3. Dopaminergic systems
Five dopaminergic systems or pathways are
important for understanding schizophrenia and
the mechanism of action of antipsychotic drugs:
• mesolimbic-mesocortical pathway
• nigrostriatal pathway
• tuberoinfundibular system
• medullary-periventricular pathway
• incertohypothalamic pathway
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4. Mesolimbic-mesocortical pathway
This is the pathway
most closely related
to behavior and
psychosis.
The mesolimbic-
mesocortical
pathway projects
from cell bodies in
the ventral
tegmentum in
separate bundles of
axons to the limbic
system and
neocortex.
Wikipedia.org
Mesocortical
Mesolimbic
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5. Nigrostriatal pathway
Consists of neurons that
project from the substantia
nigra to the dorsal striatum.
Dorsal striatum includes the
caudate and putamen.
The nigrostriatal pathway is
involved in the coordination
of voluntary movement.
Blockade of D2 receptors in
this pathway is responsible
for extrapyramidal
symptoms (EPS).
Nigrostriatal pathway
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7. Tuberoinfundibular system
The tuberoinfundibular
system arises in the
arcuate nuclei and
periventricular neurons:
releases dopamine into
the pituitary portal
circulation.
Dopamine released by
these neurons
physiologically inhibits
prolactin secretion from
the anterior pituitary. Tuberoinfundibular system
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8. Medullary-periventricular pathway
Consists of
neurons in the
motor nucleus of
the vagus.
These projections
are not well
defined.
This system may
be involved in
eating behavior.
Eating behavior
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9. Incertohypothalamic pathways
Forms connections
from the medial zona
incerta to the
hypothalamus and
the amygdala.
It appears to regulate
the anticipatory
motivational phase of
copulatory behavior
in rats.
Usdbiology.com
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10. Dopamine pathways and systems
Nigrostriatal
Coordination of
voluntary movement
Mesolimbic-mesocortical
Behavior, psychosis
Medullary-periventricular
Eating behavior
Incertohypothalamic
Copulatory behavior
in rats
Tuberoinfundibular
Inhibition of prolactin (PRL)
secretion from the anterior
pituitary
EPSBehavior PRL Food Sex
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11. Dopamine
• Dopamine effects electrical activity in
central synapses and production of the
second messenger cAMP synthesized by
adenylyl cyclase.
• Dopamine-receptor antagonists, such as
chlorpromazine, haloperidol and
thiothixene, block the effect of dopamine
to inhibit the activity of adenylyl cyclase in
the mesolimbic system.
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12. Dopamine receptors and their
effects
II.
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13. Dopamine receptors and their effects
Five dopamine receptors have
been described.
Two separate families: the D1-
like and D2-like receptor groups.
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14. Dopamine receptors and their effects
D1-like receptor group
The D1 receptor is coded by a gene on
chromosome 5.
D1 receptor increases cAMP by GS-coupled
activation of adenylyl cyclase.
It is located mainly in the putamen, nucleus
accumbens, olfactory tubercle and cortex.
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15. Dopamine receptors and their effects
D1-like receptor group
D5 receptor is coded by a gene on chromosome 4.
It also increases cAMP.
It is found in the hippocampus and
hypothalamus.
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16. Dopamine receptors and their effects
D1-like receptor group
The therapeutic potency of
antipsychotic drugs does not
correlate with their affinity
for binding to the D1 receptor.
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17. Dopamine receptors and their effects
D2-like receptor group
The D2 receptor is coded on chromosome 11.
It decreases cAMP by Gi-coupled inhibition of adenylyl cyclase.
This receptor inhibits calcium channels, but opens potassium channels.
It is found both presynaptically and postsynaptically on neurons in the caudate-
putamen, nucleus accumbens and olfactory tubercle.
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18. Dopamine receptors and their effects
D2-like receptor group
D3 receptor is coded by a gene on
chromosome 11.
It also decreases cAMP.
It is located in the frontal cortex,
medulla and midbrain.
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19. Dopamine receptors and their effects
D2-like receptor group
D4 receptors also decrease
cAMP.
These receptors are
concentrated in the cortex.
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21. Dopamine receptors and their effects
• The typical antipsychotic agents block D2
receptors stereoselectively for the most part.
• Their binding affinity is very strongly
correlated with clinical antipsychotic and
extrapyramidal potency.
• The typical antipsychotic drugs must be given
in sufficient doses to achieve at least 60%
occupancy of striatal D2 receptors.
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22. Dopamine receptors and their effects
• Atypical antipsychotic drugs, such as
clozapine and olanzapine, are effective
at lower occupancy levels of 30-50%.
• This is most likely because of their
concurrent high occupancy of 5-HT2A
receptors.
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23. Dopamine receptors and their effects
The typical antipsychotic
drugs produce EPS when
the occupancy of striatal
D2 receptors reaches 80%
or higher.
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24. Aripiprazole
• Aripiprazole causes very high occupancy of
D2 receptors.
• This drug does not cause EPS because it is a
partial D2 receptor agonist.
• Aripiprazole also gains therapeutic efficacy
through its 5-HT2A antagonism and possibly
5-HT1A partial agonism.
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27. Adverse pharmacologic effects of
antipsychotics
Type Manifestations Mechanism
Autonomic
nervous system
Loss of accommodation, dry
mouth, difficulty urinating,
constipation
Muscarinic cholinoceptor
blockade
Central nervous
system
Parkinson´s syndrome,
akathisia, dystonias
Dopamine-receptor
blockade
Tardive dyskinesia Supersensitivity of
dopamine receptors
Toxic-confusional state Muscarinic blockade
Endocrine system Amenorrhea-galactorrhea,
infertility, impotence
Dopamine-receptor
blockade resulting in
hyperprolactinemia
Other Weight gain Possibly combined H1 and
5-HT2 blockade
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29. Psychological effects
• Most antipsychotic drugs cause unpleasant
subjective effects in nonpsychotic individuals.
• People without psychiatric illness given
antipsychotic drugs, even at low doses,
experience impaired performance as judged by a
number of psychomotor and psychometric tests.
• Psychotic individuals may show improvement in
their performance as the psychosis is alleviated.
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30. Psychological effects
• Some individuals with schizophrenia and
bipolar disorder experience marked
improvement of cognition with antipsychotics,
some do not.
• Cognition should be assessed in all patients
with schizophrenia.
• A trial of an atypical agent should be
considered, even if positive symptoms are
well controlled by typical agents.
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32. EEG effects
• Antipsychotics produce shifts in the pattern of EEG
frequencies, usually slowing them and increasing
their synchronization.
• The slowing (hypersynchrony) is cometimes focal or
unilateral, which may lead to erroneous diagnostic
interpretations.
• Some of the neuroleptic agents lower the seizure
threshold and induce EEG patterns typical of seizure
disorders.
• With careful dosage titration, most can be used
safely in epileptic patients.
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34. Endocrine effects
• Older typical antipsychotics, as well as
risperidone and paliperidone, produce elevations
of prolactin.
• Newer antipsychotics olanzapine, quetiapine and
aripiprazole cause no or minimal increases of
prolactin.
• They have reduced risk of extrapyramidal system
dysfunction and tardive dyskinesia: diminished
D2 antagonism.
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36. Cardiovascular effects
• The low potency phenothiazines frequently
cause orthostatic hypotension and
tachycardia.
• Mean arterial pressure, peripheral
resistance and stroke volume are
decreased.
• These effects are predictable from the
autonomic actions of these agents.
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37. Cardiovascular effects
• Abnormal ECG have been recorded,
especially with thioridazine.
• Changes include prolongation of QT
interval and abnormal configurations of the
ST segment and T waves.
• These changes are readily reversed by
withdrawing the drug.
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and clinical pharmacology.
38. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• Wikipedia.org
• Pinterest.com
• Usdbiology.com
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and clinical pharmacology.