Neuropathophysiology Synaptic Transmission & Neurotransmitters

1. Neuropathophysiology Synaptic Transmission & Neurotransmitters September 24, 2012 Ashkan Afshin

2. Review Sessions • Format: • Questions from last review session (5 min) • Questions from last lecture (10 min) • Brief review of last lecture (15 min)

3. 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

6. Actions of the Serotonin

7. Serotonin & Norepinephrine A B C

8. Dopamine A

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

11. Synaptic Transmission

12. 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

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

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

15. 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 

17. Serotonin

18. Norepinephrine

19. Monoamine Theory • Depressionis linked to low levels of norepinephrine and/or serotonin. • Maniais linked to high levels of norepinephrine and/or serotonin. • Bipolar mood disorder is alternating cycles of depression and mania.

20. 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)

21. 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.

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

23. Selective Serotonin Reuptake Inhibitors

24. 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.

25. Atypical SSRIs

26. MAO Inhibitors

27. 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.

28. 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.

29. 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)

30. 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

31. Monoamine Oxidase Inhibitor

32. 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

33. 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.

34. 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.

35. 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.

36. 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

38. Tricyclic Antidepressants

39. Tricyclic Antidepressants

40. 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

41. 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

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

43. Psychomotor Stimulants

44. Cocaine blocks dopamine reuptake – results in feelings of euphoria http://www.nida.nih.gov/NIDA_Notes/NNVol13N2/brain.gif

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