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Bi 1 “Drugs and the Brain” Lecture 24 Thursday, May 18, 2006 Revised 5/21/06

Bi 1 “Drugs and the Brain” Lecture 24 Thursday, May 18, 2006 Revised 5/21/06 Bipolar Disease Parkinson’s Disease. Bipolar Disease 1. Clinical description 2. Genetics 3. Possible causes 4. Heterozygote advantage?

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Bi 1 “Drugs and the Brain” Lecture 24 Thursday, May 18, 2006 Revised 5/21/06

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  1. Bi 1 “Drugs and the Brain” Lecture 24 Thursday, May 18, 2006 Revised 5/21/06 Bipolar Disease Parkinson’s Disease

  2. Bipolar Disease 1. Clinical description 2. Genetics 3. Possible causes 4. Heterozygote advantage? 5. Therapeutic approaches

  3. 1. Clinical description, based on DSM-IV. Bipolar disorder affects 1-1.5% of the population in most modern societies. Like depression, bipolar disorder is a mood disorder. It was formerly termed manic-depressive disorder, because patients have one or more manic or nearly manic episodes, alternating with major depressive episodes. 1st episode often in mid-20’s. Bipolar disorder often leads to suicide.

  4. From DSM-IV Summary description of a manic episode Manic Episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required). The mood disturbance must be accompanied by at least three additional symptoms from this list: -inflated self-esteem or grandiosity, -decreased need for sleep, -pressure of speech, -flight of ideas, -distractibility, -increased involvement in goal-directed activities or psychomotor agitation, and Excessive involvement in pleasurable activities with likelihood of painful consequences If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present . . . . The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features . . . . .

  5. People with bipolar disorder are often fascinating in the early stages.

  6. 2. Genetics No single gene causes bipolar disorder. Data for concordance among twins in bipolar disorder:

  7. From Lecture 23: Three concepts used in describing complex diseases Polygenic the disease occurs only if several genotypes are present together Genetically Multifactorial several distinct genes (or sets of genotypes) can independently cause the disease Partially penetrant nongenetic factors may also be required, or the disease could be inherently stochastic Polygenic Genetically Multifactorial Partially Penetrant

  8. “Candidate genes” are investigated thoroughly using SNPs. No overwhelming candidate, yet. from Lecture 23:

  9. 3. Possible causes of bipolar disease Each new advance in neuroscience has been tried out on bipolar disorder--as for schizophrenia. There is no satisfactory explanation yet. As for schizophrenia, present theories invoke: circuit properties early developmental events rather than individual neurotransmitter systems.

  10. 4. Heterozygote advantage? Touched With Fire : Manic Depressive Illness and the Artistic Temperament by Kay Redfield Jamison "This is meant to be an illustrative rather than a comprehensive list . . .Most of the writers, composers, and artists are American, British, European, Irish, or Russian; all are deceased . . . Many if not most of these writers, artists, and composers had other major problems as well, such as medical illnesses, alcoholism or drug addiction, or exceptionally difficult life circumstances. They are listed here as having suffered from a mood disorder because their mood symptoms predated their other conditions, because the nature and course of their mood and behavior symptoms were consistent with a diagnosis of an independently existing affective illness, and/or because their family histories of depression, manic-depressive illness, and suicide--coupled with their own symptoms--were sufficiently strong to warrant their inclusion." autobiography: An Unquiet Mind by Kay Redfield Jamison

  11. from Jamison KEY:H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt WritersHans Christian Andersen, Honore de Balzac, James Barrie, William Faulkner (H), F. Scott Fitzgerald (H), Ernest Hemingway (H, S), Hermann Hesse (H, SA), Henrik Ibsen, Henry James, William James, Samuel Clemens (Mark Twain), Joseph Conrad (SA), Charles Dickens, Isak Dinesen (SA), Ralph Waldo Emerson, Herman Melville, Eugene O'Neill (H, SA), Mary Shelley, Robert Louis Stevenson, Leo Tolstoy, Tennessee Williams (H), Mary Wollstonecraft (SA), Virginia Woolf (H, S) ComposersHector Berlioz (SA), Anton Bruckner (H), George Frederic Handel, Gustav Holst, Charles Ives, Gustav Mahler, Modest Mussorgsky, Sergey Rachmaninoff, Giocchino Rossini, Robert Schumann (H, SA), Alexander Scriabin, Peter Tchaikovsky Nonclassical composers and musiciansIrving Berlin (H), Noel Coward, Stephen Foster, Charles Mingus (H), Charles Parker (H, SA), Cole Porter (H) PoetsWilliam Blake, Robert Burns, George Gordon, Lord Byron, Samuel Taylor Coleridge, Hart Crane (S) , Emily Dickinson, T.S. Eliot (H), Oliver Goldsmith, Gerard Manley Hopkins, Victor Hugo, Samuel Johnson, John Keats, Vachel Lindsay (S), James Russell Lowell, Robert Lowell (H), Edna St. Vincent Millay (H), Boris Pasternak (H), Sylvia Plath (H, S), Edgar Allan Poe (SA), Ezra Pound (H), Anne Sexton (H, S), Percy Bysshe Shelley (SA), Alfred, Lord Tennyson, Dylan Thomas, Walt Whitman ArtistsRichard Dadd (H), Thomas Eakins, Paul Gauguin (SA), Vincent van Gogh (H, S), Ernst Ludwig Kirchner (H, S), Edward Lear, Michelangelo, Edvard Meunch (H), Georgia O'Keeffe (H), George Romney, Dante Gabriel Rossetti (SA)

  12. Vincent Van Gogh 1853-1890 750 paintings; 1600 drawings; 700 letters Life history: born and raised in the Netherlands Paris 1886-88 Arles 1888 (1st episode; cut off his own ear) hospitalized 1888-1890 Auvers-sur-Oise 3 months. Shot himself 7/27/1890 1887-88 1886 1887

  13. I should like to do portraits which will appear as revelations to people in a hundred years' time.-- Letter to his sister Wil, 3 June 1890 Dr. Gachet June 1890 Early 1889

  14. July 1890

  15. 5. Therapeutic approaches to bipolar disorder Surgical and electrical intervention Surgery to remove large portions of the brain (1950’s-60’s) Electroconvulsive shock therapy (ECT). Now administered under anesthesia. Various electrode placements, pulse widths, and frequencies “In situations where medication, psychotherapy, and the combination of these interventions prove ineffective, or work too slowly to relieve severe symptoms such as psychosis (e.g., hallucinations, delusional thinking) or suicidality, electroconvulsive therapy (ECT) may be considered. ECT is a highly effective treatment for severe depressive episodes.“ -- National Institute of Mental Health Over a hundred theories have been offered to account for the efficacy of ECT. http://www.acnp.org/G4/GN401000108/CH106.html

  16. The usual ionic suspects in Bi 1 Therapeutic approaches to bipolar disorder Drugs (upper left-hand region of the periodic table, Little Alberts 2-7) Li+ ion (Nestler Pp. 35--353) Therapeutic effects begin in ~ 5 d, require several wk. Li+ is quite poisonous at higher doses. Valproic acid and other anticonvulsants These also require several wk for full effects.

  17. Three exemplar patients in the early days of Li+ How does Li+ act? • 1. We don’t know, but there are now some good guesses. • All ideas about Li+ assume an intracellular target. • Li+ enters cells freely through several channels and ion-coupled transporters that normally serve for Na+. • Intracellular concentrations of Li+ are probably several mM. • Most ideas about Li+ involve enzyme inhibition. • Most of the suspected enzymes manipulate high-energy phosphate bonds.

  18. from Lecture 12: old theory of Li action receptor Gq G protein Enzyme i q s t Ca 2+ Ca 2+ effector in vesicles in cytosol channel enzyme (not synaptic vesicles) intracellular messenger kinase cAMP Ca2+ from Lecture 14: new theory of Li action phosphorylated protein phosphorylated transcription factor kinase Nucleus Two enzymes inhibited by Li+, explaining some pathological effects of Li+ on development, and suggested to explain therapy for bipolar disease.

  19. Parkinson’s Disease 1. Clinical description 2. Genetics 3. Possible causes; animal models 4. Heterozygote advantage (none known)? 5. Therapeutic approaches

  20. no muscle atrophy (no wasting) Poor movement Neurodegenerative diseases: Parkinson’s (Nestler p 312: tremor at rest 3-5 Hz, “pill-rolling” slow movements, particularly when starting, short, rapid steps) but most Parkinson patients are either medicated or stimulated Alzheimer’s Amyotrophic lateral sclerosis “Lou Gehrig’s disease” various cerebellar ataxias, including polyglutamine proteins Michael J. Fox

  21. from several previous lectures dopamine-producing neurons die in PD Nestler Figure 8-6

  22. like several previous Lectures Only dopaminergic neurons express the cell membrane dopamine transporter. Antidepressants (“SSRIs” = serotonin- selective reuptake inhibitors): Prozac Zoloft Paxil Drugs of abuse: MDMA Attention-deficit disorder medications: Ritalin Dexedrine Drugs of abuse: Cocaine Amphetamine Na+-coupled cell membrane dopamine transporter Na+-coupled cell membrane serotonin transporter cytosol synaptic cleft

  23. reactive: oxidative damage? dopamine Parkinsonism in people • 1. Most cases are unexplained • The “frozen addict”. An impurity in synthetic heroin. • Taken up by the dopamine transporter (expressed only in dopaminergic cells). • Kills cells. • The influenza pandemic (worldwide epidemic) of 1918, which killed 20 million people. • The flu specifically killed dopaminergic neurons in many people (“Awakenings”). • Genetics: see next topic • Smoking protects against PD.

  24. Familial Parkinson’s Disease Provides a Good Review of Bi 1 (~ 10% of patients) See next 4 slides AD, autosomal dominant; AR, autosomal recessive; IP, incomplete penetrance

  25. a-synuclein has an unknown function; Mutant a-synuclein forms fibrils; But it does not contain triplet repeats

  26. Parkin is a ubiquitin protein ligase; UCH-L1 removes ubiquitin

  27. PINK1 is PTEN-Induced Putative Kinase 1 LRRK2 is Leucine-Rich Repeat Kinase 2

  28. DJ-1 has an unknown function

  29. 3. Animal Models for Parkinson’s Disease: Drosophila that overexpress synuclein 1. The 4 dopaminergic neurons die preferentially! We don’t know why. (2. The cells show dense structures like Lewy bodies) 3. The flies show a “movement disorder”

  30. 3. Animal Models for Parkinson’s Disease: Mice with hypersensitive nicotinic acetylcholine receptors an example of “Excitotoxicity” (next 6 slides, many reviewing previous Bi 1 material, Omitted to avoid duplicating P Patterson’s Watson Lecture 5/17/06))

  31. Excitotoxicity from Lecture 5: • Cells have evolved elaborate processes for pumping out intracellular Na+ and Ca2+. • These gradients can be used in two ways: • 1. The gradients are used for uphill “exchange” to control the concentrations of other small molecules. • Transient, local increases in intracellular Ca2+ and Na+ concentrations can now be used for signaling inside cells! • ……………….. • But sustained increases in Ca2+ and Na+ permeability place a metabolic strain on cells and kill them. • Another human example: stroke. • 1. Cells release glutamate because the Na-coupled transporter loses its gradient. • 2. Glutamate activates receptors, causes further depolarization.

  32. Therapeutic Approaches from Lecture 2 Another example of neutral drug permeation. In Parkinson’s Disease: most neurons that make dopamine die (Lecture 25) The challenge: replace the dopamine in the brain enzyme: decarboxylase levodopa, “L-dopa” zwitterionic permeates into brain dopamine does not enter brain . . . but L-dopa therapy eventually causes dyskinesia, a good example that GPCR pathways lead to gene activation.

  33. dopamine-producing neurons die in PD Deep brain stimulation for Parkinson’s Disease Courtesy of Visiting Professor Johannes Schwarz (Leipzig) Tremor arises in a malfunctioning feedback loop: substantia nigra, striatum, and other structures. Implanted stimulating electrodes retune this loop. Nestler Figure 8-6 (Videos are restricted to Caltech: http://www.its.caltech.edu/~lester/Bi-1/Lecture-images/CIT-only/Anders.avi http://www.its.caltech.edu/~lester/Bi-1/Lecture-images/CIT-only/Walther.avi). http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm http://www.medtronic.com/activa/physician/implantable.html Before the videos were shot, stimulating electrodes were implanted surgically. Midway through each video, the stimulators were programmed via magnetic pulses, and stimulation started.

  34. (Not taught in Bi 1) Summary of Mechanisms that may account for Neuroscience Diseases Classes of mutation: Triplet repeats (huntingtin) Nonsense mutation (stops the protein, “amber” codon, some CFTR mutants) Missense mutation (doesn’t stop the protein) (CFTR-DF508) Cell death: Protein trafficking and degradation Oxidative damage Excitotoxicity Deficits in development Migration Specification

  35. All I really need to know about life I learned in Bi 1 1. If you want a job done right, get a protein 2. Electrical circuits explain many processes 3. Most processes follow an exponential time course 4. Most processes end with a Gaussian distribution 5. Optics can show lots of details 6. Some drugs produce quasi-permanent changes in gene activation 7. Osmosis explains many processes 8. Many diseases are inherited , but some are polygenic. 9. Faulty protein degradation and excitotoxicity cause diseases.

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