1. NANCY LONG SIEBER, PH.D. SEPT. 17, 2012 A bit about more about pathogenesis and then Neuropathophysiology I Synaptic Transmission and What Can Go Wrong

2. Two types of immune response Non-specific – Innate Immunity –Evolutionarily ancient –Recognizes common conserved molecular patterns. –Immediate activation Specific – Adaptive Immunity –Includes memory –Recognizes specific molecular structures –Slower to activate (takes several days)

3. Common Types of Pathogens Bacteria Viruses Fungi Parasites

4. Staph Aureus Bacterium http://www.palmspringslife.com/media/Palm-Springs-Life/Medical- Guide/July-2007/Danger-Everywhere/StaphBacteria.jpg

5. “Bird flu” virus http:// giussani.typepad.com/photos/uncategorized/birdflunationalgeographic.jpg

6. Viruses infect host cells, & take over protein synthesis. The host cell is forced to make viral proteins.

7. Ringworm Fungus http://photography.nationalgeographic.com/staticfiles/NGS/Shared/ StaticFiles/Photography/Images/POD/r/ringworm-fungus-522315-sw.jpg

8. The Malarial Parasite http://www.biostatus.co.uk/falcip.gif

9. http://www.easterncarolinaent.com/Allergy-Triggers-copy.jpg Immune Dysfunction: Allergy

10. http://www.euromeds.co.uk/allergy-treatment-information.htm Allergen binds to IgE, which links to mast cells, triggering release of histamine.

11. Autoimmune Diseases http://www.theintellectualdevotional.com/blog/2010/01/25/autoimmune-diseases-basically- an-epic-body-fail/

12. Mechanisms of Autoimmunity  Modification of a molecule on the host cell  Molecular mimicry  Exposure of a sequestered antigen to the immune system  Inappropriate activation of lymphocytes that should be “tolerant  Imbalance of suppressor T cells, which inhibit the immune response, and helper T cells, which promote it.  Genetic factors – the risk of autoimmune disease runs in families.

13. http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancergrowth.gif The Development of Cancer

14. http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancer.html

16. http://www.medicinenet.com/images/illustrations/butterfly_rash.jpg Lupus

17. http://www.naturosante.ch/B.L.-lupus-evolution-1.jpg

22. The arrow labeled "axon" is pointing directly at the initial segment. http://medlibrary.org/medwiki/Axon_hillock EPSPs and IPSPs are integrated at a site at the base of the axon called the initial segment (also known as the axon hillock).

24. Major Neurotransmitters Involved in Mood Regulation Norepinephrine Serotonin Dopamine

25. Depression

26. http://www.drugdevelopment-technology.com/projects/rasagiline/rasagiline1.html

28. Drugs that treat depression 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

29. 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.

30. 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.

31. 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.

32. Other brain regions: The prefrontal cortex, which is considered to be the “seat of rational thought”, tends to be underactive in people who are depressed.

33. New area of research: Faster acting antidepressants Ketamine – developed as an anesthetic agent. In lower doses, it can reverse depression within hours. The improvement lasts 1-2 weeks. Especially decreases suicidal thoughts. Blocks certain glutamate receptors Often works for people who have not been helped by traditional antidepressants. Not yet available for clinical use

34. While studying modern antidepressant drugs, researchers identified a treatment that worked 75% as well as the drugs under consideration, with no side effects.

35. It was the placebo.

36. The placebo effect is greatest on conditions that respond to the body’s own biochemicals, such as endogenous opioids and dopamine. Placebos sometimes work for: Hypertension Pain Parkinson’s disease Psoriasis Rheumatoid arthritis Ulcers Placebos do not work for: Atherosclerosis Cancer Growth-hormone deficiency High cholesterol Infertility Obsessive-compulsive disorder Newsweek 2/8/10 Sharon Begley “The Placebo Effect”

37. Current thoughts on antidepressants Antidepressants appear to be most effective for severe depression and chronic mild depression In mild to moderate depression, it is difficult to distinguish between drug effect and placebo effect. Drugs work best when combined with psychotherapy.

38. Psychotherapy for Depression Cognitive behavioral therapy (CBT) is most popular. Works to identify and change thought patterns that reinforce depression, such as over-sensitivity to criticism. People who are treated by CBT are only about half as likely to experience a relapse compared to people treated by drugs.

39. What else helps? Exercise Sleep Social Engagement Stress Reduction

40. Some questions to consider: Is depression brought on by the stresses of modern life? Should depression, particularly in young people, always be treated with drugs? What are the consequences of not treating depression? How long should people stay on antidepressants? What about depression in other countries? How do different cultures think about mental health?

41. Bipolar Disorder Characterized by over activity of the amygdala (associated with fear) and under activity of the prefrontal cortex (associated with organized, rational thought). http://cwx.prenhall.com/bookbind/pubbooks/morris5/medialib/images/F02_09.jpg

42. Dopamine Parkinson’s disease is associated with a loss of dopamine-producing neurons in the basal ganglia, which is involved in movement. Schizophrenia is associated with an excess of dopaminergic transmission.

43. The art of Louis Wain (1860-1939) Throughout his career, Wain painted pictures of cats.

44. At the age of 57, Wain developed schizophrenia. The disease is reflected in his art:

45. Dopamine also helps regulate mood. Central to our feeling of pleasure and reward. Dopamine is also associated with motivation and memory. Addictive drugs and behaviors involve dopamine pathways.

46. 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

47. Methamphetamine use affects the entire body http://factoidz.com/methamphetamine-and-the-damage-it-does/

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

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

50. How to treat addiction? Detoxification – safely withdraw from drug Rehabilitation – slow process of dealing with psychological as well as physical addiction Medications used: –Safer forms of drugs that act on the same receptors as the drug of abuse. Eg: nicotine patch, methadone –Drugs that block the effect of drug, or that cause illness if drug is used. Eg: Antabuse for alcohol. –Certain antidepressants also help. Eg: Wellbutrin

51. Alcohol Consumption Per Capita

52. Source: World Health Organization

53. Major Neurotransmitters Small Molecules Neuropeptides Acetylcholine Nitric Oxide Biogenic Amines Epinephrine Norepineprine Dopamine Serotonin Histamine Amino Acids Glutamate  Aminobutyric Acid (GABA) Glycine Aspartate Homocysteine Taurine Nucleotides Adenosine Adenosine triphosphate Hypothalamic Releasing Hormones Corticotrophic Releasing Hormone Growth Hormone Releasing Hormone Thyrotrophin Releasing Hormone Pituitary Peptides ß endorphins Oxytoxin Vasopressin Adrenocorticotropic Hormone (ACTH) Thyroid Stimulating Hormone (TSH) Growth Hormone Gastrointestinal Peptides Secretin Substance P Insulin Gastrin Neurotensin Somatostatin Cholecystokinin Others Angiotensin Bradykinin Neuropeptide Y Calcitonin