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Dopaminergic Neurotransmission & Dopaminergic Drugs Flashcards

1
Q

Sites of dopamine in the brain

A

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)

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2
Q

Pathway that’s dysfunctional in schizophrenia

A

Mesolimbocortical pathway

(REWARD)

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3
Q

Synthesis, storage, release, termination, metabolism of dopamine

A
  1. Tyrosine is taken into neuron via carrier mediated transport
  2. Tyrosine is converted to dopamine in 2 steps catalysed by tyrosine hydroxylase and DOPA decarboxylase
  3. Dopamine is actively packaged into vesicles by an amine transporter
  4. Release is via classical Ca2+ mediated exocytosis
  5. Termination is via uptake by a dopamine transporter
  6. Degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase
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4
Q

Degradation of dopamine

A

Monoamine oxidase

Aldehyde dehydrogenase

catechol-o-methyltransferase

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5
Q

Receptor targets of dopamine

A

D1 type receptors

D2 type receptors

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6
Q

D1 type receptors

A

D1 - Gs (AC and increased cAMP)

D5 - Gs (AC and increased cAMP)

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7
Q

D2 type receptors

A

D2, D3, D4 via Gi (AC and decreased cAMP)

OR

Gq (PLC and increased IP3/DAG)

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8
Q

Gs

A

AC and increased cAMP

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9
Q

Gi

A

AC and decreased cAMP

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10
Q

Gq

A

PLC and increased IP3/DAG

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11
Q

Effect of activation of D1 type receptors

A

Causes excitation of post-synaptic neuron

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12
Q

Effect of activation of D2 type receptors

A

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

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13
Q

Dopamine is required for

A

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

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14
Q

Side effect of anti-schizophrenic drugs

A

inhibition of prolactin

stimulation of GH secretion

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15
Q

Parkinsons

A

Loss of dopaminergic nigrostriatal neurons and subsequent loss of striatal dopamine is what underlies this disease - dopamine replacement is first line therapy - L-DOPA

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16
Q

Schizophrenia

A

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

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17
Q

Target for anti-scizophrenic drugs

A

D2 receptor dopamine antagonists

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18
Q

MOA amphetamine

A

Release DA

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19
Q

MOA cocaine

A

Block DA reuptake

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20
Q

Symptoms of parkinsons

A

Tremor at rest

Muscle rigidity

Bradykinesia

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21
Q

Prevalence of Parkinsons

A

Affects 1% of population over 65

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22
Q

Pathophysiology of Parkinsons

A

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

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23
Q

Main MOA of PD symptom-treating drugs

A

Replace dopamine - L-DOPA

Inhibit dopamine metabolism - COMT inhibitors, MAO inhibitors

Mimic dopamine action - dopamine receptor agonists

Release dopamine

24
Q

Apart from enhancing dopamine transmission, how else is Parkinsons treated

A

Using drugs that block muscarinic ACh receptors

25
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
26
27
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
28
how is dopamine metabolism inhibited
MAO-B inhibitors COMT inhibitors
29
MAO-B inhibitor
Selegiline
30
COMT inhibitor
Entacapone
31
Dopamine receptor agonists
Non-selective dopamine receptors agonists Slightly selective D2 receptor agonists Selective D2 receptor agonists
32
Non-selective dopamine receptors agonist
apomorphine
33
Slightly selective D2 receptor agonists
Bromocriptine Pergolide Cabergoline
34
Selective D2 receptor agonists
Pramipexole Ropinrole
35
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
36
Prevalence of schizophrenia When does it manifest
1% of population Men - appears in late teens/early 20s Women - appears in late 20s/early 30s
37
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**
38
Clinical symptoms of schizophrenia - POSITIVE SYMPTOMS
Delusion Hallucinations thought disorder Abnormal behaviour (more drugs to treat positive symptoms)
39
Negative symptoms of schizophrenia
Withdrawal from society Flattening of emotional response Anhedonia
40
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)
41
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
42
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
43
MOA of all anti-schizophrenic/antipsychotic drugs
Antagonists of dopamine D2 receptors may also affect noradrenergic, histaminergic, cholinergic, serotonergic systems (hence side effects)
44
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
45
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
46
Proportion of D2 receptors that must be blocked in order to see antipsychotic effects
80%
47
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
48
Anti-schizophrenic drug - chronic
Haloperidol
49
Synonyms for anti-schizophrenic drugs
Antipsychotic drugs, neuroleptic drugs and major tranquillisers
50
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
51
Classical/typical antipsychotics
Chlorpromazine Haloperidol Thioradazine Flupenthixol
52
Recently developed/atypical antipsychotics
Sulpiride Clozapine Risperidone Sertindole Quetiapine
53
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)
54
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
55
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
56
receptors, apart from dopamine, affected by neuroleptics
Histamine Cholinergic muscarinic α adrenoceptors
57
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

Pharmacology (23 decks)

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