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Neuropathophysiology Synaptic Transmission & Neurotransmitters September 24, 2012Ashkan AfshinReview SessionsSeptember 17, 20127:30-8:30pmPathogenesisSeptember 24, 20127:30-8:30pmNeuropathophysiologyOctober 1, 20127:30-8:30pmNeuropathophysiologyFormat:

Questions from last review session (5 min)Questions from last lecture (10 min)Brief review of last lecture (15 min)

Epigenetics & MutationEpigeneticsChanges in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence (Epi: over, above, outer)

MutationsAccidental changes in a genomic sequence of DNA

Actions of the Serotonin

Serotonin & Norepinephrine

ABCDopamine

A

Chemical SynapsesAllow for one-way transmission of nerve signals.Are a site of integration of inhibitory and excitatory input.Are accessible to drugs and toxins.

Synaptic Transmission

Neurotransmitters Synthesized in the presynaptic neuronLocalized to vesicles in the presynaptic neuronReleased from the presynaptic neuron under physiological conditionsRabidly removed from the synaptic cleft by uptake or degradationPresence 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)

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

SerotoninNorepinephrine

Monoamine Theory Depression is linked to low levels of norepinephrine and/or serotonin.

Mania is linked to high levels of norepinephrine and/or serotonin.

Bipolar mood disorder is alternating cycles of depression and mania.

19Treatment of DepressionDrugs that increase the level of norepinephrine and serotonin are used in the treatment of depression.

Major antidepressant drug classes:Serotonin reuptake inhibitors (SSRIs)Atypical SSRIsTricyclic antidepressants (TCAs)Monoamine oxidase inhibitors (MAOIs)20Selective Serotonin Reuptake InhibitorsSSRIs 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.21Selective Serotonin Reuptake InhibitorsAdverse effects:GI disturbancesDry mouthSexual dysfunctionHeadacheNervousnessInsomniaTremors Decrease appetiteWeight gain

22Selective Serotonin Reuptake Inhibitors

23Atypical 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.24Atypical SSRIs

25MAO Inhibitors

Monoamine OxidaseMonoamine 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.27Monoamine Oxidase InhibitorsBy 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.28Monoamine Oxidase InhibitorDisadvantages of MOAIs:Dietary restrictionstyramineWine, beer, herring, certain cheesesAdverse effects:Dry mouth, urinary retention, constipation, blurred vision, hypotension, weight gain, sexual dysfunction, liver damage that may be fatalCNS: restlessness, dizziness, insomnia, tremors, seizures, (intensified with over dosage)

29Monoamine Oxidase InhibitorTyramine 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 OKDark beer and WinesProcessed foods Overripe Fruits, specially AvocadosSmoked and processed meat and chickenChocolate, does not contain Tyramine but it does potentiate MAOI effects

30Monoamine Oxidase Inhibitor

31Depression TreatmentMonoamine 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 depressionAntidepressant 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 AntidepressantsDrugs that block the reuptake of norepinephrine and serotonin back into the neuronal nerve endingsProduce varying degrees of sedation, anticholinergic effects, and alpha-adrenergic blocking effects

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Tricyclic Antidepressants

38Tricyclic Antidepressants

39Psychomotor StimulantsInclude the amphetamines and other closely related drugsStimulate 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 activity40Drugs and DopamineAll addictions are thought to involve dopamine it provides the drive to repeat pleasurable behaviors eg: smoking, drinking, shopping, etc.

Some drugs directly alter dopamine neurotransmissionMethamphetamine causes the release of large amounts of dopamineCocaine blocks reuptake of dopamine at the synapsePsychomotor StimulantsDisadvantages:Drug tolerance and dependenceIncrease activity of sympathetic nervous systemDry mouthRapid heartbeatIncreased blood pressureRestlessnessInsomnia

42Psychomotor Stimulants

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Cocaine blocks dopamine reuptake results in feelings of euphoriahttp://www.nida.nih.gov/NIDA_Notes/NNVol13N2/brain.gif

Methamphetamine use causes permanent damage to the brainhttp://www.nida.nih.gov/NIDA_Notes/NNVol15N4/Methamphetamine.html