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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

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Neurotransmitters Norepinephrine (NE) Serotonin (5-HT) Dopamine (DA) Acetylcholine (ACh)

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Neurotransmitters Norepinephrine (NE) Serotonin (5-HT) Dopamine (DA) Appetite Parkinson's Disease Depression Anxiety Schizophrenia Addiction

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Neurotransmitters Norepinephrine (NE): mood (Anxiety, Depression ); appetite Serotonin (5-HT): mood, appetite, sleep, Anxiety, Depression Dopamine (DA) : movement; behavior; mood; perception Schizophrenia, Parkinson's Disease and Depression Acetylcholine (ACh): wakefulness, cognition (memory and learning) - Alzheimer's Disease, Huntington's Disease, REM Sleep

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Serotonin

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Norepinephrine

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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