Transcript to Power Point slides - Department of Chemistry, York

Sex, Drugs, and the Brain
A chemical journey through pain and pleasure
Evolution of the Limbic System
Africanus had a brain about 1/3 the size
of our modern brain
Africanus was primarily instinctive in
behavior
Africanus was not capable of language
Africanus had practically no
prefrontal cortex and was probably
not capable of weighing options
Australophithecus Africanus
Yet, deep inside our brain is
the brain of Africanus. Our
limbic system has not changed
greatly in 2 million years.
The Limbic System
Ventricle
The Neuron
Photographs of Real Neurons
dendrite
axon
The Synapse
0.2 mm
terminal button of neuron 1
presynaptic neuron
dendrite of neuron 2
postsynaptic neuron
Neurons Communicate through
Chemical Messengers
neurotransmitter
neurotransmitter
receptor
Monoamine Neurotransmitters
OH
Common Features
NH2
HO
NH2
HO
2. 2-carbon aliphatic
amine chain
OH
OH
dopamine
norepinephrine
H
OH
N
HO
NH
HO
NH2
serotonin
1. phenol or catachol ring
OH
adrenaline
3. Destroyed by MAO
Biosynthesis of Dopamine and
Norepinephrine
O
O
OH
OH
NH2
HO
NH2
HO
tyrosine
L-DOPA
OH
OH
NH2
HO
NH2
HO
OH
norepinephrine
OH
dopamine
Neurotransmitters are Carefully Regulated
O
*
Simultaneous formation and
destruction affords careful
regulation of
neurotransmitter levels in
brain
OH
NH2
HO
biosynthesis
*
*
MAO
NH2
HO
OH
O
HO
OH
OH
3,4-dihydroxyphenylacetic acid
Dopamine Pathways
The mesolimbic
pathway aka the
“pleasure center”
The mesolimbic pathway is your
reward system for behavior that
needs to be reinforced (eating,
seeking warmth or shelter, sex,
winning a fight, etc.)
septum
Methamphetamine Action
Cocaine Action
Heroin Action
Septum is Focal Point for Pleasure
Dr. Robert Heath
Dr. James Olds
Stimulation of the septum produces intense pleasure
Molecular Design by Analogues
HO3S
N
N
O
N
azobenzene
N
SO3H
OH
O
N
O
NH2
H
HO3S
O
O
N
NH2
N
H
N
O
OH
SO3H
Natural Neurotransmitter Analogues
Psilocybe Mexacana
cacao
nutmeg
Peyote cactus
Yopo tree
Ergot fungus
Naturally Occurring Dopamine Analogues
O
NH2
HO
NH2
O
OH
O
mescaline (from
Peyote cactus)
dopamine (from
brain)
O
OH
NH
ephedrine (from
Ephedra)
NH
NH2
cathanone (from
Kat)
phenylethylamine
(from chocolate)
Synthetic Dopamine Analogues
NH2
amphetamine
(goofballs)
NH
methamphetamine (speed,
crystal meth, crank)
NH
NH2
O
O
O
methylenedioxoamphetamine
(MDA)
O
methylenedioxomethamphetamine
(MDMA, XTC, love drug, E)
Natural Serotonin Analogues
O
O
HO
N
N
P
HO
O
H
Yopo
from a Peruvian tree
N
N
H
O
HO
HO
N
N
H
NH2
psilocybin
from Psilocybe Mexicana
(Magic Mushroom)
OH
serotonin
from brain
N
H
N
N
H
lysergic acid
from Ergot fungus
psilocin
from Magic Mushroom
Synthetic Serotonin Analogues
N
H
O
N
N
diethyltryptamine
(DET)
N
N
H
N
H
lysergic acid diethylamide
(LSD, acid)
dimethyltryptamine
(DMT)
N
Pioneers of Neurotransmitter Analogues
Dr. Albert Hoffman
Dr. Alexander Shulgin
Harvard University Psilocybin Research Project
Dr. Timothy Leary
Aldous Huxley
Prof. Richard Alpert
Two year study of the effects of psilocybin analogs on the scholarly
creativity of students
Molecular Design of Dopamine Antagonist by QSAR
N
HO
N
Used with permission from Wyeth-Ayerst Laboratories, 2005
Practical Uses of Neurotransmitter Analogues
O
O
O
OH
NH2
HO
HN
O
O
O
OH
L-DOPA (Parkinson’s)
Tigan (antischizophrenic)
N
N
N
Cl
Cl
N
N
H
Clozapine (antipsychotic)
N
HO
F
O
Haloperidol (antipsychotic)
The Remote-Controlled Cockroach
This cockroach has an
electrode array implanted
in its brain, and can be
steered by radio control
From Northwestern University,
Chicago, IL
Sex and Love are Different
nucleus
accumbens
Think about sex
Think about love
prefrontal
cortex
Addicted to Love (quite literally!)
Dr. Helen Fisher
Rutgers University
Dr. Sue Carter
University of Illinois
Dr. Karen Bales
University of California
These researchers study the role of neuropeptides in pair-bonding
(romantic love)
What We Learned from the Prairie Vole
Prairie vole is a monogamous
species. That is, it finds a mate
and stays together for life
Its close cousin, the Montane
vole, is non-monogamous. It
never mates with the same
partner twice
Yet, the Prairie vole and
Montane vole have essentially
the same brain. So, what
causes this dramatic
behavioral difference?
Two Important Neuropeptides
different by only two amino acid residues
Effects of Oxytocin on Behavior
Injecting oxytocin into a Montane vole will cause it to
temporarily act like a Prairie vole
Injecting a Prairie vole with an oxytocin blocker will cause it to
temporarily act like a Montane vole
In humans, oxytocin levels increase when we are in love,
increase when we simply touch our pets, and, in women,
increase dramatically just after childbirth
Hypothesis: Could oxytocin be the molecule of love?
Might as Well Face it, You’re Addicted to Love …
Robert Palmer, 1995
Love
Drug addiction
high endorphin levels
High endorphin levels
High serotonin levels
High serotonin levels
Low dopamine
Low dopamine
Low testosterone
Low testosterone
Heartbreak
Drug withdrawal
Low endorphin levels
Low endorphin levels
Sudden drop in serotonin
Sudden drop in serotonin
Low dopamine
Low dopamine
Low testosterone
Low testosterone
The Chemistry of “Chemistry”
A play in three acts
Meet the Players
OH
cys
NH2
HO
tyr
norepinephrine
aka Mr. Excitement
ile
S
gln
asn
cys pro
leu gly
S
oxytocin aka Cuddles
OH
cys
NH2
HO
tyr phe gln
dopamine
aka Mr. Desire
S
asn
cys pro
arg gly
S
vasopressin aka Mother Superior
OH
OH
HO
N
H
NH2
serotonin
aka Mr. Happy
O
testosterone aka Sarge
Act 1: Strangers in the Night
Scene 1: Testosterone elevates in the blood,
signals the body to physically respond, and
influences the decision making areas of the
brain to “go for it”
Scene 2: Sensory information enters the
brainstem triggering the release of dopamine
in the ventral tegmentum
Scene 3: The ventral tegmentum fires a
series of signals into the limbic system via
the mesolimbic dopamine pathway
Scene 4: Norepinephrine elevates in the limbic
system signaling the onset of pleasure. The
hypothalamus and pituitary convert
norepinephrine into adrenaline triggering a
“fight or flight” response, resulting in
emotional excitement
The Mesolimbic Dopamine Pathway
Scene 5: dopamine signals enter the septum,
the main focal point of the “pleasure center”
Scene 6: dopamine signals reach the
nucleus accumbens, reinforcing this
behavior
Scene 7: dopamine signals make it to
the prefrontal cortex, the decision
making headquarters
Scene 8: the prefrontal cortex now makes
a series of decisions, weighing options
and consequences, and simultaneously
stimulates the septum, nucleus
accumbens, and amygdala
Act 2: Now it gets Complicated
Enter stage left: Oxytocin and Vasopressin
As our lovers become increasingly enchanted with each others charms, the
hypothalamus perks up and manufactures two neuropeptides, oxytocin (aka
cuddles) and vasopressin (aka mother superior), and releases both of them into
the cerebrospinal fluid. There they have full access to all the organs of the limbic
system
Scene 9: Oxytocin binds to hippocampus, allowing the lovers to remember
each other
Scene 10: Vasopressin binds to septum, dulling reward, and binds to amygdala
causing warning signals, fear, and inhibition of attachment
Scene 11: Oxytocin binds to nucleus accumbens, causing memory of “pleasure”
to associate with this particular person
Pair-bond? Yes or no?
Scene 12: The prefrontal cortex takes all sensory inputs, inputs from
hippocampus, and inputs from memory, and goes into high gear to make
decisions. These decisions are conveyed back to the limbic system as signals to
the cingulate (“happy” vs. “unhappy”), amygdala (fear or threat of impending
loss), septum (pleasure), and nucleus accumbens (habituation).
Scene 13: In the meantime, “cuddles” and “mother superior” are battling it out. If
cuddles wins, you’re in love. If mother superior wins, you’re just having fun.
Scene 14: Oxytocin (cuddles) wins – you’re in love!
and all this happens in just 4 minutes
The Script
The scene takes place in the limbic system of a young man sitting with his date at the
Underground Pub at York University on a Saturday night. There is no shortage of young
women dancing a few feet away.
Testosterone: Look at that one. No, look at that one. No, look at that one.
Dopamine: Boy o boy o boy, is this gonna be fun or what?
Vasopressin: Don’t look at other girls, you’ll die
Testosterone: What’s a matter with you, yella? Reach over and hold her hand
Vasopressin: Don’t touch her hand, you’ll die
Oxytocin: Oh let’s hold hands all night and stare in her eyes, and hug
Testosterone: Hug, shmug! What a waste of time. Go for the gusto soldier!
Vasopressin: Stop! Do that and you’ll die
Testosterone: Oh, don’t listen to that you’ll do nothing. Go for the gusto soldier!
Oxytocin: I need a hug
Dopamine: Boy o boy, is this gonna be fun or what?
Vasopressin: If you listen to Sarge, you’ll die
Intermission
All seems good with our lovers, BUT …..
Something nasty is happening in our lovers’ brains!!
All this limbic activity is dropping serotonin level fast and hard
HO
N
H
NH2
Exit Stage Right
New Love is a Psychosis
Within days, serotonin drops
to levels mimicking that found
in patients with obsessivecompulsive disorder
When our lovers are separated
they literally obsess over each
other.
Act 3: Oxytocin to the Rescue
Oxytocin acts as a serotonin reuptake inhibitor (naturally
occurring Prozac). In about 6 months, serotonin is back to
normal
HO
Enter stage left - Serotonin
N
H
NH2
THE END
DISCLAIMER: As serotonin levels build, physical attraction between our lovers
wanes. High oxytocin levels also inhibit the action of vasopressin and
testosterone, further diminishing excitement in the relationship. This begins at
about 17 months. There is about a 50% chance the relationship will end in
roughly 4 years.
Acknowledgements
York University Department of Chemistry
Dr. Gillian Wu, Dean of Science and Engineering
Science Speakers Bureau
You
Proximity of amygdala and nucleus
accumbens
Nucleus
accumbens
amygdala
The Bonobo Chimpanzee
Dr. Susan Block
The Bonobo is a hominid and is our closest
genetic relative sharing 99.7% of our genes
OH
HO
OH
O
Pheromones
O
N
S
O
DEET (alarm
pheromone for
ticks, fleas,
mosquitoes)
S
O
Cockroach (sex
attractant)
Hamsters (sex
attractant)
OH
O
Gypsy moth (male sex attractant)
Truffles and Sex

Truffles have historically been used to “impress” a female date

Truffles are very expensive and are a sign of power and wealth


Consequently it had been assumed that the “power of the truffle”
was due to it’s symbolism for wealth
HOWEVER …. It may be more complicated!
Truffles and Pigs
Truffles are mushrooms that
grow underground
Female pigs can smell truffles over 1 meter underground. Sometimes
they dig so ferociously that they have to be physically restrained.
Why do pigs like truffles so much?
HINT: They don’t eat them
1981 - Drs. Claus and Hoppen at
the Technical University of
Munich and Dr. Kong at the
Lubeck School of Medicine
independently found the active
attractant in truffles
HO
androstenol
Sows exposed to pure androstenol become uncontrollably “sexcrazed”
Androstenol


HO
Androstenol

OH

O
Androstenol is an analogue
of testosterone
Androstenol is produced in
the testes of boars and
transported to the salivary
glands
Sows exhibit a pronounced
Lordosis reflex when they
smell the breath of a boar
Androstenol is also
produced in the testes of
humans and transferred to
underarm sweat glands
testosterone
Could androstenol be a human sex pheromone?
Obvious next experiment
Let female humans smell androstenol and see if they
become uncontrollably sex-crazed
Dr. Michael Kirk-Smith, University of Birmingham (every male
graduate student volunteered to conduct the experiment)

Women (who self-identified as straight) were shown pictures of men
and asked to rate them on a scale from 1 to 10

Control group rated them at 6 (average)

Androstenol group rated them at 6 (average)

HOWEVER --- androstenol group rated photos of OTHER WOMEN at
8, as opposed to 5 for control group!
CONCLUSION: androstenol makes women more attractive to women
So, is androstenol a real human sex pheromone?
Apparently not – social factors can
override any pheromone control (if there
is any)
But it’s sure being marketed like it is
Women – don’t feel left out
The same company markets
to you too
Androstenol smells like musk
O
(CH2)11


Muskone (from
Musk Deer)
O

It has been known for centuries that
perfumes and colognes that smell
“musky” tend to be better received by
the opposite sex
Women can smell exaltolide, an analogue
of muskone, men cannot!
After inhaling exaltolide, women become
more social
O

(CH2)11
Exaltolide
(synthetic
analogue)

Exaltolide is currently used in almost all
colognes for men
If a man is injected with estrogen, he
can suddenly smell exaltolide!
The Martha McClintock Story





Martha McClintock, age 19
Harvard University psychology major
Heard that women who live
together get their periods together
Performed a study of 135 residents
of a women’s dorm (8 to a room)
Found that by March all roommates
had periods within 5 days of each
other
Demonstrated for the first time the
existence of a human pheromone
Published her work in Nature
Essence of Genevieve
Dr. Mark Russel, Brain Behavior Research Institute, Sonoma State Hospital, California





read McClintock paper in Nature and became interested in
identifying the pheromone
Had a lab assistant named Genevieve wear sterile cotton
underarm pads for several days
Extracted the pads with alcohol and applied the extraction
to upper lip of eight women
Found all 8 women’s periods synchronized to within 4 days
in less than 2 months
Conclusion: pheromone is in underarm sweat
Now she found another one
Took the breast pads (unwashed) of over 100
nursing women and extracted them with alcohol
Treated handkerchiefs with the alcohol solution
and had other women wear the handkerchiefs
close to their faces for several days
FINDINGS
The other women had a dramatic increase in
sexual fantasies.
Breast “essence” from non-breastfeeding women
had no effect.
Professor Martha McClintock
University of Chicago
No effect of any kind on men