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H 3C
O
O
CH 3
N
N
N
N
CH 3
caffeine
Bi 1 Lecture 13
Monday, April 24, 2005 revised 4/27
Recreational drugs
1
Disclaimer
1.
Do not alter your pattern of prescription drug compliance as a
result of this course.
2.
Consult a medical professional for further guidance about
prescription drugs. H. A. L. is not aware of all trends in current medical
practice, is not a physician, and cannot prescribe.
2
CH 3
HO
OH
O
N CH
3
HO
morphine
O
H 3C
N
N
O
H3C
H 3C
H 3C
O
C5H11
H2
C
OH
ethanol
tetrahydrocannabinol
C2H5
O
N C
C2H5
CH 3
N
N CH 3
N
N
CH 3
N
phencyclidine
caffeine
LSD
N
CH 3
N
H3C
O
OC
C
O
nicotine
O
CH 3
N
NH 2
CH 3
amphetamine
cocaine
3
Coca Harvest in Bolivia, ca. 1950
4
cocaine in the test tube
cocaine base:
directly extracted from the plant
with organic solvents
H3C
O
OC
C
O
CH 3
N
cocaine hydrochloride:
a salt, readily soluble
treatment with HCl
H+
O
H3C
O
OC
C
O
CH3
+
HN
Cl -
O
“crack” cocaine
treatment with base:
ammonia or Na bicarbonate,
then heat to drive off HCl
5
cocaine in the body
H3C
O
OC
blood
C
O
CH 3
N
H3C
O
OC
H+
O
C
O
CH3
+
HN
O
Lipid barrier,
e. g. membrane(s)
lungs,
nose,
stomach
H3C
O
OC
C
O
O
cocaine base
(crack)
CH 3
N
cocaine hydrochloride
H+
H3C
O
OC
C
O
CH3
HN
+
Cl-
O
South American Indians use Ca(OH)2
from limestone to shift this equilibrium
6
Targets for Recreational Drugs
amphetamine(*)
phencyclidine
cocaine
nicotine
neurotransmitter
transporters
ligand-activated
channels
GPCRs
enzymes
N
C
LSD
a
G protein-activated
channels
morphine-heroin
tetrahydrocannabinol
caffeine*
?alcohol?
(*= intracellular target)
7
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,
Celexa, Luvox
Drugs of abuse:
MDMA
Na+-coupled
cell membrane
serotonin
transporter
Attention-deficit
disorder medications:
Trademarks:
Ritalin, Dexedrine,
Adderall
Presynaptic
terminals
Drugs of abuse:
cocaine
amphetamine
Na+-coupled
cell membrane
dopamine
transporter
cytosol
NH 3+
HO
outside
HO
N
H
HO
H2
C
C
H2
NH3+
8
enzyme inhibitors
neurotransmitter transport inhibitors
9
Endogenous ligand
morphine-heroin
agonist
endorphins (peptides)
THC
agonist
anandamide
nicotine
agonist
acetylcholine
cocaine
antagonist
dopamine
amphetamine
“false substrate”,
antagonist
noradrenaline, serotonin,
dopamine
ethanol
agonist
?G protein?
LSD
agonist
serotonin
caffeine
inhibitor
cyclic AMP (intracellular)
phencyclidine
antagonist
glutamate
11
Primary Target
Details
(dates:
)
morphine-heroin
GPCR (G protein-coupled
receptor) (Gi)
m-opioid receptor
1985-1993
THC
GPCR (Gi)
cannabinoid receptor 1988
nicotine
agonist-activated channel
a4b2 nicotinic acetylcholine
receptor 1905-1995
cocaine
cell membrane
neurotransmitter transporter
dopamine transporter
1980-1991
amphetamine
vesicular & cell membrane
neurotransmitter transporter
vesicular monoamine
transporter 1990 - 1995
ethanol
? K channel ?
G protein-gated inward
rectifier GIRK1/2 1993 - 1999
LSD
GPCR (Gq)
5-HT2a receptor 1985-1990
caffeine
enzyme
cyclic AMP
phosphodiesterase 1965
phencyclidine
ligand-activated channel
NMDA glutamate receptor
1965
12
Knockout mice and one application for them
Hypothesis: the response
to a drug requires your
favorite molecule
Gene (DNA)
Interrupt the gene
with a detectable protein
(knock out the gene)
EGFP
Replace the mouse gene
with the
altered gene
Breed many
identical mice
Select the mouse
with the
altered gene
measure drug response
vs
13
Knockout mice in Drugs and the Brain
(Behavioral observations)
1. The m-opioid receptor
m-opioid receptor KOs specifically lack responses to certain types of pain (next slide).
2. The a4b2 nicotinic receptor
a4 or b2 nicotinic receptor knockouts:
(1) respond less to nicotine in pain tests (next slide)
(2) fail to self-administer nicotine (next slide).
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 don’t 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
14
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, jump, etc.
The experiment terminates at 30 s, regardless of the outcome.
A pain-relieving drug increases the time to react
No permanent harm to the mouse . . . Carefully regulated:
http://www.olar.caltech.edu/iacuc-sops.htm
Self-administration of a drug
15
Source (species:
)
“poppy that brings sleep”
(opium)
morphine-heroin
Papaver
somniferum
tetrahydrocannabinol
Cannabis
sativa
marijuana, hemp
nicotine
Nicotiana
tabacum
tobacco
cocaine
Erythroxylum
coca
coca
synthetic
amphetamine
ethanol
yeast
LSD
synthetic
caffeine
phencyclidine
Coffea sp.,
Camellia
sinensis
Based on plant
Saccharomyces
cerevisiae
(fermentation)
ergot
coffee
tea
wheat fungus;
Salem witch trials?
synthetic
16
Gordon A. Alles noted the properties
of Ephedra vulgaris, used against
asthma.
He synthesized amphetamine
(Benzedrine).
Caltech BS, 1922;
MS, 1924; PhD, 1926.
Research Associate in Biology, 19391963
17
from Lecture 9
pH effects also account for some drug actions on synaptic vesicles
O
H
N
O
CH3
H2C
CH3
3,4-methylenedioxymethamphetamine
(“ecstasy”, XTC)
pKa ~ 8.5
ATP-driven proton pump
proton-coupled
neurotransmitter pump
cytosol
Neurotransmitter
and
ATP
(1,000 to 10,000 molecules
of each)
18
from Lecture 9
MDMA (“ecstasy”) or amphetamine itself
dissipate the vesicle’s H+ store,
preventing the vesicle from pumping serotonin
Weak acids and weak bases
short-circuit many vesicles!
ATP-driven proton pump
cytosol
proton-coupled
vesicular
serotonin transporter
depleted
serotonin
vesicle
serotonin vesicle
H+
“false substrate”
for two
transporters
MDMA
MDMA-H+
MDMA-H+
Na+-coupled
cell membrane
serotonin transporter
MDMA
synaptic cleft
serotonin
19
The adjacent hydroxyl groups of dopamine are readily oxidized
(may partially cause the degeneration of dopaminergic neurons in Parkinson’s disease)
HO
H2
C
C
H2
NH3+
HO
. . . 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
20
A modified patch clamp circuit and pipette allow us to detect
dopamine electrochemically
A
cytosol
synaptic
cleft
carbon fiber
HO
HO
H2
C
C
H2
NH3+
21
In dopamine transporter knockout mice (“DAT -/-”),
presynaptic stimuli (“^”) lead to longer individual dopamine release pulses;
but amphetamine fails to release dopamine
Amphetamine
Jones et al J Neurosci 18, p 1979
22
Routes into the body
Eat
Inhale
Smoke
Inject

morphine-heroin


tetrahydrocannabinol


nicotine
chew

cocaine
amphetamine

ethanol

LSD

caffeine

phencyclidine









23
Neurons that make dopamine:
“pleasure-reward” system highlighted.
Most drugs of abuse affect this system
Nestler Figure 8-6
24
Most recreational drugs act at < 10-5 M.
Ethanol is an exception
Active Concentration
morphine-heroin
~ 1 mM
tetrahydrocannabinol
~ 1 mM
nicotine
~ 1 mM
cocaine
~ 1 mM
amphetamine
~ 1 mM
ethanol
LSD
> 1 mM
~ 10 nM
~ 10 mM
caffeine
phencyclidine
~ 1 mM
25
System-level Action
Dopamine
“Pleasure”
system
morphine-heroin
Noradrenaline
“Readiness”
system
“PerceptionAssociation”
system

“Decreased
neuronal
activity”


tetrahydrocannabinol
nicotine


cocaine


amphetamine


ethanol




LSD
caffeine

phencyclidine




26
Only a few thousand neurons in the brain make noradrenaline
Nestler Figure 8-5
27
System-level Action
Dopamine
“Pleasure”
system
morphine-heroin
Noradrenaline
“Readiness”
system
“PerceptionAssociation”
system

“Decreased
neuronal
activity”


tetrahydrocannabinol
nicotine


cocaine


amphetamine


ethanol
?



LSD
caffeine

phencyclidine




28
Neurons that make serotonin project to many higher brain regions
raphe
nuclei
simplified from Nestler Figure 9-3
29
Recreational drugs have varying overall effects
Overall Action
morphine-heroin
inhibitory
tetrahydrocannabinol
inhibitory
nicotine
excitatory
cocaine
excitatory
amphetamine
excitatory
ethanol
inhibitory
LSD
caffeine
phencyclidine
hallucinations
excitatory
hallucinations
30
Legal status of Recreational Drugs
Recreational
use
Prescription
use
morphine-heroin
Illegal
Schedule II
pain control
tetrahydrocannabinol
Illegal; see next
occasional
nicotine
Taxed;
no sales to
minors
cocaine
Illegal
ENT surgery
amphetamine
Illegal
Schedule II
ADD / ADHD
Diet pills
ethanol
Taxed;
no sales to
minors
LSD
Illegal
With antihistamines
Non-prescription use
Smoking cessation:
gum, patch
caffeine
Legal
In some
migraine
medications
phencyclidine
Illegal
none current
31
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.html
New York Times editorial page response 4/22/2006: “The Politics of Pot”
“The Bush administration'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
32
opposition to the medical use of marijuana.”
H 3C
O
O
CH 3
N
N
N
N
CH 3
caffeine
End of Lecture 13
33