what are the agonists and antagonists of D2 receptors?
agonists = dopamine, apomorphine, bromocriptine, all produce stereotypic behaviour
antagonists = chloroproamzine, haloperidol, sulpiride, clozapine
- treat schizophrenia
where are D2 receptors found and what do they do?
found in pituitary gland and on dopaminergic neurons
- inhibitory autoreceptors
- dopamine inhibits/regulate prolactin release
inhibition of D2 receptors causes increased prolactin secretion
how do amphetamines effect dopamine (DA) and NA transmission?
- stimulate secretion of DA/NA
- they displace DA/NA from vesicles, causing reuptake transporters to work in reverse
- buildup of DA/NA in cytosol causes the transporters to expel the amines into the synaptic cleft, causing greater receptor signalling
amphetamine-like drugs treat narcolepsy and ADHD to stimulate wakefulness and increase concentration, respectively
how does cocaine affect DA and NA transmission?
- inhibits DA transporter so that DA remains in the cleft for longer and has more signalling
- increased signalling leads to increased motor activity
- in animals, there are stereotypic behaviours, activation of reward pathways and euphoric feelings
what is schizophrenia?
- caused by problems in the dopamine system
- symptoms characterised by disturbances in areas of the brain associated with thought, perception, attention, motor behaviour and emotion
what are the positive symptoms of schizophrenia?
D2 receptors implicated - increased activity in mesolimbic pathway:
- Hallucinations (voices) and delusions (paranoid)
- thought disorders (irrational/wild, delusions of grandeur, garbled
sentences)
- defects in selective attention
- bizarre behaviour: aggression, stereotyped movements, catatonia
what are the negative symptoms of schizophrenia?
D1 receptors implicated - decreased activity in mesocortical pathway
- blunting of emotions
- withdrawal from social contacts
- flattening of emotional responses
- anhedonia (cannot feel pleasure)
- reluctance to perform everyday tasks
what are the causes of schizophrenia?
- combination of environmental and genetic factors
- hereditary as a result of abnormalities arising early in life which disrupt brain development
- no single gene is responsible
- consumption of cannabis in adolescence is an environmental factor
what are the structural differences in a schizophrenic brain and a healthy brain?
- schizophrenic brains have larger ventricles and smaller volume of tissue in the left temporal lobe
what drugs can treat schizophrenia?
- D2 antagonists: reduce dopamine signalling to treat positive schizophrenia symptoms
- NMDA agonists
- decreased glutamate signalling by NMDA antagonists (phencyclidine and ketamine) contributes to psychotic symptoms of schizophrenia
- therefore NMDA agonists can reverse these symptoms by increasing glutamate signalling - 5-HT2A antagonists - block serotonin 2a receptors
- serotonin 2a agonists (LSD) produce hallucinations and schizophrenia like symptoms, so serotonin contributes to the disease
- therefore antipsychotics such as 5-HT2A antagonists can block serotonin signalling to treat schizophrenia
what causes the positive symptoms of schizophrenia?
Overactivity of mesolimbic pathway in VTA associated with positive symptoms – projects into amygdala and cortex:
- Increased D2 activity
- In mesolimbic areas, NMDA receptor hypofunction causes increased dopamine signalling, as here the NMDA receptors are inhibitory GABAergic interneurons
what causes the negative symptoms of schizophrenia?
Decreased activity in mesocortical pathway associated with negative symptoms
- D1 receptors implicated
- In mesocortical areas, NMDA receptor hypofunction reduces activity of dopaminergic neurons
what is the dopamine theory of schizophrenia?
- Amphetamine (increases dopamine signalling) produces behaviours similar to acute schizophrenic episode
- Hallucinations are side effect of treating Parkinson’s patients with L-DOPA
- DA release in animals produces stereotypic behaviour
- D2 receptor agonists induce stereotypic behaviours in animals and like amphetamine exacerbate symptoms of schizophrenia patients
- Dopamine antagonists and drugs that block dopamine storage (reserpine) control positive symptoms of schizophrenia and amphetamine-induced behaviours
how is the reduced function of NMDA receptors implicated in schizophrenia?
- Drugs which inhibit these receptors and reduce glutamate signalling (e.g. ketamine and phencyclidine) produce positive, negative and cognitive symptoms
- Transgenic mice with reduced NMDA receptor expression show stereotypical behaviours
give an example of an antipsychotic drug:
dopamine D2 antagonists
- 80% occupancy in brain eeded to decrease positive sympoms
what is the first generation of antipsychotics?
D2 antagonists:
- typical, classical or conventional:
- e.g. chlorpromazine, haloperidol
- Side effects: motor disturbances (extrapyramidal effects) and prolactin secretion
what is the second generation of antipsychotics?
Atypical: NMDA agonists, 5-HT2a antagonists
- E.g. clozapine, risperidone
- Less extrapyramidal side effects
what are the unwanted side effects of antipsychotics?
- Parkinson’s-like symptoms
- Acute reversible dystonias – painful muscle spasms caused by incorrect brain signals
- Slowly developing, irreversible tardive dyskinesia (involuntary movements)
- Increased prolactin release
- Sedation, hypotension, weight gain, dry mouth and blurred vision
what are the new developments in schizophrenia treatments?
- agonist drugs targeting glutamate (mGluR) receptors
- serotonin receptor antagonists
e.g. caplyta: targets serotonin, dopamine and glutamate transmitters in the brain
how is schizophrenia related to dopamine and the striatum?
Muscarinic modulation of striatal dopamine release:
- M4 positive allosteric modulators (PAMs) act on striatal MSNs to specifically inhibit dorsal striatum dopamine release by endocannabinoid signalling
muscarinic antagonists therefore could be useful in treating the disease
