Bi 1

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Bi 1 Drugs and the Brain Lecture 24
Thursday, May 18, 2006 Revised 5/21/06 Bipolar
Disease
Parkinsons Disease
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Bipolar Disease 1. Clinical description 2.
Genetics 3. Possible causes 4. Heterozygote
advantage? 5. Therapeutic approaches
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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-20s. Bipolar disorder often leads to
suicide.
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• 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 . . . . .

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People with bipolar disorder are often
fascinating in the early stages.
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2. Genetics
No single gene causes bipolar disorder. Data for
concordance among twins in bipolar disorder
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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
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Candidate genes are investigated thoroughly
using SNPs. No overwhelming candidate, yet.
from Lecture 23
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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.
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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
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from Jamison KEYH Asylum or psychiatric
hospital S Suicide SA Suicide Attempt
Writers Hans 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) Composers Hector 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 musicians Irving Berlin (H), Noel
Coward, Stephen Foster, Charles Mingus (H),
Charles Parker (H, SA), Cole Porter (H) Poets
William 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 Artists Richard 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)
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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
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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
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July 1890
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5. Therapeutic approaches to bipolar disorder
Surgical and electrical intervention
Surgery to remove large portions of the brain
(1950s-60s) 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
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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.
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Three exemplar patients in the early days of Li
How does Li act?

• 1. We dont 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.

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Two enzymes inhibited by Li, explaining some
pathological effects of Li on development, and
suggested to explain therapy for bipolar disease.
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Parkinsons Disease 1. Clinical description 2.
Genetics 3. Possible causes animal models 4.
Heterozygote advantage (none known)? 5.
Therapeutic approaches
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Neurodegenerative diseases Parkinsons (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 Alzheimers Amyot
rophic lateral sclerosis Lou Gehrigs
disease various cerebellar ataxias, including
polyglutamine proteins
Michael J. Fox
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from several previous lectures
dopamine-producing neurons die in PD
Nestler Figure 8-6
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like several previous Lectures
Only dopaminergic neurons express the cell
membrane dopamine transporter.
Antidepressants (SSRIs serotonin- selective r
euptake 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
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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.

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Familial Parkinsons Disease Provides a Good
Review of Bi 1 ( 10 of patients) See next 4
slides
AD, autosomal dominant AR, autosomal recessive
IP, incomplete penetrance
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a-synuclein has an unknown function Mutant
a-synuclein forms fibrils But it does not
contain triplet repeats
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Parkin is a ubiquitin protein ligase UCH-L1
removes ubiquitin
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PINK1 is PTEN-Induced Putative Kinase 1 LRRK2
is Leucine-Rich Repeat Kinase 2
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DJ-1 has an unknown function
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3. Animal Models for Parkinsons Disease
Drosophila that overexpress synuclein
1. The 4 dopaminergic neurons die
preferentially! We dont know why.
(2. The cells show dense structures like Lewy
bodies)
3. The flies show a movement disorder
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3. Animal Models for Parkinsons 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 Pattersons Watson Lecture
5/17/06))
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from Lecture 13
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from Lecture 13
Knockout mice in Drugs and the Brain (Behavioral
observations)
1. The m-opioid receptor m-opioid receptor
knockouts specifically lack responses to certain
types of pain. 2. The a4 nicotinic receptor a4
nicotinic receptor knockouts (1) respond less
to nicotine in pain tests (2) fail to
self-administer nicotine. 3. The dopamine
transporter Dopamine transporter knockout mice
(1) are hyperactive, (2) show less response
to cocaine, (3) self-administer cocaine
less 4. Cannabinoid receptors Cannabinoid
receptor knockouts have little overt differences
to normal mice. They dont show these effects
of THC and anandamide (1) decreased pain
responses and (2) decreased heart rate.
------------------------------------------------
--- 5. But NMDA receptor knockouts die at
birth an uninformative result

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Labarca and colleagues (2001) hoped to make a
strain of mice that were hypersensitive to
nicotine. (This would also be useful for
research on nicotine addiction). They knew, from
site-directed mutagenesis in frog eggs, that
mutating a single amino acid in the a4 nicotinic
receptor produced a hypersensitive receptor
whose channel opened at lower concentrations of
acetylcholine.
from Lecture 7
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Knock-in mice site-directed mutagenesis in an
animal
Hypothesis Your favorite behavior
event requires your favorite protein . . .
. . . and a subtle change in the proteins
function will change that behavior.
Gene (DNA)
Mutate just one amino acid in the gene of interest
Replace the mouse gene with the altered gene
Breed many identical mice
study the animals
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Neurons that make dopamine pleasure-reward
system highlighted Neurons that make dopamine
express a4 nicotinic acetylchioline receptors
Nestler Figure 8-6
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Some strains of these a4 nicotinic receptor
hypersensitive knock-in mice died, because they
were born with very few dopaminergic neurons.
The reason The hypersensitive nicotinic
receptor channels in the dopaminergic neurons
were opened by the small circulating amounts of
acetylcholine-like molecules in the body. This
constant activation short-circuited the membrane
potential the cells could not pump ions quickly
enough, and they died.
WT
mutant
Immunostaining for the enzyme that makes dopamine
from tyrosine
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A better excitotoxic model for Parkinsons
disease Activate the excitotoxic a4 gene in the
adult. This was accomplished by injecting a
virus that eliminates an attenuating sequence
from the excitotoxic a4 gene in the adult mouse
(Sigrid Schwarz, Johannes Schwarz, Oliver
Dorigo, Arnie Berk).
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An adult mouse model for dopaminergic degeneration
Tests of movement
Important controls
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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.

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Therapeutic Approaches
from Lecture 2
Another example of neutral drug permeation. In
Parkinsons 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.
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Deep brain stimulation for Parkinsons
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-i
mages/CIT-only/Anders.avi http//www.its.caltech.e
du/lester/Bi-1/Lecture-images/CIT-only/Walther.av
i). http//www.ninds.nih.gov/disorders/deep_brai
n_stimulation/deep_brain_stimulation.htm
http//www.medtronic.com/activa/physician/implant
able.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.
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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 (doesnt stop the
protein) (CFTR-DF508) Cell death Protein
trafficking and degradation Oxidative
damage Excitotoxicity Deficits in
development Migration Specification
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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.