Neuropathophysiology Synaptic Transmission & Neurotransmitters September 24, 2012 Ashkan Afshin

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)

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

Actions of the Serotonin

Serotonin & Norepinephrine

Dopamine

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.

Synaptic Transmission

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

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

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

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

Serotonin

Norepinephrine

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.

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)

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.

Selective Serotonin Reuptake Inhibitors  Adverse effects:  GI disturbances  Dry mouth  Sexual dysfunction  Headache  Nervousness  Insomnia  Tremors  Decrease appetite  Weight gain

Selective Serotonin Reuptake Inhibitors

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.

Atypical SSRIs

MAO Inhibitors

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.

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.

Monoamine Oxidase Inhibitor  Disadvantages of MOAIs:  Dietary restrictions—tyramine  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)

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

Monoamine Oxidase Inhibitor

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

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.

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.

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.

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

Tricyclic Antidepressants

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

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

Psychomotor Stimulants  Disadvantages:  Drug tolerance and dependence  Increase activity of sympathetic nervous system  Dry mouth  Rapid heartbeat  Increased blood pressure  Restlessness  Insomnia

Psychomotor Stimulants

Cocaine blocks dopamine reuptake – results in feelings of euphoria

Methamphetamine use causes permanent damage to the brain