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Bi 1
“Drugs and the Brain”
Lecture 1
Monday, March 27, 2006
Organization of the Course
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The Bi 1 2006
Home Page
http://www.its.caltech.edu/~bi1/
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Biology 1 at Caltech
•In the mid-1990’s, the Caltech faculty instituted a requirement that all
students must take biology as part of the “core curriculum”
•We have ~220 freshmen
•~ 35 Biology majors and other interested Freshmen take a two-course intro
to molecular and cellular biology
•~ 185 Freshmen take Bi 1 in the Spring
•Math, physics, chemistry, and engineering majors
•All believe that biology should be derived from first principles
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Henry Lester’s Goal: provide the principles that will allow Caltech grads to
appreciate the progress in clinical neuroscience over the next 5-20 years
College freshmen are not interested in disease
Challenge: provide a “stealth” introduction to clinical neuroscience, while
addressing Caltech students’ interest in quantitative descriptions
No illegal drugs, please
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Biology 1
“Drugs and the Brain”
1. quantitative descriptions
2. single-molecule phenomena
3. lots of Caltech connections
How do we progress from biophysics to clinically relevant neuroscience?
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A 20-minute survey of Bi 1
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What’s a Drug?
nicotine
(Nestler Fig. 12-4)
procaine
(Nestler p. 50)
H3CH 2C
N
morphine
(Nestler Fig. 16-3)
botulinum toxin
(Nestler p. 203, 323)
CH 2CH 3
H2C
HO
CH 2
N
CH 3
N
O
O
C O
N CH
3
HO
morphine
NH 2
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Most drug receptors are membrane proteins. Proteins are beautiful.
~ 100 Å
(10 nm)
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We’ll learn to view and manipulate pictures of molecules
http://www.its.caltech.edu/~lester/Bi-1/AChBP-2004-BindingSite.pdb
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Front
Back
What is a Brain?
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Electricity is a language of the nervous system
Nestler Figure 3-1B
Nestler Figure 3-1B
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The synapse is a point of information processing
presynaptic neuron
postsynaptic neuron
Nestler Box 2-3 Figure A
An adult human brain contains ~ 1011 neurons,
and each of these might receive 103 synapses apiece,
for a total of 1014 synapses.
Most of these synapses form during the first 2 yr of life.
Thus 1014synapses/108 s = 106 synapses/s form in a fetus and infant!
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Principle of the Stereo Tetrode
Voltage minus
Channel 1
Channel 2
Channel 3
Amp. Channel 3
Amp. Channel 4
Channel 4
Amp. Channel 2
Amp. Channel 1
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A functional magnetic resonance
imaging (fMRI) image. This is the
rear view of a human brain
activation associated with
performance of a task that utilizes
motor, visual and planning
cognitive processes. The subject
was moving a joystick to follow a
target around a video display.
http://www.cmrr.umn.edu/research/functional.shtml
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The Central Dogma of Drugs and the Brain,
Part 1:
Drugs Activate and Block Ion Channels
Drug
Receptor
current
time
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Drug interactions at the nicotinic acetylcholine receptor
Some drugs compete with nicotine
Some drugs bind on the axis
~ 100 Å
(10 nm)
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n =1
time constant
= 1/k21
0
time constant
= 1/(k21+ k23)
+
etc
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Site-Directed Mutagenesis on Ion Channels
DNA
Mutate the desired codon(s)
RNA polymerase promoter
in vitro RNA synthesis
measure
Express by injecting into
immature frog eggs
measure 19
Channels are miniature conductors that add in parallel
GNa = SgNa
GK = SgK
outside
GNa
GK
=
ENa
EK
(- 60 mV)
gK
gNa
(+60 mV)
inside
gNa
mostly Na+
mostly K+
gK
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Little Alberts Panel 1-1
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The Central Dogma of Drugs and the Brain, Part 2:
Drugs Act on G protein pathways
How fast?
100 ms to 10 s
Neurotransmitter or hormone
binds to receptor
How far?
Probably less 1 mm
activates
G protein
Effector:
enzyme or channel
outside
b g
a
GTP
a
GDP + Pi
b g
inside
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Targets for Recreational Drugs
amphetamine*
phencyclidine
cocaine
nicotine
neurotransmitter
transporters
neurotransmitter-activated
channels
postsynaptic
cell
GPCR
N
G protein-activated
channels
enzymes
C
a
LSD
morphine-heroin
tetrahydrocannabinol
caffeine*
?alcohol?
(*= intracellular target) 23
Neurons that make dopamine;
“pleasure/reward system” highlighted
Nestler Figure 8-6 24
Seymour Benzer
Thomas Hunt Morgan
How do we study
the fundamental
bases of drug
addiction?
Drosophila melanogaster
Ed Lewis
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outside
receptor
membrane
b g
G protein
i q s t
a
b g
a
inside
effector
channel enzyme
The Central Dogma of
Drugs and the Brain,
Part 3:
Drugs Activate Genes
intracellular
messenger
Ca2+ cAMP
cytosol
kinase
phosphorylated
protein
nucleus
How fast?
10 s to days
How far?
Up to 1 m
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Mid-Term Exam
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Genomics and genetics in Bi 1
“Drugs and the Brain”
15, 17. Genomics
18. Implementing the Genetic Code: from DNA to Protein
20. Genetics: Formal and Molecular
21,22. Exemplar Simple Genetic Diseases:
Cystic Fibrosis, long-QT syndrome, epilepsies
23. Stem cells and stem cell therapy
24. Another exemplar simple genetic disease:
Huntington’s disease.
24,25 Schizophrenia, bipolar disorder, and the complex genetics of psychiatric
diseases
27. Evolution 1: Inferences from Molecular Biology
28. Evolution 2: The eye as an example
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Single-molecule measurements in genomics
E = force x distance;
force is generated by viscosity
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Cystic Fibrosis: A Genetic Disease
1. Clinical description
2. Genetics
3. Gene structure
4. CFTR as a protein
5. Physiology of CFTR
6. What’s wrong with DF508?
7. The cholera connection
8. Selective advantage of CF?
9. Therapeutic approaches:
Incremental approaches
Gene therapy
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David Helfgott plays
Rachmaninov Piano Concerto #3
Copenhagen Philharmonic Orchestra,
1995
RCA Victor-BMG Classics
as in the movie “Shine”
Born in Melbourne 1947
1962-1970 several schizophrenic
episodes
1966-70 Royal College of Music
1970-1980 Hospitalized in Australia
1984- present concert pianist
According to the biography by his wife,
his present medication consists of:
D2 receptor blocker for schizophrenia;
anticholinergic for tardive dyskenesia
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Huntington’s Disease: Simple genetics, unknown mechanism
Onset at 30-40 yr.
Neurons in the striatum and cerebral cortex die, leading to movement disorders
(“chorea”), dementia, and eventually death.
Woody Guthrie 1912-1967
Mother died of Huntington’s chorea; Woody began suffering in ~ 1945
He had 8 children.
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Bipolar Disease
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
1886
1887
1887-88
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July 1890
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Cell cycle and stem-cell therapy
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Neurons that make dopamine die in Parkinson’s Disease
Nestler Figure 8-6 36
Testing our understanding of evolution: the eye
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“Study nature, not books”
(Louis Agassiz)
Flightless cormorant
Voyages to the Galapagos
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Final Exam
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Bi 1 Fonts:
Largest font size
Medium font size
Smallest font size
(Slide projector sound)
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Problem set #1 will be posted Tuesday on the Bi 1 Web Site;
it’s a pdf.
Due next Monday 4/3 11 AM in the Bi 1 Closet
You might wish to inspect PS #1 before this week’s section meetings.
Bi 1 Home Page:
http://www.its.caltech.edu/~bi1/
Bi 1 Collaboration policies:
http://www.its.caltech.edu/~bi1/Bi-1-policy-sheet.pdf
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If you drop the course,
or if you register late,
please email Patricia Mindorff [email protected]
(in addition to the Registrar’s cards).
Also, if you want to change sections,
please email Patricia Mindorff [email protected]
Patricia Mindorff works 9 AM - 5 PM M-F
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