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Bi 1 “Drugs and the Brain”

Lecture 24 Thursday, May 18, 2006 Revised 5/21/06

Bipolar Disease Parkinson’s 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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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.

1. Clinical description, based on DSM-IV.

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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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No single gene causes bipolar disorder.

Data for concordance among twins in bipolar disorder:

“narrow”

definition

“broad”

definition

monozygotic

(n = 55)79% 97%

monozygotic,

reared apart

(n = 12)

69%

dizygotic

(n = 52)24% 38%

2. Genetics

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From Lecture 23:

Polygenicthe disease occurs only if several genotypes are present together

Genetically Multifactorialseveral distinct genes (or sets of genotypes) can independently cause the disease

Partially penetrantnongenetic factors may also be required,

or the disease could be inherently stochastic

PolygenicGenetically

Multifactorial

PartiallyPenetrant

Three concepts used in describing complex diseases

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“Candidate genes” are investigated thoroughly using SNPs. No overwhelming candidate, yet.

20%

80%

60%

40%

20%

80%

30%

70%

Locus AChomosome 12

no linkage toschizophrenia

Locus BChomosome 1

may be near a gene that helps to cause

schizophrenia

sequence A1

sequence A2

sequence A1

sequence A2

Controls Schizophrenics

sequence B1

sequence B2

sequence B1

sequence B2

Hunting for Genes with SNPsfrom Lecture 23:

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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.

3. Possible causes of bipolar disease

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Touched With Fire : Manic Depressive Illness and the Artistic Temperamentby 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."

4. Heterozygote advantage?

autobiography:An Unquiet Mind by Kay Redfield Jamison

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from JamisonKEY:H= 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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1887 1887-88

Vincent Van Gogh 1853-1890750 paintings; 1600 drawings; 700 letters

Life history: born and raised in the NetherlandsParis 1886-88Arles 1888 (1st episode; cut off his own ear)hospitalized 1888-1890Auvers-sur-Oise 3 months. Shot himself 7/27/1890

1886

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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

Early 1889

Dr. GachetJune 1890

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July 1890

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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

5. Therapeutic approaches to bipolar disorder

Surgical and electrical intervention

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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.

Therapeutic approaches to bipolar disorder

Drugs(upper left-hand regionof the periodic table,Little Alberts 2-7)

The usual ionic suspects in Bi 1

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1. We don’t know, but there are now some good guesses.

2. 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.

3. Most ideas about Li+ involve enzyme inhibition.

Most of the suspected enzymes manipulate high-energy phosphate bonds.

How does Li+ act?

Three exemplar patients in the early days of Li+

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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.

kinase

phosphorylatedprotein

cAMPCa2+

intracellularmessenger

receptor

tsqiG protein

enzymechannel effector

from Lecture 14: new theory of Li action

Nucleus

kinase

phosphorylatedtranscription factor

from Lecture 12: old theory of Li action

Enzyme

Ca2+

in cytosol

Ca2+

in vesicles(not synaptic vesicles)

Gq

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Parkinson’s 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:

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 eithermedicated or stimulated

Alzheimer’s

Amyotrophic lateral sclerosis“Lou Gehrig’s disease”

various cerebellar ataxias, including polyglutamine proteins

no muscle atrophy (no wasting)

Michael J. Fox

Poor movement

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Nestler Figure 8-6

from several previous lectures

dopamine-producing neurons die in PD

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Only dopaminergic neurons express the cell membrane dopamine transporter.

Antidepressants (“SSRIs” = serotonin-selectivereuptake inhibitors): Prozac Zoloft Paxil

Drugs of abuse: MDMA

Attention-deficit disorder medications: Ritalin Dexedrine

Drugs of abuse: Cocaine Amphetamine

like several previous Lectures

Na+-coupledcell membrane serotonintransporter

Na+-coupledcell membrane dopamine transporter

NH

HO NH3+

HO

HO

H2C

CH2

NH3+

cytosol

synapticcleft

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1. Most cases are unexplained

2. The “frozen addict”. An impurity in synthetic heroin.

Taken up by the dopamine transporter (expressed only in dopaminergic cells).

Kills cells.

3. The influenza pandemic (worldwide epidemic) of 1918, which killed 20 million

people.

The flu specifically killed dopaminergic neurons in many people (“Awakenings”).

4. Genetics: see next topic

5. Smoking protects against PD.

HO

HO

H2C

CH2

NH3+

dopamine

reactive:oxidative damage?

Parkinsonism in people

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Familial Parkinson’s Disease Provides a Good Review of Bi 1(~ 10% of patients)See next 4 slides

LocusChromosome location

Gene or protein nameInheritance pattern

PARK1 & PARK4 4q21–q23 -synuclein(Unknown function)

AD

PARK2 6q25.2-q27 parkin AR

PARK3 2p13 Unknown AD, IP

PARK5 4p14 UCH-L1 unclear

PARK6 1p35-p36 PINK1 AR

PARK7 1p36 DJ-1 AR

PARK8 12p11.2–q13.1 LRRK2 AD

AD, autosomal dominant; AR, autosomal recessive; IP, incomplete penetrance

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-synuclein has an unknown function;

Mutant -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 Parkinson’s Disease: Drosophila that overexpress synuclein

1. The 4 dopaminergic neurons die preferentially!

We don’t know why.

3. The flies show a “movement disorder”

(2. The cells show dense structures like Lewy bodies)

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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))

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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.

2. 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.

from Lecture 5:

Excitotoxicity

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levodopa, “L-dopa”zwitterionic

permeates into brain

dopamine

does not enter brain

enzyme:decarboxylase

Therapeutic Approaches

HO

HO

H2C NH3

+

CO2-

HO

HO

H2C

CH2

NH3+

from Lecture 2

. . . but L-dopa therapy eventually causes dyskinesia, a good example that GPCR pathways lead to gene activation.

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

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dopamine-producing neurons die in PD

(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.

Deep brain stimulation for Parkinson’s DiseaseCourtesy of Visiting Professor Johannes Schwarz (Leipzig)

Nestler Figure 8-6

Tremor arises in a malfunctioning feedback loop: substantia nigra, striatum, and other structures.

Implanted stimulating electrodes retune this loop.

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Classes of mutation:Triplet repeats (huntingtin)Nonsense mutation (stops the protein, “amber” codon,

some CFTR mutants)Missense mutation (doesn’t stop the protein)

(CFTR-F508)

Cell death:Protein trafficking and degradation Oxidative damageExcitotoxicity

Deficits in developmentMigrationSpecification

Summary of Mechanisms that may account for Neuroscience Diseases

(Not taught in Bi 1)

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All I really need to know about lifeI 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.