Bi 1 Lecture 13

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Bi 1 Lecture 13 Monday, April 24, 2005 revis
ed 4/27
Recreational drugs
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Disclaimer 1. Do not alter your pattern of pres
cription drug compliance as a result of this
course. 2. Consult a medical professional for f
urther guidance about prescription drugs. H. A.
L. is not aware of all trends in current medical
practice, is not a physician, and cannot
prescribe.
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Coca Harvest in Bolivia, ca. 1950
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cocaine in the test tube
cocaine base directly extracted from the plant
with organic solvents
cocaine hydrochloride a salt, readily soluble
treatment with HCl
H
crack cocaine
treatment with base ammonia or Na bicarbonate,
then heat to drive off HCl
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cocaine in the body
blood
Lipid barrier, e. g. membrane(s)
lungs, nose, stomach
cocaine base (crack)
cocaine hydrochloride
H
Cl-
South American Indians use Ca(OH)2
from limestone to shift this equilibrium
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Targets for Recreational Drugs
amphetamine() cocaine
phencyclidine nicotine
neurotransmitter transporters
ligand-activated channels
GPCRs
enzymes
N
C
G protein-activated channels
LSD morphine-heroin tetrahydrocannabinol
caffeine ( intracellular target)
?alcohol?
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From Lecture 5
Na-coupled cell membrane neurotransmitter
transporters

major targets for drugs of therapy and abuse
Antidepressants (SSRIs serotonin-selective
reuptake inhibitors) Prozac, Zoloft, Paxil, Ce
lexa, Luvox
Drugs of abuse MDMA
Attention-deficit disorder medications Rit
alin, Dexedrine, Adderall Drugs of abuse
cocaine
amphetamine
Presynaptic terminals
Na-coupled cell membrane dopamine transporte
r
Na-coupled cell membrane serotonin transporte
r
cytosol outside
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enzyme inhibitors
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The Synapse as an Electrochemical Machine
amphetamine cocaine
phencyclidine nicotine
neurotransmitter transporters
agonist-activated channels
GPCRs
enzymes
N
C
G protein-activated channels
LSD morphine-heroin tetrahydrocannabinol
caffeine ( intracellular target)
?alcohol?
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Knockout mice and one application for them
Hypothesis the response to a drug requires your
favorite molecule
Gene (DNA)
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Knockout mice in Drugs and the Brain
(Behavioral observations)
1. The m-opioid receptor m-opioid receptor KOs s
pecifically lack responses to certain types of
pain (next slide). 2. The a4b2 nicotinic rece
ptor a4 or b2 nicotinic receptor knockouts (1
) respond less to nicotine in pain tests (next
slide) (2) fail to self-administer nicotine (nex
t slide). 3. The dopamine transporter Dopami
ne transporter knockout mice
(1) are hyperactive, (2) show less response to
cocaine, (3) self-administer cocaine less 4
. Cannabinoid receptors Cannabinoid receptor kn
ockouts have little overt differences to normal
mice. They dont show these effects of THC and
anandamide (1) decreased pain responses a
nd (2) decreased heart rate. -----------------
----------------------------------
5. But NMDA receptor knockouts die at birth an
uninformative result
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Two behavioral tests often used on knockout mice
Pain Mice are placed on a hotplate at 55o C.
The experimenter notes the time to lick paws, ju
mp, etc. The experiment terminates at 30 s, reg
ardless of the outcome. A pain-relieving drug in
creases the time to react No permanent harm to th
e mouse . . . Carefully regulated
http//www.olar.caltech.edu/iacuc-sops.htm
Self-administration of a drug
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Based on plant
ergot
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Gordon A. Alles noted the properties of Ephedra
vulgaris, used against asthma.
He synthesized amphetamine (Benzedrine).
Caltech BS, 1922 MS, 1924 PhD, 1926. Re
search Associate in Biology, 1939-1963
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from Lecture 9
pH effects also account for some drug actions on
synaptic vesicles
3,4-methylenedioxymethamphetamine
(ecstasy, XTC) pKa 8.5
ATP-driven proton pump
Neurotransmitter and ATP (1,000 to 10,000 mol
ecules
of each)
proton-coupled neurotransmitter pump
cytosol
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from Lecture 9
Weak acids and weak bases short-circuit many ves
icles!
MDMA (ecstasy) or amphetamine itself
dissipate the vesicles H store,
preventing the vesicle from pumping serotonin
ATP-driven proton pump

proton-coupled vesicular serotonin transporter
serotonin vesicle
cytosol
false substrate for two transporters
Na-coupled cell membrane serotonin transporter
synaptic cleft
MDMA
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The adjacent hydroxyl groups of dopamine are
readily oxidized (may partially cause the degener
ation of dopaminergic neurons in Parkinsons
disease)
. . . but we can use the fact to detect dopamine
in real time in the brain
A 20th-Century battery from Chem 1 textbook (OGN)

Figure 12-06
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A modified patch clamp circuit and pipette allow
us to detect dopamine electrochemically
A
cytosol synaptic cleft
carbon fiber
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In dopamine transporter knockout mice (DAT
-/-), presynaptic stimuli () lead to longer
individual dopamine release pulses
but amphetamine fails to release dopamine
Jones et al J Neurosci 18, p 1979
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Routes into the body
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Neurons that make dopamine pleasure-reward sy
stem highlighted. Most drugs of abuse affect this
system
Nestler Figure 8-6
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Most recreational drugs act at Ethanol is an exception
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Only a few thousand neurons in the brain make
noradrenaline
Nestler Figure 8-5
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Neurons that make serotonin project to many
higher brain regions
simplified from Nestler Figure 9-3
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Recreational drugs have varying overall effects
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Legal status of Recreational Drugs
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More on marijuana legal status April 20, 2006
US Inter-Agency Advisory Regarding Claims That
Smoked Marijuana Is a Medicine
http//www.fda.gov/bbs/topics/NEWS/2006/NEW01362.h
tml
New York Times editorial page response 4/22/2006
The Politics of Pot The Bush administrat
ion's habit of politicizing its scientific
agencies was on display again this week when the
Food and Drug Administration, for no compelling
reason, unexpectedly issued a brief, poorly
documented statement disputing the therapeutic
value of marijuana. The statement was described
as a response to numerous inquiries from Capitol
Hill, but its likely intent was to buttress a
crackdown on people who smoke marijuana for
medical purposes and to counteract state efforts
to legalize the practice. Ordinarily, when
the F.D.A. addresses a thorny issue, it convenes
a panel of experts who wade through the latest
evidence and then render an opinion as to whether
a substance is safe and effective to use. This
time the agency simply issued a skimpy one-page
statement asserting that "no sound scientific
studies" supported the medical use of marijuana.
That assertion is based on an evaluation by
federal agencies in 2001 that justified the
government's decision to tightly regulate
marijuana under the Controlled Substances Act.
But it appears to flout the spirit of a 1999
report from the Institute of Medicine, a unit of
the National Academy of Sciences.
The institute was appropriately cautious in
its endorsement of marijuana. It said the active
ingredients of marijuana appeared useful for
treating pain, nausea and the severe weight loss
associated with AIDS. It warned that these
potential benefits were undermined by inhaling
smoke that is more toxic than tobacco smoke. So
marijuana smoking should be limited, it said, to
those who are terminally ill or don't respond to
other therapies. Yet the F.D.A. statement,
which was drafted with the help of other federal
agencies that focus on drug abuse, does not allow
even that much leeway. It argues that state laws
permitting the smoking of marijuana with a
doctor's recommendation are inconsistent with
ensuring that all medications undergo rigorous
scrutiny in the drug approval process.
That seems disingenuous. The government is
actively discouraging relevant research,
according to scientists quoted by Gardiner Harris
in yesterday's Times. It's obviously easier and
safer to issue a brief, dismissive statement than
to back research that might undermine the
administration's inflexible opposition to the
medical use of marijuana.
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End of Lecture 13