Dopaminergic Neurotransmission & Dopaminergic Drugs Flashcards
Sites of dopamine in the brain
Cells in SN → striatum - nigrostriatal pathway - regulation of motor function
Cells in ventral tegmental area → nucleus accumbens, frontal cortex & amygdala (mesolimbocortical pathway) - REWARD - make actions pleasurable - eating, drinking, procreating, caring for young - dysfunctional in schizophrenia
Cells in ventral hypothalamus → median eminence and pituitary gland (tuberohypophyseal system)
Pathway that’s dysfunctional in schizophrenia
Mesolimbocortical pathway
(REWARD)
Synthesis, storage, release, termination, metabolism of dopamine
- Tyrosine is taken into neuron via carrier mediated transport
- Tyrosine is converted to dopamine in 2 steps catalysed by tyrosine hydroxylase and DOPA decarboxylase
- Dopamine is actively packaged into vesicles by an amine transporter
- Release is via classical Ca2+ mediated exocytosis
- Termination is via uptake by a dopamine transporter
- Degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase
Degradation of dopamine
Monoamine oxidase
Aldehyde dehydrogenase
catechol-o-methyltransferase
Receptor targets of dopamine
D1 type receptors
D2 type receptors
D1 type receptors
D1 - Gs (AC and increased cAMP)
D5 - Gs (AC and increased cAMP)
D2 type receptors
D2, D3, D4 via Gi (AC and decreased cAMP)
OR
Gq (PLC and increased IP3/DAG)
Gs
AC and increased cAMP
Gi
AC and decreased cAMP
Gq
PLC and increased IP3/DAG
Effect of activation of D1 type receptors
Causes excitation of post-synaptic neuron
Effect of activation of D2 type receptors
Widespread
Located both presynaptically and postsynaptically
Mostly inhibitory effects on presynaptic and postsynaptic neurons e.g. D2 receptors can be presynaptic inhibitory receptors and/or presynaptic inhibitory autoreceptors (on dopamine neurons themselves) suppressing release of dopamine from dopaminergic neurons
Also stimulates or inhibits hormone release
Dopamine is required for
Motor control - nigrostriatal pathway
Controls voluntary movement
Mediating effects of rewarding stimuli - mesolimbical pathway
Dopamine mediates the hedonic impact of natural reward (especially nucleus accumbens)
Neuroendocrine function - tuberohypophyseal pathway
dopamine inhibits prolactin and stimulates growth hormone secretion
Side effect of anti-schizophrenic drugs
inhibition of prolactin
stimulation of GH secretion
Parkinsons
Loss of dopaminergic nigrostriatal neurons and subsequent loss of striatal dopamine is what underlies this disease - dopamine replacement is first line therapy - L-DOPA
Schizophrenia
Drugs which release dopamine (e.g. amphetamine) can cause schizophrenia like symptoms
Hyperactivity of mesolimbocortical DAergic pathway has been implicated in schizophrenia
Dopamine antagonists (especially D2 receptor) are used to treat this disorder
Target for anti-scizophrenic drugs
D2 receptor dopamine antagonists
MOA amphetamine
Release DA
MOA cocaine
Block DA reuptake
Symptoms of parkinsons
Tremor at rest
Muscle rigidity
Bradykinesia
Prevalence of Parkinsons
Affects 1% of population over 65
Pathophysiology of Parkinsons
Associated with degeneration of dopaminergic neurons of the nigrostriatal pathway and formation of Lewy bodies (misfolding proteins containing alpha-synuclein)
Consequent loss of dopamine from the striatum is what underlies the motor symptoms
Symptoms only manifest after 60% of nigral dopamine neurons have already degenerated and 80% of striatal dopamine has been lost
Main MOA of PD symptom-treating drugs
Replace dopamine - L-DOPA
Inhibit dopamine metabolism - COMT inhibitors, MAO inhibitors
Mimic dopamine action - dopamine receptor agonists
Release dopamine
Apart from enhancing dopamine transmission, how else is Parkinsons treated
Using drugs that block muscarinic ACh receptors
Most effective treatment for Parkinsons
Dopamine replacement - L-DOPA
Usually given with a DOPA decarboxylase inhibitor that is unable to cross the BBB (carbidopa, benserazide) so that conversion to dopamine only occurs in the brain, thus reducing peripheral side effects
Effectiveness wears off - intact dopamine neurons are at least partially required for its effectiveness
Main side effects of levodopa treatment
Dyskinesias
- Abnormal involuntary movements affecting face and limbs
- Manifest in the majority of patients within 2 years of starting levodopa therapy
- Can be reduced by lowering the dose but this causes symptoms to reappear
On-off effects
- rapid fluctuations in clinical state where symptoms reappear suddenly and can last for mins → hrs
- Reason is unclear but may relate to changes in plasma levodopa concentrations
how is dopamine metabolism inhibited
MAO-B inhibitors
COMT inhibitors
MAO-B inhibitor
Selegiline
COMT inhibitor
Entacapone
Dopamine receptor agonists
Non-selective dopamine receptors agonists
Slightly selective D2 receptor agonists
Selective D2 receptor agonists
Non-selective dopamine receptors agonist
apomorphine
Slightly selective D2 receptor agonists
Bromocriptine
Pergolide
Cabergoline
Selective D2 receptor agonists
Pramipexole
Ropinrole
Muscarinic cholinergic antagonists
MOA
Trihexyphenidyl
Benztropine
Cholinergic interneurons in the striatum oppose the effects of dopamine blocking their actions - partly overcomes the loss of dopamine
Prevalence of schizophrenia
When does it manifest
1% of population
Men - appears in late teens/early 20s
Women - appears in late 20s/early 30s
what type of disorder is schizophrenia
Neurodevelopmental in which certain brain structures (especially cerebral cortex) do not develop properly
disease can be
relapsing and remitting
chronic and progressive
Clinical symptoms of schizophrenia - POSITIVE SYMPTOMS
Delusion
Hallucinations
thought disorder
Abnormal behaviour
(more drugs to treat positive symptoms)
Negative symptoms of schizophrenia
Withdrawal from society
Flattening of emotional response
Anhedonia
Apart from + and -ve symptoms, what are other symptoms of schizophrenia
Deficits in cognitive function e.g. attention/memory
anxiety
guilt
depression
self-punishment (up to 50% of suicide attempts)
NT systems implicated in schizophrenia
Dopaminergic system - most evidence in favour
Glutamatergic system
(drugs came first - neurochemical theory came after)
ALSO
serotonergic system
noradrenergic system
Dopamine hypothesis for schizophrenia
Overactivity in the dopaminergic system leads to disease
BASED ON 2 OBSERVATIONS
- All anti-schizophrenic drugs act as antagonists at dopamine receptors and clinical potency correlates with D2 receptor affinity
- Amphetamine (which releases dopamine from neurons) causes schizophrenia like symptoms in users
MOA of all anti-schizophrenic/antipsychotic drugs
Antagonists of dopamine D2 receptors
may also affect noradrenergic, histaminergic, cholinergic, serotonergic systems (hence side effects)
5-HT receptors and anti-psychotic drugs
Can act as antagonists at 5-HT2A receptors
agonists at 5-HT1A receptors
provides clinical benefit or a reduced side effect profile
MOA of anti-schizophrenic drugs - acute
Blocking the effects of dopamine released from the mesolimbic pathway accounts for antipsychotic effects - reduced positive symptoms
Blocking the effects of dopamine released from nigrostriatal pathways accounts for the side effects
clinical efficacy correlates strongly with affinity for D2 receptor
Antipsychotic effects require 80% block of D2 receptors
Proportion of D2 receptors that must be blocked in order to see antipsychotic effects
80%
MOA of anti-schizophrenic drugs - chronic
clinical effects take weeks to develop => acute pharmacological effects cannot account for their antipsychotic activity
antipsychotic drugs initially transiently increase the activity of dopaminergic neurons
their longer term effect is to decrease the activity of DAergic neurons
Anti-schizophrenic drug - chronic
Haloperidol
Synonyms for anti-schizophrenic drugs
Antipsychotic drugs, neuroleptic drugs and major tranquillisers
Effectiveness of antipsychotic drugs
what do they treat in schizophrenia
only effective in 70% of patients - 30% are treatment resistant
They can only control the positive symptoms of schizophrenia
they do not control the negative symptoms - while occurence of delusions/hallucinations can be suppressed, schizophrenia patients remain withdrawn and emotionally flattened
Classical/typical antipsychotics
Chlorpromazine
Haloperidol
Thioradazine
Flupenthixol
Recently developed/atypical antipsychotics
Sulpiride
Clozapine
Risperidone
Sertindole
Quetiapine
Distinction between typical and atypical schizophrenia
incidence of side effects - atypical < typical
efficacy in treatment resistant patients - atypical > typical
Efficacy against negative symptoms - atypical > typical
Receptor profile (atypical more selective for dopamine D2 receptor)
Side effects of anti-schizophrenic drugs
Blocking the effects of striatal dopamine from nigrostriatal pathway leads to motor disturbances (extrapyramidal)
Acute dystonia
parkinsons like syndrome with involuntary movements
common in first few weeks of treatment - acute
reversible on stopping treatment
Tardive dyskinesia
Severe disabling involuntary movements affecting face and limbs
occur after months or years of treatment (tardive)
often gets worse on stopping treatment
→ the occurence of motor side effects is less frequent with the newer atypical anti-psychotics
Consequences of blockage of tuberohypophyseal pathway
Leads to hormonal imbalances
Increase in plasma prolactin conc
dopamine via D2 receptor is responsible for inhibiting prolactin secretion
blocking these receptors causes an increase in plasma prolactin conc
causes breast swelling, pain and even lactation (gynecomastia) in men and women
receptors, apart from dopamine, affected by neuroleptics
Histamine
Cholinergic muscarinic
α adrenoceptors
Side effects of neuroleptics
- Sedation - H1 block - causes daytime drowsiness and difficulty in concentrating
- Anticholinergic effects - muscarinic block - dry mouth, constipation, blurred vision, urinary retention
- Postural hypotension - α adrenoceptor block
- Neuroleptic malignant syndrome - muscle rigidity, fever, autonomic instability, delerium
- Miscellaneous reactions - jaundice, urticaria (hives), leucopenia/agranulocytosis (reduction in WBCs), antipsychotic malignant syndrome
