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