Neuropathophysiology Synaptic Transmission & Neurotransmitters September 24, 2012 Ashkan Afshin
Transcript
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Neuropathophysiology Synaptic Transmission &
Neurotransmitters September 24, 2012 Ashkan Afshin
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Review Sessions September 17, 20127:30-8:30pmPathogenesis
September 24, 20127:30-8:30pmNeuropathophysiology October 1,
20127:30-8:30pmNeuropathophysiology Format: Questions from last
review session (5 min) Questions from last lecture (10 min) Brief
review of last lecture (15 min)
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Epigenetics & Mutation Epigenetics Changes in gene
expression or cellular phenotype caused by mechanisms other than
changes in the underlying DNA sequence (Epi: over, above, outer)
Mutations Accidental changes in a genomic sequence of DNA
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Actions of the Serotonin
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Serotonin & Norepinephrine
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Dopamine
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Chemical Synapses Allow for one-way transmission of nerve
signals. Are a site of integration of inhibitory and excitatory
input. toxins Are accessible to drugs and toxins.
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Synaptic Transmission
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Neurotransmitters Synthesized in the presynaptic neuron
Localized to vesicles in the presynaptic neuron Released from the
presynaptic neuron under physiological conditions Rabidly removed
from the synaptic cleft by uptake or degradation Presence of
receptor on the post-synaptic neuron. Binding to the receptor
elicits a biological response
Monoamine Theory Depression Depression is linked to low levels
of norepinephrine and/or serotonin. Mania Mania is linked to high
levels of norepinephrine and/or serotonin. Bipolar mood disorder
Bipolar mood disorder is alternating cycles of depression and
mania.
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Treatment of Depression Drugs that increase the level of
norepinephrine and serotonin are used in the treatment of
depression. Major antidepressant drug classes: Serotonin reuptake
inhibitors (SSRIs) Atypical SSRIs Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
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Selective Serotonin Reuptake Inhibitors SSRIs block the
reuptake of serotonin back into the serotonergic nerve endings.
This increases the serotonin available to work on the system. SSRIs
are the preferred treatment for major depression and effective for
PTSD and OCD.
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Selective Serotonin Reuptake Inhibitors Adverse effects: GI
disturbances Dry mouth Sexual dysfunction Headache Nervousness
Insomnia Tremors Decrease appetite Weight gain
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Selective Serotonin Reuptake Inhibitors
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Atypical SSRIs They block reuptake of serotonin and act on
other neurotransmitters and receptors as well. (NE and/or Dopamine)
Like the SSRIs, they have little effect in blocking cholinergic,
adrenergic, or histamine receptors.
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Atypical SSRIs
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MAO Inhibitors
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Monoamine Oxidase Monoamine oxidase (MAO) is an enzyme found in
adrenergic and serotonergic nerve endings. Normal function of MAO
is to break down norepinephrine and serotonin. In mental
depression, there appears to be a decrease in the levels of brain
norepinephrine and serotonin.
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Monoamine Oxidase Inhibitors By inhibiting MAO, these drugs
decrease the amounts of NE and serotonin that are decreased.
Consequently, the MAO inhibitors permit the levels of NE and
serotonin in the brain to increase. They have many drug
interactions; caution must be exercised with use of other
drugs.
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Monoamine Oxidase Inhibitor Disadvantages of MOAIs: Dietary
restrictionstyramine Wine, beer, herring, certain cheeses Adverse
effects: Dry mouth, urinary retention, constipation, blurred
vision, hypotension, weight gain, sexual dysfunction, liver damage
that may be fatal CNS: restlessness, dizziness, insomnia, tremors,
seizures, (intensified with over dosage)
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Monoamine Oxidase Inhibitor Tyramine contained in several food
items needs MAO-A for it's break down. If the patient is taking MAO
inhibitor then there will be great risk of Hypertensive Crisis.
Foods should be avoided: Aged Cheese and most strong tasting
cheeses such as cheddar, but cottage cheese is OK Dark beer and
Wines Processed foods Overripe Fruits, specially Avocados Smoked
and processed meat and chicken Chocolate, does not contain Tyramine
but it does potentiate MAOI effects
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Monoamine Oxidase Inhibitor
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Depression Treatment Monoamine oxidase inhibitors (MAOIs) block
the enzyme that breaks down norepinephrine and serotonin Selective
serotonin reuptake inhibitors (SSRIs) block reuptake of serotonin
by the presynaptic neuron. Eg: Prozac Serotonin-Norepinephrine
reuptake inhibitors block reuptake of both serotonin and
norepinephrine. Some also block dopamine reuptake. Eg:
Wellbutrin
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However, the monoamine hypothesis is not sufficient to explain
major depression Antidepressant drugs are effective in less than
50% of cases of depression. Antidepressants must be used for
several weeks before their effects are seen this suggests a more
complex interaction between the drug and the nervous system.
Antidepressants and mood stabilizing drugs have wide-spread side
effects, suggesting their actions go beyond simply adjusting levels
of monoamines.
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Genetic polymorphisms may explain why some people are more
prone to depression than others. Eg: there are two forms of the
gene for the serotonin transporter. People with the short form of
the gene are more likely to experience depression after a major
life stress (eg: job loss, divorce, etc). Similarly, children who
have experienced abuse or neglect are more likely to become
depressed if they have the short version of the gene.
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Stress-induced alterations to the brain may contribute to
depression. The stress response triggers release of hormones that
affect certain brain regions, including the hippocampus (short-term
memory) and the amygdala (fear). In experimental animals, stress
can lead to changes in the hippocampus that are similar to what is
seen in depression. The same serotonin gene described above appears
to make the amygdala hypersensitive.
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Tricyclic Antidepressants Drugs that block the reuptake of
norepinephrine and serotonin back into the neuronal nerve endings
Produce varying degrees of sedation, anticholinergic effects, and
alpha-adrenergic blocking effects
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Tricyclic Antidepressants
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Psychomotor Stimulants Include the amphetamines and other
closely related drugs Stimulate the CNS by increasing the activity
of norepinephrine and dopamine in the brain (reticular formation)
Used to treat narcolepsy, elevate mood (limited), and increase
psychomotor activity
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Drugs and Dopamine All addictions are thought to involve
dopamine it provides the drive to repeat pleasurable behaviors eg:
smoking, drinking, shopping, etc. Some drugs directly alter
dopamine neurotransmission Methamphetamine causes the release of
large amounts of dopamine Cocaine blocks reuptake of dopamine at
the synapse
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Psychomotor Stimulants Disadvantages: Drug tolerance and
dependence Increase activity of sympathetic nervous system Dry
mouth Rapid heartbeat Increased blood pressure Restlessness
Insomnia
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Psychomotor Stimulants
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Cocaine blocks dopamine reuptake results in feelings of
euphoria
http://www.nida.nih.gov/NIDA_Notes/NNVol13N2/brain.gif
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Methamphetamine use causes permanent damage to the brain
http://www.nida.nih.gov/NIDA_Notes/NNVol15N4/Methamphetamine.html