sex, drugs, and the brain a chemical journey through pain and pleasure
TRANSCRIPT
Sex, Drugs, and the Brain
A chemical journey through pain and pleasure
Evolution of the Limbic SystemEvolution of the Limbic System
Australophithecus Africanus
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.
The Limbic SystemThe Limbic SystemVentricle
The NeuronThe Neuron
Photographs of Real NeuronsPhotographs of Real Neurons
axon
dendrite
The SynapseThe Synapse
terminal button of neuron 1
dendrite of neuron 2
0.2
m presynaptic neuron
postsynaptic neuron
Neurons Communicate Neurons Communicate through Chemical Messengersthrough Chemical Messengers
neurotransmitter
neurotransmitter receptor
Monoamine NeurotransmittersMonoamine Neurotransmitters
NH2
OH
HONH2
OH
HO
OH
NH
OH
HO
OHN
NH2
HO
H
dopamine norepinephrine
serotonin adrenaline
Common Features
1. phenol or catachol ring
2. 2-carbon aliphatic amine chain
3. Destroyed by MAO
Biosynthesis of Dopamine and Biosynthesis of Dopamine and NorepinephrineNorepinephrine
HO
OH
O
NH2HO
OH
O
NH2
OH
HONH2
OH
HONH2
OH
OH
tyrosine L-DOPA
norepinephrine dopamine
Neurotransmitters are Carefully Neurotransmitters are Carefully RegulatedRegulated
NH2
OH
HOO
OH
HO
OH
HO
OH
O
NH2
biosynthesis
MAO
3,4-dihydroxyphenylacetic acid
Simultaneous formation and destruction affords careful regulation of neurotransmitter levels in brain
*
* *
Dopamine PathwaysDopamine 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 ActionMethamphetamine Action
Cocaine ActionCocaine Action
Heroin ActionHeroin Action
Septum is Focal Point for Septum is Focal Point for PleasurePleasure
Dr. Robert Heath Dr. James Olds
Stimulation of the septum produces intense pleasure
Molecular Design by Analogues
NN
NN
HO3S
OH
O
SO3H
NN
HO3S
OH
SO3H
O
N
H
NH2
O
O
O
N
H
NH2
O
azobenzene
Natural Neurotransmitter Natural Neurotransmitter AnaloguesAnalogues
Psilocybe Mexacana
cacao nutmeg
Peyote cactus Yopo tree Ergot fungus
Naturally Occurring Dopamine Naturally Occurring Dopamine AnaloguesAnalogues
NH2
OH
HONH2
O
O
O
NH
OH
NH
O
dopamine (from brain)
mescaline (from Peyote cactus)
NH2
ephedrine (from Ephedra)
cathanone (from Kat)
phenylethylamine (from chocolate)
Synthetic Dopamine AnaloguesSynthetic Dopamine Analogues
NH2 NH
NH2
O
O
NHO
O
amphetamine (goofballs)
methamphetamine (speed, crystal meth, crank)
methylenedioxoamphetamine (MDA)
methylenedioxomethamphetamine (MDMA, XTC, love drug, E)
Natural Serotonin AnaloguesNatural Serotonin Analogues
N
H
NH2
HO
N
H
N
OP
O
HO
HO
N
H
N
OH
N
H
N
O
N
H
N
O
HO
serotonin
Yopo
psilocybin
from a Peruvian tree
from Psilocybe Mexicana (Magic Mushroom)
psilocin
from Magic Mushroom
from brain
lysergic acidfrom Ergot fungus
Synthetic Serotonin AnaloguesSynthetic Serotonin Analogues
N
H
N
O
N
N
H
N
N
H
N
lysergic acid diethylamide (LSD, acid)
diethyltryptamine (DET)
dimethyltryptamine (DMT)
Pioneers of Neurotransmitter Pioneers of Neurotransmitter AnaloguesAnalogues
Dr. Albert Hoffman Dr. Alexander Shulgin
Harvard University Psilocybin Research Harvard University Psilocybin Research ProjectProject
Dr. Timothy Leary Prof. Richard AlpertAldous Huxley
Two year study of the effects of psilocybin analogs on the scholarly creativity of students
Molecular Design of Dopamine Antagonist by Molecular Design of Dopamine Antagonist by QSARQSAR
Used with permission from Wyeth-Ayerst Laboratories, 2005
HO N
N
Practical Uses of Neurotransmitter Practical Uses of Neurotransmitter AnaloguesAnalogues
OH
HONH2
O
OH
L-DOPA (Parkinson’s)
N
NCl
H
N
N
Clozapine (antipsychotic)
O
O
O
O
HN
O
NTigan (antischizophrenic)
Haloperidol (antipsychotic)
N
O
FHO
Cl
The Remote-Controlled CockroachThe 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 DifferentSex and Love are Different
Think about sex
Think about love
nucleus accumbens
prefrontal cortex
Addicted to Love (quite Addicted to Love (quite literally!)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 What We Learned from the Prairie VoleVole
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 Two Important NeuropeptidesNeuropeptides
different by only two amino acid residues
Effects of Oxytocin on BehaviorEffects 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 Might as Well Face it, You’re Addicted to Love … … Robert Palmer, 1995Robert 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
The Chemistry of “Chemistry”The Chemistry of “Chemistry”
A play in three acts
Meet the Players
NH2
OH
HO
OH
NH2
OH
HO
N
H
NH2
HO
cys tyr ile gln asn cys pro leu gly
S S
cys tyr phe gln asn cys pro arg gly
S S
OH
O
norepinephrine
aka Mr. Excitement
dopamineaka Mr. Desire
serotoninaka Mr. Happy
oxytocin aka Cuddles
vasopressin aka Mother Superior
testosterone aka Sarge
Act 1: Strangers in the NightAct 1: Strangers in the NightScene 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 The Mesolimbic Dopamine PathwayPathway
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 ComplicatedAct 2: Now it gets ComplicatedEnter stage left: Oxytocin and
VasopressinAs 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?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 ScriptThe ScriptThe 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
IntermissionIntermission
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
N
H
NH2
HO
Exit Stage Right
New Love is a PsychosisNew 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.
Act 3: Oxytocin to the RescueAct 3: Oxytocin to the Rescue
N
H
NH2
HO
Enter stage left - Serotonin
Oxytocin acts as a serotonin reuptake inhibitor (naturally occurring Prozac). In about 6 months, serotonin is back to normal
THE ENDTHE 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.
AcknowledgementsAcknowledgements
York University Department of Chemistry
Dr. Gillian Wu, Dean of Science and Engineering
Science Speakers Bureau
You
Proximity of amygdala and Proximity of amygdala and nucleus accumbensnucleus accumbens
amygdala
Nucleus accumbens
The Bonobo ChimpanzeeThe Bonobo Chimpanzee
The Bonobo is a hominid and is our closest genetic relative sharing 99.7% of our genes
Dr. Susan Block
OH
O
OH
HO
PheromonesPheromonesO
N
OO
O
OH
S S
Gypsy moth (male sex attractant)
DEET (alarm pheromone for ticks, fleas, mosquitoes)
Cockroach (sex attractant)
Hamsters (sex attractant)
Truffles and SexTruffles and Sex
Truffles have historically been used to “impress” a female dateTruffles have historically been used to “impress” a female date
Truffles are very expensive and are a sign of power and wealthTruffles are very expensive and are a sign of power and wealth
Consequently it had been assumed that the “power of the Consequently it had been assumed that the “power of the truffle” was due to it’s symbolism for wealthtruffle” was due to it’s symbolism for wealth
HOWEVER …. It may be more complicated!HOWEVER …. It may be more complicated!
Truffles and PigsTruffles 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 Why do pigs like truffles so much?much?
HINT: They don’t eat them
HO
androstenol
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
Sows exposed to pure androstenol become uncontrollably “sex-crazed”
HO
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
Androstenol
AndrostenolAndrostenol
testosteroneCould androstenol be a human sex pheromone?
Obvious next experimentObvious next experiment
Women (who self-identified as straight) were shown pictures Women (who self-identified as straight) were shown pictures of men and asked to rate them on a scale from 1 to 10of men and asked to rate them on a scale from 1 to 10
Control group rated them at 6 (average) Control group rated them at 6 (average)
Androstenol group rated them at 6 (average)Androstenol group rated them at 6 (average)
HOWEVER --- androstenol group rated photos of OTHER HOWEVER --- androstenol group rated photos of OTHER WOMEN at 8, as opposed to 5 for control group!WOMEN at 8, as opposed to 5 for control group!
Dr. Michael Kirk-Smith, University of Birmingham (every male graduate student volunteered to conduct the
experiment)
Let female humans smell androstenol and see if they become uncontrollably sex-crazed
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 outWomen – don’t feel left out
The same company markets to you too
Androstenol smells like muskAndrostenol smells like musk
(CH2)11
O
O
(CH2)11
O
It has been known for centuries that It has been known for centuries that perfumes and colognes that smell perfumes and colognes that smell “musky” tend to be better received “musky” tend to be better received by the opposite sexby the opposite sex
Women can smell exaltolide, an Women can smell exaltolide, an analogue of muskone, men cannot!analogue of muskone, men cannot!
After inhaling exaltolide, women After inhaling exaltolide, women become more socialbecome more social
Exaltolide is currently used in Exaltolide is currently used in almost all colognes for menalmost all colognes for men
If a man is injected with estrogen, If a man is injected with estrogen, he can suddenly smell exaltolide!he can suddenly smell exaltolide!
Muskone (from Musk Deer)
Exaltolide
(synthetic
analogue)
The Martha McClintock StoryThe Martha McClintock Story Heard that women who live Heard that women who live
together get their periods together get their periods togethertogether
Performed a study of 135 Performed a study of 135 residents of a women’s dorm (8 residents of a women’s dorm (8 to a room)to a room)
Found that by March all Found that by March all roommates had periods within 5 roommates had periods within 5 days of each otherdays of each other
Demonstrated for the first time Demonstrated for the first time the existence of a human the existence of a human pheromonepheromone
Published her work in NaturePublished her work in NatureMartha McClintock, age 19
Harvard University psychology major
Essence of Genevieve
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
Dr. Mark Russel, Brain Behavior Research Institute, Sonoma State Hospital, California
Now she found another oneNow she found another one
Professor Martha McClintockUniversity of Chicago
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