Sex, Drugs, and the Brain

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Sex, Drugs, and the Brain

• A chemical journey through pain and pleasure

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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
Yet, deep inside our brain is the brain of
Africanus. Our limbic system has not changed
greatly in 2 million years.
Australophithecus Africanus
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The Limbic System
Ventricle
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The Neuron
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Photographs of Real Neurons
dendrite
axon
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The Synapse
terminal button of neuron 1
presynaptic neuron
0.2 mm
dendrite of neuron 2
postsynaptic neuron
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Neurons Communicate through Chemical Messengers
neurotransmitter
neurotransmitter receptor
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Monoamine Neurotransmitters

• Common Features
• phenol or catachol ring
• 2-carbon aliphatic amine chain
• Destroyed by MAO

dopamine
norepinephrine
serotonin
adrenaline
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Biosynthesis of Dopamine and Norepinephrine
tyrosine
L-DOPA
norepinephrine
dopamine
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Neurotransmitters are Carefully Regulated

Simultaneous formation and destruction affords
careful regulation of neurotransmitter levels in
brain
biosynthesis


MAO
3,4-dihydroxyphenylacetic acid
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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
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Methamphetamine Action
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Cocaine Action
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Heroin Action
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Septum is Focal Point for Pleasure
Dr. Robert Heath
Dr. James Olds
Stimulation of the septum produces intense
pleasure
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Molecular Design by Analogues
azobenzene
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Natural Neurotransmitter Analogues
Psilocybe Mexacana
cacao
nutmeg
Peyote cactus
Yopo tree
Ergot fungus
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Naturally Occurring Dopamine Analogues
mescaline (from Peyote cactus)
dopamine (from brain)
cathanone (from Kat)
phenylethylamine (from chocolate)
ephedrine (from Ephedra)
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Synthetic Dopamine Analogues
amphetamine (goofballs)
methamphetamine (speed, crystal meth, crank)
methylenedioxoamphetamine (MDA)
methylenedioxomethamphetamine (MDMA, XTC, love
drug, E)
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Natural Serotonin Analogues
Yopo
from a Peruvian tree
psilocybin
from Psilocybe Mexicana (Magic Mushroom)
serotonin
from brain
lysergic acid
psilocin
from Ergot fungus
from Magic Mushroom
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Synthetic Serotonin Analogues
diethyltryptamine (DET)
lysergic acid diethylamide (LSD, acid)
dimethyltryptamine (DMT)
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Pioneers of Neurotransmitter Analogues
Dr. Albert Hoffman
Dr. Alexander Shulgin
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Harvard University Psilocybin Research Project
Dr. Timothy Leary
Prof. Richard Alpert
Aldous Huxley
Two year study of the effects of psilocybin
analogs on the scholarly creativity of students
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Molecular Design of Dopamine Antagonist by QSAR
Used with permission from Wyeth-Ayerst
Laboratories, 2005
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Practical Uses of Neurotransmitter Analogues
L-DOPA (Parkinsons)
Tigan (antischizophrenic)
Clozapine (antipsychotic)
Haloperidol (antipsychotic)
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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
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Sex and Love are Different
nucleus accumbens
Think about sex
Think about love
prefrontal cortex
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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)
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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?
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Two Important Neuropeptides
different by only two amino acid residues
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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?
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Might as Well Face it, Youre Addicted to Love
Robert Palmer, 1995
Love high endorphin levels High serotonin
levels Low dopamine Low testosterone Heartbreak
Low endorphin levels Sudden drop in serotonin Low
dopamine Low testosterone
Drug addiction High endorphin levels High
serotonin levels Low dopamine Low
testosterone Drug withdrawal Low endorphin
levels Sudden drop in serotonin Low dopamine Low
testosterone
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The Chemistry of Chemistry
A play in three acts
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Meet the Players
norepinephrine
aka Mr. Excitement
oxytocin aka Cuddles
dopamine
aka Mr. Desire
vasopressin aka Mother Superior
serotonin
aka Mr. Happy
testosterone aka Sarge
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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
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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
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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
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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,
youre in love. If mother superior wins, youre
just having fun.
Scene 14 Oxytocin (cuddles) wins youre in
love!
and all this happens in just 4 minutes
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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
Dont look at other girls, youll
die Testosterone Whats a matter with you,
yella? Reach over and hold her hand Vasopressin
Dont touch her hand, youll die Oxytocin Oh
lets 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 youll die Testosterone Oh,
dont listen to that youll 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, youll
die
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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
Exit Stage Right
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New Love is a Psychosis
Within days, serotonin drops to levels mimicking
that found in patients with obsessive-compulsive
disorder
When our lovers are separated they literally
obsess over each other.
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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
Enter stage left - Serotonin
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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.
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Acknowledgements
York University Department of Chemistry
Dr. Gillian Wu, Dean of Science and
Engineering Science Speakers Bureau You
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Proximity of amygdala and nucleus accumbens
Nucleus accumbens
amygdala
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The Bonobo Chimpanzee
Dr. Susan Block
The Bonobo is a hominid and is our closest
genetic relative sharing 99.7 of our genes
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Pheromones
DEET (alarm pheromone for ticks, fleas,
mosquitoes)
Hamsters (sex attractant)
Cockroach (sex attractant)
Gypsy moth (male sex attractant)
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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 its symbolism for
  wealth
• HOWEVER . It may be more complicated!

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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.
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Why do pigs like truffles so much?
HINT They dont 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
androstenol
Sows exposed to pure androstenol become
uncontrollably sex-crazed
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Androstenol

• 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

Androstenol
testosterone
Could androstenol be a human sex pheromone?
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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
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So, is androstenol a real human sex pheromone?
Apparently not social factors can override any
pheromone control (if there is any)
But its sure being marketed like it is
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Women dont feel left out
The same company markets to you too
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Androstenol smells like musk

• 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
• Exaltolide is currently used in almost all
  colognes for men
• If a man is injected with estrogen, he can
  suddenly smell exaltolide!

Muskone (from Musk Deer)
Exaltolide (synthetic analogue)
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The Martha McClintock Story

• Heard that women who live together get their
  periods together
• Performed a study of 135 residents of a womens
  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

Martha McClintock, age 19
Harvard University psychology major
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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 womens periods synchronized to
  within 4 days in less than 2 months
• Conclusion pheromone is in underarm sweat

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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. No
effect of any kind on men
Professor Martha McClintock
University of Chicago