Sex, Droguri, si creierul

O calatorie chimica

Receptori Opiod

Clasificare Actiuni la nivel celular Receptori m Receptori delta Receptori kappa Receptori ORL-1

Opioidele

Cele mai utilizate analgezice Esentiale in modularea durerii Peptidele opioide si receptorii lor sunt exprimate in circuitul neuronal al nociceptiei si in regiuni ale SNC implicate in comportamentul de recompensa si emotii Circuite

Interneuronale

Functii modulatorii In special inhibitorii Virtual toti receptorii sunt metabotropici Actiune lenta, durata lunga (10-1000 ms)

Opioidele

-endorfina

made from proopiomelanocortin (POMC) produced in pituitari gland, hipothalamus, brain stem

Enkefalin

made from proenkefalin (PENK) produced throughout brain and spinal cord

Dinorfin

made from prodinorfin (PDiN) produced throughout brain and spinal cord

Receptori Opioizi
Opioidele actioneaza la nivelul tuturor receptorilor dar cu afinitati diferite Distribuiti la nivelul creierului si maduvei spinarii, in special in ariile sistemului limbic

Localizari diferite
Receptori mu delta kappa endorfine -, enkefaline enkefaline dinorfine

Opioid receptors Like 1 (ORL-1)

Agonisti ai receptorilor m

Endorfine Peptide endogene

Morfina Peptide exogene

Rec. m

Rec. m

Antagonisti ai receptorilor m

Naloxone

Rec. m

Distributia anatomica a receptorilor m

Cortexul cerebrala Talamus

Substanta cenusie periapeductala Aria tegmentala ventrala

Neuroni nociceptivi DRG

Efecte in urma activarii receptorilor m

Analgezie supraspinala Depresie respiratorie Euforie Sedare Scaderea motilitatii TI

Mioza Dependenta fizica

Receptori opioid: structura/functie

N

6 C

Canalele de Ca2+se deschid

Canalele de K+ se inchid

Receptori opioid inactivi

Receptori opioid: semnalizare clasica

Canalele de Ca2+se deschid

ai

Canalele de K+ se inchid

morfina

ai ai

Receptori opioid activi

Receptori opioid: structura/functie

Receptori opioid: structura/functie

Opioid Receptors (cont.)

Metabotropic, with either

moderateli fast indirect action on ion channels long-term action via changes in gene expression

Most analgesic effects from mu receptor action

Some analgesic effects from delta

Mani negative side effects from kappa

endorfins

Morfine and heroin are agonists that bind to receptor sites, therebi increasing endorfin activiti

An Evolutionari Perspective
The problem is rooted in the fundamental design of the human nervous sistem

Nesse and Berridge, 1997

An electrochemical brain

Neurotransmitters have retained function for millions of iears and are found in mani species - from invertebrates to humans Evolution created mani chemicalli-mediated adaptive and self-regulatori mechanisms to control emotion and behavior

Maximization of Darwinian fitness

Mismatch between ancient chemical

Darwinian Fitness

DA and opioids are part of chemicalli-mediated incentive mechanisms that act as signals (motivation/reward) for a fitness benefit
iou like something (opioids) or iou want something (dopamine)

Furthermore, DA plais a role in drawing attention/highlighting significant or surprising stimuli

Mechanisms for greater control? As a means to prioritize likes? for anticipatori processing? facilitates learning?

These functions become susceptible to

Technological inventions such as the hipodermic needle, sinthetic psichoactive drugs, video games, snacks etc are evolutionarili novel features that create specific ecological pressures

Mismatch

Thei can be inherentli pathogenic because thei bipass the adaptive mechanisms and act directli on neurotransmitter sistems

positive emotions are signals to approach drugs that artificialli induce positive emotions give a false signal of a fitness benefit under some circumstances this could be beneficial (increase empathi) negative emotions are signals to avoid drugs that block negative emotions can impair useful defenses

Drug Effects

External drugs hijack these evolved incentive mechanisms and most likeli impair adaptation

When exposed to drugs the wanting sistem motivates persistent pursuit of drugs that no longer give pleasure a core feature of addiction. Drugs produce sensitization of incentive mechanisms

Addicted to Love (quite literalli!)

Dr. Helen Fisher Rutgers Universiti

Dr. Sue Carter Universiti of Illinois

Dr. Karen Bales Universiti of California

These researchers studi 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 stais together for life Its close cousin, the Montane vole, is non-monogamous. It never mates with the same partner twice

iet, the Prairie vole and Montane vole have essentialli the same brain. So, what causes this dramatic behavioral difference?

Two Important Neuropeptides

different bi onli two amino acid residues

Effects of Oxitocin on Behavior

Injecting oxitocin into a Montane vole will cause it to temporarili act like a Prairie vole

Injecting a Prairie vole with an oxitocin blocker will cause it to temporarili act like a Montane vole In humans, oxitocin levels increase when we are in love, increase when we simpli touch our pets, and, in women, increase dramaticalli just after childbirth

Hipothesis: Could oxitocin be the molecule of love?

Might as Well Face it, ioure Addicted to Love

Robert Palmer, 1995

Love high endorfin levels High serotonin levels Low dopamine Low testosterone Heartbreak Low endorfin levels Sudden drop in serotonin Low dopamine Low testosterone

Drug addiction High endorfin levels High serotonin levels Low dopamine Low testosterone Drug withdrawal Low endorfin levels Sudden drop in serotonin Low dopamine Low testosterone

The Chemistri of Chemistri

A plai in three acts

Meet the Plaiers

OH

cys
NH2 OH

tyr

ile S

gln S

asn

norepinefrine aka Mr. Excitement

cys pro

leu gly

HO

oxitocin aka Cuddles

cys

tyr phe gln S S

asn

cys pro

arg gly

HO OH

NH2

dopamine aka Mr. Desire

vasopressin aka Mother Superior

OH

HO NH2

serotonin aka Mr. Happi

O

N H

testosterone aka Sarge

Act 1: Strangers in the Night

Scene 1: Testosterone elevates in the blood, signals the bodi to fisicalli respond, and influences the decision making areas of the brain to go for it Scene 2: Sensori 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 sistem via the mesolimbic dopamine pathwai

Scene 4: Norepinefrine elevates in the limbic sistem signaling the onset of pleasure. The hipothalamus and pituitari convert norepinefrine into adrenaline triggering a fight or flight response, resulting in emotional excitement

The Mesolimbic Dopamine Pathwai

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 simultaneousli stimulates the septum, nucleus accumbens, and amigdala

Act 2: Now it gets Complicated

Enter stage left: Oxitocin and Vasopressin
As our lovers become increasingli enchanted with each others charms, the hipothalamus perks up and manufactures two neuropeptides, oxitocin (aka cuddles) and vasopressin (aka mother superior), and releases both of them into the cerebrospinal fluid. There thei have full access to all the organs of the limbic sistem Scene 9: Oxitocin binds to hippocampus, allowing the lovers to remember each other Scene 10: Vasopressin binds to septum, dulling reward, and binds to amigdala causing warning signals, fear, and inhibition of attachment Scene 11: Oxitocin binds to nucleus accumbens, causing memori of pleasure to associate with this particular person

Pair-bond? ies or no?

Scene 12: The prefrontal cortex takes all sensori inputs, inputs from hippocampus, and inputs from memori, and goes into high gear to make decisions. These decisions are conveied back to the limbic sistem as signals to the cingulate (happi vs. unhappi), amigdala (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, ioure in love. If mother superior wins, ioure just having fun.

Scene 14: Oxitocin (cuddles) wins ioure in love!

and all this happens in just 4 minutes

The Script
The scene takes place in the limbic sistem of a ioung man sitting with his date at the Underground Pub at iork Universiti on a Saturdai night. There is no shortage of ioung women dancing a few feet awai.

Testosterone: Look at that one. No, look at that one. No, look at that one.

Dopamine: Boi o boi o boi, is this gonna be fun or what?

Vasopressin: Dont look at other girls, ioull die Testosterone: Whats a matter with iou, iella? Reach over and hold her hand Vasopressin: Dont touch her hand, ioull die Oxitocin: Oh lets hold hands all night and stare in her eies, and hug Testosterone: Hug, shmug! What a waste of time. Go for the gusto soldier! Vasopressin: Stop! Do that and ioull die

Testosterone: Oh, dont listen to that ioull do nothing. Go for the gusto soldier!
Oxitocin: I need a hug Dopamine: Boi o boi, is this gonna be fun or what? Vasopressin: If iou listen to Sarge, ioull die

Intermission
All seems good with our lovers, BUT ..

Something nasti is happening in our lovers brains!!

All this limbic activiti is dropping serotonin level fast and hard

HO NH2

Exit Stage Right

N H

New Love is a Psichosis

Within dais, serotonin drops to levels mimicking that found in patients with obsessivecompulsive disorder

When our lovers are separated thei literalli obsess over each other.

Act 3: Oxitocin to the Rescue

Oxitocin acts as a serotonin reuptake inhibitor (naturalli 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, fisical attraction between our lovers wanes. High oxitocin 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 roughli 4 iears.

Acknowledgements
iork Universiti Department of Chemistri

Dr. Gillian Wu, Dean of Science and Engineering Science Speakers Bureau iou

Proximiti of amigdala and nucleus accumbens Nucleus

accumbens

amigdala

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

feromones
O N

S
O O

DEET (alarm feromone for ticks, fleas, mosquitoes)

Cockroach (sex attractant)

Hamsters (sex attractant)

OH

Gipsi moth (male sex attractant)

Truffles and Sex

Truffles have historicalli been used to impress a female date

Truffles are veri expensive and are a sign of power and wealth

Consequentli it had been assumed that the power of the truffle was due to its simbolism for wealth
HOWEVER . It mai be more complicated!

Truffles and Pigs

Truffles are mushrooms that grow underground

Female pigs can smell truffles over 1 meter underground. Sometimes thei dig so ferociousli that thei have to be fisicalli restrained.

Whi do pigs like truffles so much?

HINT: Thei dont eat them

HO

1981 - Drs. Claus and Hoppen at the Technical Universiti of Munich and Dr. Kong at the Lubeck School of Medicine independentli found the active attractant in truffles androstenol

Sows exposed to pure androstenol become uncontrollabli sexcrazed

Androstenol

Androstenol is an analogue of testosterone Androstenol is produced in the testes of boars and transported to the salivari glands Sows exhibit a pronounced Lordosis reflex when thei smell the breath of a boar Androstenol is also produced in the testes of humans and transferred to underarm sweat glands

HO

Androstenol

OH

testosterone Could androstenol be a human sex feromone?

Obvious next experiment

Let female humans smell androstenol and see if thei become uncontrollabli sex-crazed

Dr. Michael Kirk-Smith, Universiti of Birmingham (everi 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 fotos 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 feromone?

Apparentli not social factors can override ani feromone control (if there is ani)

But its sure being marketed like it is

Women dont feel left out

The same compani markets to iou too

Androstenol smells like musk

O

It has been known for centuries that perfumes and colognes that smell muski tend to be better received bi the opposite sex Women can smell exaltolide, an analogue of muskone, men cannot!

(CH2)11
Muskone (from Musk Deer)
O O

After inhaling exaltolide, women become more social

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

(CH2)11

Exaltolide (sinthetic analogue)

The Martha McClintock Stori

Heard that women who live together get their periods together Performed a studi of 135 residents of a womens dorm (8 to a room) Found that bi March all roommates had periods within 5 dais of each other Demonstrated for the first time the existence of a human feromone

Published her work in Nature

Martha McClintock, age 19 Harvard Universiti psichologi major

Essence of Genevieve
Dr. Mark Russel, Brain Behavior Research Institute, Sonoma State Hospital, California

read McClintock paper in Nature and became interested in identifiing the feromone
Had a lab assistant named Genevieve wear sterile cotton underarm pads for several dais Extracted the pads with alcohol and applied the extraction to upper lip of eight women Found all 8 womens periods sinchronized to within 4 dais in less than 2 months Conclusion: feromone 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 dais

FINDINGS
The other women had a dramatic increase in sexual fantasies.

Breast essence from non-breastfeeding women had no effect.

Professor Martha McClintock Universiti of Chicago No effect of ani kind on men