>> I THINK WE'LL BEGIN.

WE'LL VERY FORTUNATE TO HAVE TWO

GLOBAL LEADERS IN THE FIELD OF

ADDICTION.

I'LL TELL YOU JUST A LITTLE BIT

ABOUT THEM IN A MOMENT.

BUT IN THINKING ABOUT TODAY'S

SESSION AND TALKING ABOUT IT

WITH SEVERAL POST DOCS AND

FELLOWS, SOME OF THESE QUESTIONS

POPPED UP AS THE THINGS THA

CROSSED OUR MINDS.

AND I SUSPECT FOR THOSE OF YOU

WHO ARE NOT DEEPLY FAMILIAR WITH

ALL OF THIS, VERY SIMILAR

THINGS.

SO THIS ISN'T REALLY A QUIZ BUT

IT'S SOMETHING YOU MIGHT THINK

ABOUT.

THESE ARE WHAT WE WERE TALKING

ABOUT, IS ADDICTION A

PSYCHOLOGICAL OR AN ORGANIC

BRAIN DISEASE?

OR IS IT BOTH?

CAN YOU PREDICT VULNERABILITY?

WHO IS ON GOIN GOING TO BECOME ADDICTED.

ISN'T THERE ANY WAY IT'S

POSSIBLE TO DETERMINE OR GET

SOME CLUES ABOUT THAT.

SO IF THERE IS SOME

VULNERABILITY, IS THERE A

GENETIC BASIS AND IF SO HOW

IMPORTANT IS THAT.

IN A WAY, A SUBTITLE OF TODAY'S

SESSION COULD BE ADDICTION IN

THE GENOMIC ERA, BECAUSE THIS IS

A POWERFUL TOOL FOR PROBING

BEYOND THE CLASSICAL

EPIDEMIOLOGY TYPE STUDIES OF

ADDICTION AND FAMILIES OR

DIFFERENT TIMES AND JERN AND GENDERS AND

SUCH.

A VERY IMPORTANT QUESTION THAT

ONE OF MY POST DOCS ASKED ME WAS

IS ADDICTION A DEVELOPMENTAL

DISEASE.

MEANING IS IT SOMETHING THAT

OCCURS ESSENTIALLY, IS THE STAGE

SET EARLY IN LIFE.

OR IS IT SOMETHING YOU CAN SORT

OF ACQUIRE ANYWHERE.

THE NEUROBIOLOGY COUNTERPART OF

THAT IS WHEN DOES THE BRAIN

CEASE DEVELOPING.

DOES IT STOP DEVELOPING AT ALL.

OR ARE WE ALWAYS CHANGING.

I MEAN, WAY BACK WHEN MY TIME WE

WERE TOLD THAT NEURONS ARE THERE

FOR THE LIFETIME AND THEY COME,

THEY GO, THAT'S THE END OF THIS.

BUT MAYBE THAT'S NOT TRUE

ANYMORE.

AND WHAT'S THE STATUS OF

PSYCHOPHARMACOLOGY REGARDING THE

TREATMENT OF ADDICTION.

IN OTHER WORDS, WHAT CAN WE DO

ABOUT IT.

WELL I'M SURE YOU HAVE MANY

QUESTIONS IN YOUR MIND

CONTEMPLATING THIS DEPENDING AT

WHAT LEVEL OF EXPERIENCE YOU

HAVE.

AND SOME OF THESE PROBABLY HAVE

YES AND SOME HAVE NO AND SOME

HAVE MAYBE.

AND THOSE ARE THE SUBJECTS THAT

WE'RE GOING TO HEAR ABOUT TODAY.

SO WE ARE REALLY MOST FORTUNATE

THAT A YOUNG LADY WHO IS A

PATIENT IS GOING TO TELL US

ABOUT HER WIFE AND WHA LIVE AND WHAT

ADDICTION HAS MEANT AND HOW IT

ALL SEEMED TO COME ABOUT.

AND THEN TO DISCUSS THIS ARE

DAVID, THE FIRST TO DISCUSS IT

WILL BE DAVID GOLDMAN, WHO

GRADUATED, IS A PHYSICIAN WHO IS

TRAINED IN PSYCHIATRY IN TEXAS,

CAME TO THE NIH AND DAVID HAS

BEEN IN THE INSTITUTE OF ALCOHOL

AND ALCOHOL ADDICTION.

AND HAS BEEN IN THE LABORATORY

OF NEUROGENETICS WHERE HE'S BEEN

CHIEF SINCE 1991.

THIS LABORATORY IS ONE OF THE

MAJOR CENTERS IN THE WORLD FOR

LINKING GENOMIC STUDIES WITH

THESE KIND OF QUESTIONS AND

OTHERS.

AND THEN OUR SECOND SPEAKER

IS -- WHO IS THE SCIENTIFIC

DIRECTOR OF THE NATIONAL

INSTITUTE OF DRUG ADDICTION.

NOW, HE'S ALSO A PHYSICIAN.

HE GRADUATED IN ITALY AND THEN

TRAINED IN NEUROLOGY IN ITALY

AND DID A POST DOC TROUBLE

FELLOWSHIP AT THE -- INSTITUTE

OF ADVANCED BIOLOGICAL, WHICH IS

A GREAT INSTITUTE IN PORT LUM

AND THEN CAME TO THE NIH WHERE I

TOLD YOU ELSE THE SCIENTIFIC

DIRECTOR.

HE'S ONE OF THE LEADING PSYCHO

PHARMACOLOGISTS IN THE WORLD AND

SO WE LOOK FORWARD TO HEARING

WHAT YOU WILL TEACH US ABOUT THE

STATE OF THE ART.

OH, I HAVE ONE ANNOUNCEMENT TO

TELL YOU THAT THOSE OF YOU WHO

ARE TAKING THIS COURSE FOR

CERTIFICATE, IF YOU ATTENDED 50%

OF THE SESSIONS AND PASSED THE

FINAL EXAM AND IS NOT A BACK

BREAKER THAT WILL APPEAR IN

THREE WEEKS ELECTRONICALLY.

YOU CAN TAKE IT AND YOU'LL GET A

CERTIFICATE.

AND DON'T STAY UP LATE AT NIGHT

STUDYING BECAUSE THAT'S NOT THE

PURPOSE OF THE EXAM.

IT'S A LEARNING EXPERIENCE.

YOU CAN TAKE IT SEVERAL TIMES.

OKAY.

SO DAVID, WOULD YOU PLEASE

INTRODUCE.

>> I WOULD BE DELIGHTED TO, YES.

I'M DELIGHTED TO INTRODUCE ANN

BRADLEY.

EYE KNOWN ANI'VE KNOWN ANN SINCE I BECAME 
A

LAB CHIEF THERE.

SINCE 2010.

SHE HAS BEEN WITH THE ASSISTANT

SECRETARY OF HEALTH AND SHE'S

UNIQUELY SUITED TO HELP US TO

BEGIN TO ADDRESS THESE QUESTIONS

BECAUSE SHE BOTH HAS A HISTORY

OF ALCOHOLISM AND ALSO SHE'S AN

EXPERT IN COMMUNICATIONS.

WHICH IS WHAT SHE DID IN OUR

INSTITUTE AND ALSO WHAT SHE'S

DOING WITH THE ASSISTANT

SECRETARY OF HEALTH.

IN FACT, SHE MANAGES SEVERAL

MAJOR COMMUNICATIONS

INITIATIVES.

IN OUR INSTITUTE, SHE ALSO WAS A

MEMBER OF OUR HUMAN RESEARCH

COMMITTEE.

I WAS THE CHAIR AT THE TIME AND

RECRUITED ANN TO BRING A NEW

PERSPECTIVE TO THE COMMITTEE.

I THINK IT HAD THE SAME SORT OF

VALUE THAT I HOPE THAT WE SEE

HERE TODAY.

ANN, MAYBE WE'LL JUST START OFF

BY HAVING YOU TELL US A LITTLE

BIT ABOUT YOURSELF AND HOW YOU

STARTED HAVING PROBLEMS WITH

ALCOHOLISM AND WHAT THAT WAS

LIKE.

>> GLADLY.

I'LL SAY AT THE OUTSET I HAVE A

VOCAL PROBLEM AND AT ANY POINT

MY VOICE MAY GO ALTOGETHER SO

I'M GOING TO TALK AS RAPIDLY AS

POSSIBLE.

I DON'T THINK ANYBODY WILL BE

DISAPPOINTED IN THAT BUT I HAVE

LOTS OF SAY.

BUT DO STOP ME IF I'M UNCLEAR AT

ANY POINT OR IF YOU HAVE A

BURNING QUESTION THAT CAN'T

WAIT.

I AM 64 YEARS OLD.

I HAVE NOW BEEN SOBER FOR 31

YEARS.

AND IF YOU DO THE MATH WHICH YOU

NEEDN'T BOTHER YOU, YOU WILL

FIGURE IT OUT THAT I AM OLD AND

THAT I ALSO AM A LONG WAY FROM

WHAT WAS ONCE THE COMPELLING

INFLUENCE IN MY LIFE.

I WAS BORN IN 1947 IN THE DEEP

AMERICAN SOUTH TO A PROSPEROUS

FAMILY OF ACHIEVERS.

MY FATHER WAS AN INTERNIST IN

THE LOCAL COMMUNITY.

MY MOTHER WAS A CIVIC LEADER.

EVERYTHING THAT, EVERYTHING

SHOULD HAVE BEEN RIGHT FOR

NORMAL DEVELOPMENT EXCEPT FOR A

COUPLE THINGS.

I WAS OVERWEIGHT VERY MUCH SO AS

A YOUNG GIRL.

AND AS A CONSEQUENCE OF THAT

FELT A GREAT DEAL OF SOCIAL

ISOLATION.

IN RETROSPECT, OF COURSE, CAN BE

KIND OF GLAD ABOUT THAT.

IT ALLOWED ME TO DEVELOP IN

OTHER WAYS THAT HAVE COME IN A

LOT HAND YUR THA HANDIER THAN IT WOULD HAV
E

BEEN BEING THING.

I WAS KIND OF BOOKISH AND I

BEGAN WRITING AT A YOUNG AGE.

THAT WAS A LARGE INFLUENCE IN

THE EARLY YEARS.

ANOTHER THAT I HAVE A HARD TIME

ARTICULATING, I THINK I NEED TO

TRY TO ARTICULATE BECAUSE IT

ACTUALLY IMPORTANT, AND THAT IS

THAT GROWING UP IN THE AMERICAN

SOUTH IN THE 1950'S AND 650'S

WAS -- 60'S WAS A VERY DIFFICULT

TIME.

AND GROWING UP AT THE LEVEL OF

THAT SOCIETY WHERE MY PARENTS

FUNCTIONED AND WHERE I

FUNCTIONED AS A CONSEQUENCE OF

BIRTH.

I FOUND EVEN HARDER BECAUSE I

WAS STRUCK BY THE FACT THAT THE

ENTIRE SOCIETY SEEMED DISHONEST.

YOU KNOW, I WAS THE DAUGHTER OF

GOOD PEOPLE WHO I SAW GO TO

CHURCH, DO GOOD WORK, DISCUSS

EQUALITY AND HIGH MINDED VALUES,

BUT WE PAID THE HOUSEKEEPER $25

A WEEK AND ALL THAT SHE COULD

CARRY WHAT WAS THE GOIN CHFS WHICH WAS THE
 GOING RATE.

AT A DIFFERENT KIND OF LEVEL, I

RECOGNIZED AS DISHONESTY A LOT

OF THE COMMUNICATION AMONG MY

PARENTS, PEERS AND AMON PEERS AND AMONG MY

PEERS.

FOR A WILD TRYING TO GET HER

BEARING I FOUND THAT VERY

DIFFICULT SO I CAM AWAY FROM

THAT WITH A SENSE THAT I HAD

GROWN UP IN AN ENVIRONMENT THAT

COULD NOT SPEAK ITS MIND.

NEVERTHELESS, I WAS REASONABLY

HAPPY THROUGH HIGH SCHOOL.

AND CLOUDY THE END OF THAT

EXPERIENCE WAS MY FATHER'S

ILLNESS.

HE HAD AN EYE DISEASE WHOSE NAME

I CAN'T CALL, I THINK IT WAS

CORNEAL -- I'M NOT EVEN GOING TO

TRY.

BUT IT NECESSITATED TRANSPLANTS.

AND IT WAS AT A TIME WHEN IT WAS

CONSIDERED RARE AND NOBODY IN

MOBILE, ALABAMA KNEW HOW TO

DIAGNOSE IT.

HE HAD SEVERE HEADACHES AND

BEGAN SELF PRESCRIBING AND

SHOOTING HIMSELF WITH DEMEROL.

I WAS AWAKEELED IN THENED IN THE MIDDLE OF

THE NIGHT OFTEN AND TAKEN DOWN

TO THE CLINIC SO THAT HE COULD

GET A SHOT AND I KNEW NOTHING

OTHER THAN HE WAS TRYING TO

RELIEVE PAIN.

BUT ULTIMATELY, AND THIS DIDN'T

HAPPEN UNTIL MY FIRST YEAR IN

COLLEGE.

HE LOST THE PRACTICE.

HE WAS DISCOVERED BY A

PHARMACIST.

HE WENT AHEAD TO TRANSPLANT

NUMBER ONE SOMEWHAT DEPRESSED,

HAD THE TRANSPLANT HERE AT

HOPKINS AND THEN DIED, SOME

SUSPECT IN WITHDRAWAL FROM

DEMEROL.

BUT BETWEEN TRANSPLANTS ONE AND

TWO.

AND THAT WAS THE DESTRUCTION, HE

HAD ACKNOWLEDGED HIS ADDICTION

AND WE HAD HAD GOOD CONVERSATION

AT AN ADULT LEVEL, WHICH I WILL

ALWAYS TREASURE.

BUT SUFFICE TO SAY, I STARTED

COLLEGE WITH THE WHOLE WORLD

JUST KIND OF BLOWN TO EVERYTHING

THAT I HAD KNOWN WAS BLOWN.

I WAS ILL AT THE OUTSET, LOST ON

ON -- A LOT OF WEIGHT AND

SUDDENLY WAS FACED WITH SOCIAL

SITUATIONS THAT MALE AND FEMALE,

I DIDN'T KNOW HOW TO CONFRONT.

I WAS MOURNING THE LOSS OF MY

FATHER.

I WAS TURNED ON ACADEMICALLY.

I WAS ALSO TURNED ON

SOCIOLOGICALLY TO THE ACTIVIST

MOVEMENT, THE SEL CIVIL RIGHTS

MOVEMENT AND I WAS JUST PLAIN

TURNED ON TO SOME OF MY FELLOW

CLASSMATES.

SO I HAD A KIND OF MULTIPLE

PERSONALITY EXISTENCE THROUGH

THOSE YEARS AND I FOUND ALCOHOL

CURED ALL ISMS, INCLUDING SOCIAL

DISCOMFORT.

IT ASSED PHYSICA EASED PHYSICAL PAIN AND E
ASED

UNCOMFORTABLENESS WITH

BEHAVIORS.

IT INHIBITED WRITING STYLE WHICH

WAS GOING TO BE MY CLAIM TO FAME

THE GREAT AMERICAN NOVEL AND

MADE IT A WHOLE LOT EASIER TO

WRITE LIKE HEMINGWAY.

SO I DID A LOT OF THAT.

AND IT WORKED VERY WELL AS THEY

SAY UNTIL IT STOPPED WORKING,

WHICH WAS SOME YEARS LATER I

MARRIED RIGHT OUT OF COLLEGE

DELIGHTED TO HEAD FOR BOSTON AND

KIND OF CONTINUED DOWN AN

INCREASINGLY MORE SEVERE COURSE

OF ALCOHOLISM AND A NOT VERY

HAPPY MARRIAGE BUT SOME

PRODUCTIVE WORK MIXED IN.

AND I GUESS AT THE END OF NINE

YEARS, IT BEGAN TO, NOTHING WAS

WORKING SUDDENLY.

THE MARRIAGE WAS NOT WORKING,

THE DRINKING WAS NOT WORKING,

ALTHOUGH NO ONE HAD EVER RAISED

IT TO ME.

I WAS NOT DRIVING FROM IT THE

SAME LEVEL OF SATISFACTION THAT

I HAD TO THAT TIME.

I DID IT BECAUSE I NEEDED IT AND

I NEEDED IT IN ORDER TO

FUNCTION.

I LEFT OUT A FEW SALIENT POINTS

IN THERE THAT I'LL TRY TO

CORRAL.

WHEN WE WERE IN ATLANTA FOR SOME

OF THAT MARRIAGE, I DID JOIN THE

OLD SOUTHERN ORIGINAL COUNCIL

WHICH WAS THE FIRST BY RACIAL

CIVIL RIGHTS ASSOCIATION AND

MANAGED TO SWAWJ SOM ASSUAGE, SOME OF IT

WAS BUILT ON CHOFL, NICOTINE AND

CAFFEINE AND NOTHING FURTHER.

IN A WAY IT ROMANTICIZED THE

DRINKING AND I GUESS I STILL HAD

NOT HAD ENOUGH TO RECOGNIZE THAT

IT HAD ME.

THERE WERE MANY ADVENTURES WHICH

I'LL SKIP IN THE INTEREST OF

TIME, BUT I'LL REPORT THAT AFTER

I LEFT ATLANTA, MOVED TO

ST. SIMMONS.

GEORGIA WAS RUNNING THE COASTAL

AREA OF PLANNING AND DEVELOPMENT

COMMISSION COMMUNICATIONS

ACTIVITY THERE.

AND WITH A COASTAL PLANNER WHICH

IS COMPLETE DEPARTURE FROM WHAT

I'D DONE BEFORE.

I WAS FIRED AND THEY GAVE ME

REASONS FOR THE FIRING.

AS I RECALL, THERE WERE ABOUT 20

OF THEM.

NOT A ONE MENTIONED ALCOHOL.

BUT THEY REFERENCED SUCH THINGS

AS BEING TEN MINUTES LATE TO X

MEETING OR NOT COMPLETING

SOMETHING BY A GIVEN TIME.

AND I TOOK GREAT ACCEPTANCE TO

THAT TO THIS DAY.

THEY SUSPECTED THAT I WAS

DRINKING BUT NO ONE WAS HONEST

ENOUGH TO CALL IT TO MY

ATTENTION.

MY MOTHER SHOWED UP SHORTLY

THEREAFTER TO MOVE EVERYTHING OF

VALUE FROM THE APARTMENT.

I CALL IT THE THANKSGIVING DAY

MASS CUR BECAUSE SHMASSACRE BECAUSE SHE MA
NAGED

OVER THANKSGIVING DINNER TO

PERSUADE A FAMILY TO RUN A JET

AND COME TO GEORGIA WHERE THE

PLAN HAD BEEN TO COMMIT ME.

BROUGHT ALONG A LAWYER COUSIN

WHO WAS PLANNING TO CHECK ME

INTO I DON'T KNOW WHAT ASYLUM.

BUT MY MOTHER BEING THE PERFECT

SOUTHERN LADY THAT SHE WAS

CALLED TO LET ME KNOW SHE WAS

COMING.

WHICH GAVE ME AMPLE TIME AT

LEAST TO DEPAR THE PREMISES AND

NOT BE PRESENT WHEN SHE REMOVED

EVERYTHING OF VALUE FROM THE

CONDO.

I WAS MEN DOWN TO A BARE MATT

MATTRESS.

NOT MUCH IN THE WAY OF CASH AND

WITHOUT A JOB.

OF COURSE I NEEDED ALCOHOL, SO I

USED WHAT CASH I HAD AND I WOULD

WALK TO ONE OF THE THREE LIQUOR

OUTLETS ON ST. SIMON'S ISLAND.

I THINK I SOLD A CAR TOO.

WHICH WAS ABOUT TEN MILES

CIRCUMFERENCE.

I DIDN'T WANT TO GO THE TO THE

SAME STORE, THE SAME DAY, THE

NEXT DAY SO I'D HAVE TO MAKE A

CIRCUIT AND IT WAS A FULL TIME

JOB.

SOME DAYS TO GO TO THE WHOLE TEN

MILES.

I USED WHAT MONEY THERE WAS FOR

ALCOHOL.

I THINK AT THAT TIME I WAS

DRINKING A LITER OF SPIRITS A

DAY.

AND I COULDN'T KEEP IT UP AT

THAT PACE.

IT MUST HAVE BEEN NOT LONGER

THAN THREE WEEKS THE ORDEAL

CONTINUED.

THERE CAME A TIME ONE WEEK INTO

THAT ORDEAL WHEN I STOCKED UP ON

EVERYTHING THAT I HAD AND LAID

DOWN ON THE BARE MATTRESS IN THE

APARTMENT.

BY THEN I WAS VOMITING ALL THE

TIME.

I DIDN'T REALIZE IT AT THE TIME

BUT I WAS PREGNANT.

AND I MUST HAVE BEEN IN VERY

DIRE STRAITS BUT ON DAY 14 WHICH

I KNEW WAS DAY 14 BECAUSE THERE

WAS A CALENDAR ON THE WALL

BEHIND ME.

I RAISED MYSELF FROM THE

MATTRESS AND SAID YOU KNOW SELF,

THE ONLY THING YOU HAVE LEFT IS

SELF DETERMINATION.

AND I SOMEHOW GOT MYSELF INTO

THE LITTLE TOWN OF BRUNSWICK,

GEORGIA WHERE I KNOCKED ON THE

FIRST SHINGLE THAT I COULD FIND

AND HAD THE GOOD FORTUNE TO

ENCOUNTER A LAWYER WHO HAD A

GREAT DEAL OF ADDICTION IN HIS

FAMILY.

AND HE PROBABLY COULD SMELL IT

ON ME JUST BY MY BEST EFFORTS TO

CLEAN MYSELF UP.

AND I REMEMBER HE SAID TO ME,

YOU DON'T ME NEARLY AS MUCH AS

YOU NEED THIS PLACE ACROSS THE

STREET.

WHICH WAS AN OLD NATIONAL

INSTITUTE OF MENTAL HEALTH

COMMUNITY MENTAL HEALTH CENTER.

WHERE I WENT SIMPLY TO BE

COMPLIANT.

I SAW A LOT OF MATERIAL ON

ALCOHOLISM.

NONE OF IT SEEMED TO HAVE LOGIC

TO IT, TO ME.

BUT I DID CONSENT TO SAY FOR

FOUR DAYS AND I DID DETOX.

IT WAS FOUND THAT I HAVE A

LITTLE BIT OF FAT ON MY LIVER

AND I RECEIVED THE ADVICE TO

JOIN AA AND DRINK NO MORE.

I LEFT WITH THE CONVICTION THAT

I MIGHT BE AN ALCOHOLIC.

I WAS NOT READY TO ADMIT THAT

THAT WAS THE CASE, BUT IT SEEMED

TO MAKE RATIONAL GOOD SENSE NOT

TO DRINK.

I BEGAN TO DO THAT AND BEGAN

HAUNTING THE LIBRARY RATHER THAN

THE LIQUOR STORE TO FIND OUT

WHAT ALCOHOLISM IS AND WHETHER I

HAD IT.

BACK THEN IT WAS SO LONG AGO,

THAT THE DEFINITIONS WERE SPARSE

IN THE FIRST PLACE AND UNMATCHED

THE OTHER AND VERY EASY TO POKE

HOLES IN WHEN PLAYED UP AGAINST

MY OWN HISTORY.

THIS WAS ABOUT 1979.

BUT I KNEW SOMETHING WASN'T

RIGHT AND I KNEW THAT I

SHOULDN'T BE DRINKING.

AND SO I MANAGED TO ATTEND A FEW

OUTPATIENT SESSIONS, A FEW

MEETINGS OF AA WHICH I STILL

FOUND INCONGRUENT.

BUT TO KEEP MYSELF FROM DRINKING

FOR A FULL YEAR, UNFORTUNATELY

OR FORTUNATELY DURING THAT TIME

I MET THE MAN WHO IS NOW MY

HUSBAND.

AND IT WAS MUCH TOO SOON AND I

WAS MUCH TOO MUCH OF A MESS FOR

ANY KIND OF SERIOUS RELATIONSHIP

WHICH WAS THE FIRST THING I SAID

TO HIM.

BUT HE STUCK AROUND AND WE

ULTIMATELY MARRIED.

AND THAT'S IMPORTANT BECAUSE IT,

WHEN I HAD THE NEXT SERIOUS

RELAPSE WHICH I DID AFTER THE

MARRIAGE AND WHICH I WAS TAKEN

TO THE EMERGENCY ROOM IN

JACKSONVILLE, FLORIDA WHERE THEY

THOUGHT I WOULD DIE.

I TRIED THE JOURNEY BACK FROM

THAT AND REALIZED THAT I HAD

SOMETHING TO WHICH TO RETURN.

I WAS A NEW WIFE AND A NEW

STEPMOTHER OF BOYS 11 AND 13.

AND I ALSO HA THE MEMORY OF THE

GOOD WORK I HAD DONE AND A

LOVING FAMILY STRONG SOCIAL

SUPPORTS THAT WERE NOW GONE, OF

COURSE.

BUT FROM AN EARLIER TIME IN MY

LIFE.

AND THAT WAS ENOUGH.

FOR ME.

I THINK DIFFERENT PEOPLE REQUIRE

DIFFERENT SUPPORTS.

I USED AA WITH A GREAT DEAL OF

SKEPTICISM BUT I DID GO FOR FIVE

YEARS REGULARLY.

AFTER THAT LESS OFTEN.

AND I THINK I WENT PRIMARILY

BECAUSE THOSE PEOPLE IN THOSE

ROOMS HAD FOUND SOMETHING THAT I

HAD NOT, AND IT DIDN'T MATTER

THAT I DIDN'T YET ACCEPT THEIR

VERSION OF REALITY.

I NEEDED TO LEARN WHAT IT WAS

THEY HAD, HOW THEY HAD

ACCOMPLISHED WHAT THEY HAD.

AND SO OF COURSE WHILE THERE I

MANAGED TO MAKE FRIENDS.

AND THOSE RELATIONSHIPS FORMED

ADDITIONAL SUPPORTS.

I WENT TO WHAT WAS THEN

TREATMENT.

IT WAS PRETTY BARE BONES.

MOSTLY A LILT BI LITTLE BIT OF TALKING

WITH THERAPY AND A SUPPORT

GROUP.

AND AFTER ALL THAT, JOINED THE

FIELD IN A PARAPROFESSIONAL

CAPACITY.

I WOULD LOVE TO TELL YOU BUT

WE'RE KIND OF OUT OF TIME.

THERE'S AN INTERESTING

PERSPECTIVE FROM WHERE I AM NOW

AT 31 YEARS SOBER AND IF AN

OPPORTUNITY AVAILS LATER IN THE

PROGRAM, I WILL BE GLAD TO

SUPPLY THAT.

[APPLAUSE]

>> ANN THANK YOU.

>> I TALK TOO MUCH.

>> NO, NOT AT ALL.

SO LET ME START OBVIOUS BY

MAKING A COUPLE OF COMMENTS

ABOUT WHAT WE'VE JUST HEARD FROM

ANN.

FIRST OF ALL, THANK YOU FROM THE

BOTTOM OF OUR HEARTS WHICH

YOU'VE JUST DONE THRA THERE AS AN

EXTRAORDINARY AND I SUSPECT THAT

NOTHING THAT -- AND I ARE GOING

TO SAY IN THE NEXT HOUR IS GOING

TO HAVE THE IMPACT OF WHAT WE

JUST HEARD WHICH IS WHY IT'S

VERY IMPORTANT TO HEAR THE STORY

DEVELOP.

THE THING THAS THAT WE'VE HEARD IN

PROFESSIONPROSE ARE THINGS THAT PHYSICIANS

DESCRIBE IN JUST CO CAPPUAL DE--

CAPSULE DESCRIPTIONS.

ADDICTION TO ALCOHOLISM,

DEVELOPMENTAL EXPOSURE IN EARLY

EDUCATION, ESCALATING USE,

COMPULSIVE USE.

THE DAMAGING EFFECTS IN WORK AND

THEN PERSONAL RELATIONSHIPS THAT

DEFINE A DSM DIAGNOSIS.

AND THEN FINALLY, IN YOUR

SEEKING OF TREATMENTS IN

RECOVERY, THE DUMENTS THA DEPTHS YOU HAD T
O

HIT AND ALSO THE RELAXING

REMITTING NATURE AT LEAST

INITIALLY OF WHAT YOU UNDERWENT

AND IT'S VERY INTERESTING IN

TERMS THAT THE MODERN

NEUROSCIENCE THAT I THINK --

WILL BE TELLING US ABOUT, TO

THINK ABOUT HOW IN THE EARLY

PHASES OF YOUR USE, THERE WAS

SEEMING BENEFIT BUT THEN LAYER

THE DARK SIDE -- LATER, THE DARK

SIDE EFFECT OF THIS DRUG.

I JUST THOUGHT IT WAS EXTRA

EXTRAORDINARILY PROFOUND.

AS WIN HAD INDICATED WHEN WE

PLANNED THIS DAY THAT IT WOULD

BE THE MOST IMPORTANT ASPECT OF

THE PRESENTATION.

AND DON'T DISAPPOINT.

THE TRICK IS TO GET SOMEBODY WHO

HAS LIVED IT AND WHO IS ALSO

COMMUNICATIONS HOWEVER.

THANK YOU AN-- COMMUNICATIONS

OFFICER.

THANK YOU, ANN.

I'M GOING TO APPLAUD YOU A

SECOND TIME IF YOU DON'T MIND.

[APPLAUSE]

SO MY TALK IS GOING TO BE

FOCUSED ON JUST ONE ASPECT OF

THE ADDICTIONS.

THE GENETICS OF THE ADDICTIONS.

AND THE ADDICTIONS ARE AN

ANCIENT WIDE SPREAD AND

MULTIFACTORIAL PROBLEM.

THEY MIGHT ZIM SEEM AMONG AWE AMONG YIELDI
NG.

THIS IS THE ADDICTION.

THIS IS THE DRUNKENNESS OF NOAH

WITH HIS SONS.

HIS FAMILY DISCOVERING HIM.

SHORTLY THEREAFTER THE FLOOD AND

HE HAD PLANTED HIS GARDEN AND A

VINEYARD AND THE NEXT THING

DRUNKENNESS.

AND TRANSNATIONALLY, ADDICTIONS

OF ALL KINDS ARE HIGHLY VARIABLE

IN THEIR FREQUENCY.

THIS IS PER CAPITA ALCOHOL

CONSUMPTION LEADERS PE LITERS PER YEAR OF

COUNTRIES WORLDWIDE.

YOU SEE THE UNITED STATES IS

RIGHT HERE ABOUT THE MIDDLE.

AND THE CIRRHOSIS STIP DESPITE

THE FACT THERE'S VARIATION OF

HEPATITIS VIRUS AND OTHER FACTOR

THAT CAUSE LIVER DISEASE.

CIRRHOSIS DEATH IN THE COUNTRY

IS ROUGHLY PROPORTIONAL TO THE

PER CAPITA ALCOHOL CONSUMPTION.

THIS IS ALSO BECAUSE OF HALF OF

THE ALCOHOL THAT IS CONSUMED,

AND THIS IS THE SAME FOR A

NUMBER OF ADDICTIVE AGENTS,

ABOUT HALF OF THAT ALCOHOL IS

CONSUMED BY ADDICTS.

THIS THEN IS THE EFFECT OF

TEMPORAL VARIATION AND

AVAILABILITY.

DURING PROHIBITION AND THE YEARS

THAT LED UP TO PROHIBITION WHEN

THERE WAS THE POWERFUL

TEMPERANCE MOVEMENT, ALCOHOL

CONSUMPTION DROPPED DRAMATICALLY

AND YOU CAN SEE HERE THAT

CIRRHOSIS DEATH DROPPED BY ABOUT

HALF TO RETURN TO THE FORMER

FORM AFTER THE SOLDIERS RETURNED

FROM WORLD WAR II AND WITH THE

CHANGES IN THE LAWS.

THIS WAS THE PROFOUND SOURCE OF

ENVIRONMENTAL EXPERIENCE,

EXPERIMENTS IN THE UNITED

STATES.

HERE'S THE TEMPERAMENT MOVEMENTS

BY RUSH.

THIS WAS IN 1988 AND THEY HAD

THEIR DREAMS FULFILLED WITH THE

19TH AMENDMENT.

FOR THIS ONE DRUG A SECOND

CONSTITUTIONAL AMENDMENT IN 1933

REVERSING PROHIBITION.

AND SO AS I SAID A COUPLE SLIDES

AGO, A LITTLE OUT OF PLACE I'M

SORRY, YOU MIGHT THINK THEN THAT

ADDICTIONS BEING SO DEPENDENT

UPON EXPOSURE TO ADDICTIVE

AGENTS AND A CHOICE TO CONSUME

ADDICTIVE AGENTS WOULD BE AMONG

THE LAST DISORDERS THAT WOULD BE

AMENABLE OR HIGHLY USEFUL FOR

GENETIC ANALYSIS.

DON'T LISTEN TO ANY OF THIS THAT

I'M SAYING NOW, GEORGE.

SO WHAT DO WE KNOW ABOUT THE

ENVIRONMENTITY OF VULNERABILITY.

THERE'S A MINOR ROLE OF SHARED

ENVIRONMENT IN THE FAMILY.

WE KNOW THAT FROM LOOKING AT

CROSS SPOTS IN THE STUDIES AND

ADOPTIVE STUDIES.

WE KNOW THAT IN PREVENTION OR

TREATMENT COULD EMERGE FROM

THOSE QUANTITATIVELY SMALL

FACTORS.

THERE ARE THESE VERY LARGE

POPULATION DIFFERENCES AND

ADDICTIONS AS WELL AS MANY OTHER

PSYCHIATRIC DISORDERS AND

THERE'S A MAJOR ROLE FOR EARLY

LIFE STRESS AND TRAUMA.

THIS IS A GENETICS TALK AND NOW

I WANT TO TURN TO INHERITANCE.

THIS LITTLE SLIDE HERE WHICH IS

A CHARLES ADAM CARTOON

EMPHASIZES THE REMARKABLE

SIMILARITY IN MANY OF THE

IDENTICAL TWINS WHO WERE

SEPARATED AT BIRTH, RAISED APART

EVEN IN DIFFERENT CULTURES, AND

THEN BROUGHT BACK TOGETHER LATER

IN LIFE.

THIS IS A SORT OF OBSERVATION

THAT TIPS PEOPLE OFF TO THE FACT

THAT ADDICTIONS ARE HIGHLY

INHERITABLE.

BECAUSE WHEN MANY THOUSANDS OF

TWIN PAIRS HAD BEEN SELECTED FOR

DIFFERENT ADDICTIONS, AND HERE

WE ARE, THEY ARE RATED FROM LEFT

TO RIGHT, FROM LOWEST

INHERITABILITY TO HIGHEST

INHURTABILITY.

YOU CAN SEE THE TWIN PAIRS

COLLECTED FOR EACH ADDICTION.

THESE ARE ALL STUDIES IN WHICH

THE TWIN PAIRS WERE ASCERTAINED

EPIDEMIOLOGICALLY.

FOR EXAMPLE IN THE WHOLE STATE

OF VIRGINIA OR FROM THE COUNTRY

OF AUSTRALIA.

WHEN THE CONCORDANCE OR THE

DEGREE OF SIMILARITY OF THE --

ZYGOTIC TWINS, THE IDENTICAL

TWINS COMPARED TO THE FRATERNAL

TWINS, IT WOULD SEEM THAT THE

RATIOS TENDED TO BE ABOUT TWO TO

ONE, AND FROM THESE CONCORDANCE

RATIOS, THESE HERITABILITY

VALUES WERE DERIVED.

AND THESE ARE THE ESTIMATES OF

THE AMOUNT OF VARIATION AND

VULNERABILITY FROM ONE PERSON TO

THE NEXT THAT IS AWE DRIBBL ATTRIBUTABLE T
O

GENES.

THAT'S REALLY WHAT A

HERITABILITY NUMBER MEANS.

YOU LOOK AT THESE NUMBERS AND

YOU SEE THAT THE HERITABILITY

VARIES FROM ABOUT 40% HERE WITH

HOW IT'S AT THE LOW END TO ABOUT

65% FOR OPIOID AWE DECKION ADDICTIONS HERE

AT THE HIGH END.

THERE OF COURSE IS A LOT OF

VARIATION FROM ONE STUDY TO THE

NEXT.

IN PART BECAUSE YOU'RE

ESTIMATING A HERITABILITY BASED

UPON A CORRELATION COEFFICIENT

AND THERE'S SAMPLING VARIATION

FROM ONE POPULATION TO ANOTHER.

THERE ALSO ARE PROBABLY SOME

DIFFERENCES IN HERITABILITY AND

THE EFFECTS OF GENES FROM ONE

POPULATION TO THE NEXT.

SO WHAT IS IT THAT'S INHERITED.

IS IT A GENERAL PROPENSITY FOR

THE USE AND ABUSE OF ADDICTIVE

SUBSTANCES, OR ARE THERE

SPECIFIC INHERENTANCES FOR ONE

ADDICTIVE AGENT OR ANOTHER.

THERE ARE BOTH.

THERE ARE, THERE'S EVIDENCE FROM

THE TWIN STUDIES IN WHICH ONE

CAN LOOK AT CROSS INHERITANCE OF

VULNERABILITY FOR ONE DISORDER

IN ONE TWIN TO CAUSE THE

VULNERABILITY TO ANOTHER

ADDICTIVE DISORDER IN THE SECOND

TWIN.

THERE'S EVIDENCE FOR CROSS

INHERITANCE, THAT THERE ARE

SHARED FACTORS ACROSS ALCOHOL

AND OPIOIDS AND OTHER DRUGS.

AND NICOTINE ESPECIALLY.

BUT ON THE OTHER HAND, THERE

ALSO ARE SPECIFIC GENETIC RISK

FACTORS AND NOW WE'RE GOING TO

TALK ABOUT AN EXAMPLE OF THE

SPECIFIC GENETIC RISK FACTORS.

THIS IS THE, THESE ARE THE

ALCOHOL METABOLIC ENZYMES

VARIANCE THAT ARE VERY COMMON IN

EAST ASIA.

THE FIRST OF THESE IS THE ADH1B

GENE, ADH IS ONE OF THE ENZYMES

THAT CONVERTS ETHANOL TO

ACID ALDEHYDE WHICH IS A

METABOLITE.

AND THE SECOND ENZYME GETS RID

OF THIS TOXIN BY CONVERTING IT

TO ACETATE.

AND THIS IS ALDEHYDE.

THERE ARE OTHER ENZYMES THAT ARE

INVOLVED IN THIS PROCESS BUT

THESE TWO ENZYMES ARE KEY.

AND IN FACT, IF ALDEHYDE AWE --

AWYOU DRINK ALCOHOL THEN THE

ALDEHYDE BUILDS UP AND THERE'S A

FLUSHING REACTION AND THAT

DISCOURAGES DRINKING.

AND SIMILARLY IF YOU HAVE THIS

GENETIC VARIANCE THAT LEADS TO

THE MORE RAPID PRODUCTION OF

ACID HASTLED HID ALDEHYDE OR THIS THAT

BLOCKS ACID ALDEHYDE THEN AGAIN

AFTER JUST A GLASS OR TWO OF

WINE, THERE'S A DISFORK QUESTION

REACTION WHICH DISCOURAGES THE

PERSON FROM DRINKING AND THAT'S

WHY THE SULFUR WAS ONE OF THE

FIRST MEDICATIONS INVOLVED FOR

THE TREATMENT OF ALCOHOLISM.

THERE'S ALSO A FLIP SIDE TO

THIS, WHICH IS THAT ALTHOUGH

THESE GENETIC VARIANTS

DISCOURAGE DRINKING, VIA

FLUSHING.

IF YOU CARRY THE GENETIC

VARIANCE THAT ELEVATE ACID HALED

HALED -- ALDEHYDE LEVELS AND YOU

CONTINUE TO DRINK YOU'RE AT RISK

FOR UPPER GI CANCER.

AS IS NOW RECOGNIZED BY THE

NATIONAL, BY THE INTERNATIONAL

COMMISSION ON MUTAGENS AND

CARCINOGENS.

AND HERE IS THEN WHAT THIS

FLUSHING REACTION LOOKS LIKE

MPLEGHT BEFORE AND AFTER.

AND THIS IS A PARTICULAR

INDIVIDUAL WHO CAN SENSE IT FOR

HIS PHOTOS TO BE ACTUALLY POSTED

ON-LINE.

AND SO IT'S IN THIS ARTICLE

WHICH IS IN THE JOURNAL PLUS

ONE.

FINANCIAL THIS IS IN JAPAN AND

THE SQUAMOUS CARCINOMA TYPE AND

THEY LUMP ALWAYS ARRIVE AS A

RESULT OF ALCOHOL EXPOSURE.

NOW, A GENE LIKE THE ALDEHYDE,

THE DRAWJ FACE GENE HAS AN

EFFECT ON GENETIC RISK.

BUT THAT EFFECT CAN VEER

DEPENDING UPON -- VARY DEPENDING

UPON THE CONTEXT.

LET'S SAY THE PERSON WAS NEVER,

POSED TO THE AGENT.

AND THE OTHER THING THAT MATTERS

IN DOING A GENETIC ANALYSIS IS

WHAT PHENOTYPE IS MEASURED.

THERE'S A VERY STRONG EFFECT OF

THESE GENES ON FLUSHING OR ON

ALCOHOL METABOLISM AND THEN A

MORE MODERATE EFFECT ON THE RISK

OF THE ALCOHOLISM ITSELF.

THIS ILLUSTRATES A PROCESS THAT

OUR FIELD REALLY ALL PSYCHOLOGY

IS GOING THROUGH.

BIOLOGICAL PSYCHIATRIST HOPE TO

IDENTIFY PHENOTYPE, VARIATIONS

IN BRAIN CIRCUITRY, VARIATIONS

IN INTERMEDIATE BEHAVIORS THAT

ARE PREDISPOSING, THAT ARE

STRONGLY INFLUENCED NOT ONLY BY

GENES BUT ALSO BY OTHER CAUSAL

FACTORS AND THAT ARE

EXPLANATORY.

AND THEY ENABLE US TO DISSECT

PSYCHIATRIC DISEASES, INCLUDING

ADDICTIONS, IN MUCH THE SAME WAY

THAT MEDICINE HAS DISSECTED

OTHER COMMON DISEASES.

SO THE DISEASE OF ANEMIA, IF YOU

GO BACK 150 YEARS AGO WAS AN

UNDIFFERENCE SHADE MIXTURE OF

ALL KIND OF GENETIC DISEASES AND

ALSO ENVIRONMENTALLY CAUSED

DISEASES.

BUT NOBODY TODAY WOULD BE HAPPY

IF THEY SAW A HEMATOLOGIST

BECAUSE THEY WERE TIRED AND PALE

AND THE DIAGNOSIS THAT YOU CAME

HOME WITH WAS ANEMIA.

YOU EXPECT TO KNOW IF YOU HAVE

NON--- HEMATOMA LYTIC OR

WHATEVER THE SPECIFIC CAUSE

MIGHT BE.

THERE WOULD BE A SPECIFIC

TREATMENT BUT TODAY WITH THE

ADDICTIONS, WE'RE VERY MUCH

STILL UP HERE WHEN WE TALK ABOUT

CLINICALLY RELEVANT PHENOTYPE.

THE DISEASE IS THE CLINICAL

MANIFESTATION MEASURED BY DSM.

ITS PATTERN OF USE WITH

DELETERIOUS EFFECTS.

IF YOU MEET A CERTAIN NUMBER OF

THESE CRITERIA, THEN YOU'RE

RECORDED AS HAVING THE DIAGNOSIS

AND YOU MAY HAVE COME TO THAT

DIAGNOSIS WHICH IS REALLY AN END

DIAGNOSIS BY MANY DIFFERENT

MECHANISMS THAT'S OUR CLINICAL

RELEVANCE BUT THE RELATIONSHIP

TO GENOTYPE OR OTHER CAUSATIVE

GENEALOGY IS CLOSER WHEN YOU'RE

DOWN TO THE MOLECULAR LEVEL.

THE RELATIONSHIPS THAT THE RNA

LEVEL AND PROTEIN LEVEL AND

SMALL MOLECULE LEVEL OF GENES

AND INTERMEDIATE LEVEL

RELATIONSHIPS IF WE'REK

FUNCTION OF BRAIN8v–a<B>Ö"It)vqiP>=

THREE OF THESE PROCESSES MIGHT

BE IMPORTANT IN VULNERABILITY TO

ADDICTION.

IT'S FASCINATING THAT PEOPLE

HAVE INNATE DIFFERENCES IN THE

PROCESSES.

HERE A GENE THAT REFLECTS THE

CIRCUITS OF AWARD.

THESE ARE GENES THAT WERE FOUND

TO BE RESPONSIBLE FOR A PORTION

OF THE VULNERABILITY TO NICOTINE

ADDICTION.

IT WAS FOUND THROUGH A NEW TYPE

OF STUDY WHICH MOST OF YOU

PROBABLY HEARD ABOUT WHICH IS

THE GENOME-WIDE ASSOCIATION

STUDY INVOLVING UPWARDS OF TWO

AND-A-HALF MILLION OR FIVE

MILLION GENETIC MARKERS THAT

CONSISTS OF THE ENTIRE GENOME

THAT ARE INFLUENCING A TRAIT.

ONE DOES THIS WOULD I TAKING

ADVANTAGE OF DISEQUILIBRIUM

WHERE THE MARKER MAY BE NEARBY

AND LINKAGES THE EQUA EQUILIBRIUM IN

ALTERING THE VULNERABILITY FOR

THE TRAIT.

SO IT WAS DONE BY THIS G WAS

APPROACH AND THERE EMERGED A

NICOTINIC RECEPTOR CRNH5 WHICH

HAS AN AMINO SUBSTITUTION AT

POSITION 398 AND -- AND THAT

VARIANCE NOW IS REPLICATED NOT

ONLY FOR ITS ROLE IN SMOKING BUT

ALSO ITS SECONDARY ROLE IN LUNG

CANCER.

BUT THE ATTRIBUTABLE RISK OF

THIS ONE LOAK E LOCUS IS MUCH LESS THAN

5% OF THE OVERALL

INTERINDIVIDUAL VARIATION AND

VULNERABILITY WHAT ABOUT AT THE

BRAIN LEVEL.

IT TERMS OUT IT HAS A MUCH

STRONGER EFFECT ON THIS CIRCUIT

THAT MODULE LAC MODULATES NICOTINE CRAVING
.

THIS IS A SCROAR OF THAT ASKS

QUESTIONS LIKE HOW SOON AFTER

YOU GET UP IN THE MORNING DO YOU

LIGHT UP A CIGARETTE AND DO YOU

HAVE AN IMMEDIATE CRAVING FOR

SMOKE.

IF YOU ARE A NICOTINE ADDICT OF

COURSE YOU WANT TO LIGHT UP

QUICKLY AFTER YOU WAKE UP IN THE

MORNING.

AND THE STRENGTH OF THIS CIRCUIT

IS INVERSELY PROPORTIONAL TO

THAT NICOTINE CRAVING.

THE WEAKER THAT THE CONTROL OF

THE NUCLEUS -- THIS PLEASURE

CENTER HERE AT THE BASE OF THE

BRAIN, THE WEAKER THE CONTROL OF

THAT CENTER IS BY THE, BY

PORTION OF THE FRONTAL CORTEX

KNOWN AS THE DORSAL ANSWER

TERIOR SING LATE, THE WEAKER

THAT CIRCUIT THE STRONGER WAS

THE CRAVING.

THIS IS FROM WORK OF MY

COLLABORATOR AT NIDA ELLIOTT

STEIN ALSO WORKING WITH ELLIOTT

HONG.

WHAT WAS FOUND IN THIS STUDY IS

THIS JEANNI GENOTYPE WAS PREDICTING THE

STRENGTH OF THAT.

I WON'T GO INTO ANY DETAILS HERE

BECAUSE IT'S NOT THAT TYPE OF

TALK BUT DISMIEFS IT T SUFFICE IT TO SAY T
HIS

ONE GENOTYPE OIKDZ FOR MORE THAN

10% OF THE VARIANTS IN THE

CIRCUIT OF CRAVING.

WE BELIEVE THAT'S HOW IT MAY BE

MEDIATING VULNERABILITY TO

NICOTINE ADDICTION.

NOW ANOTHER MEDIATING TRAIT IS

IMPULSIVITY.

SOME PEOPLE ARE MORE LIKELY TO

TAKE A CHANCE THAN OTHERS.

PERSONALLY I CAN'T IMAGINE EVER

THAT FIRST TIME TAKING THE

CHANCE OF INJECTING A DRUG

INTRAVENOUSLY INTO MY VEIN AND

WITHOUT BEING IN SOME FORM OF

MEDICAL IF NOT SOME SAY SPOUSAL

SUPERVISION.

BUT PEOPLE WHO ARE MORE

IMPULSIVE TEND TO UNDERTAKE SUCH

ACTIONS WITHOUT FORESIGHT MUCH

MORE OFTEN.

AND THIS CARRYOVER IN ONE

IMPULSIVE BEHAVIOR TO THE

LIKELIHOOD OF OTHER IMPULSIVE

BEHAVIORS.

THIS IS A GENE WE FOUND BY DEEP

SEQUENCING JUST ABOUT A YEAR AGO

AND I'M NOT GOING TO GO INTO ALL

DETAILS BUT SUFFICE IT TO SAY

THAT WE DEEP SEQUENCED A SERIES

OF GENES THAT ARE INVOLVED IN

NEUROTRANSMITTER FUNCTION AND

THAT COULD MODULATE IMPULSIVE

BEHAVIOR.

WE DID THAT SEQUENCING IN PEOPLE

WHO ARE HIGHLY IMPULSIVE AND WHO

WERE ALCOHOLICS AND HAD OTHER

IMPULSIVE DISORDERS LIKE

ANTI-SOCIAL PERSONALITY

DISORDER.

AND COMPARED THEM TO CONTROLS.

AND IN THOSE HIGHLY IMPULSIVE

INDIVIDUALS, WE FOUND A HIGH

FREQUENCY OF THIS STOCK CODON

WHICH TAKES THE HGR2 RECEPTOR

WITH ITS DOMAINS AND FRONT

INDICATES IT.

INSTEAD OF -- TROUBLE INDICATES

IT.

TROUBLE INDICATEYOU CAN HAVE A LITTLE

PACKAGEMENT OF THFRAGMENTOF THE MOLECULE T
HAT CAN'T

FUNCTION TO TRANSMIT THE MESSAGE

OF THE NEUROTRANSMITTER

SEROTONIN.

THIS WAS SHOWN TO BE ASSOCIATED

IN POPULATIONS AND IT WAS SHOWN

TO BE MOLECULARLY FUNCTIONAL AND

ALSO TO CO-TRANSMIT IN FAMILIES.

AND SO THAT'S HOW ONE ATTEMPTS

TO NOT ONLY FIND SUCH A

VARIATION BUT ALSO NAILED DOWN

ITS RELATIONSHIP TO BEHAVIOR.

IT'S ALSO TAKEN TO THE MOUTH

BECAUSE IN THE MOUTH OF COURSE

YOU CAN KNOCK OUT THE GENE AND

THE EQUIVALENT MOUSE MODEL WOULD

BE THE HGR2B KNOCKOUT MOUSE

BECAUSE THAT'S LIKE STOCK CODON.

THE ORDER MOUSE IS THE PATIENT

LITTLE MOUSE AND IT'S NOT HIGHLY

NOVELTY SEEKING, IT'S CAUTIOUS

WHEN YOU PUT IT INTO A NEW

ENVIRONMENT.

EVEN IF IT'S HUNG TREE, IT

DOESN'T GO -- HUNGRY IT DOESN'T

GO RIGHT OUT TO THE CENTER OF

THE FIELD AND GET THE FOOD

PELLET RIGHT AWAY.

IF IT KNOWS THAT IT CAN WAIT A

LITTLE BIT LONGER TO GET A

LARGER REWARD, IT WILL DO SO.

BUT THE MOUSE WITH THE SEROTONIN

2B RECEPTOR KNOCKS OUT DOESN'T

WAIT LONG BEFORE IT GOES TO THE

CENTER OF THE FIELD TO GET THE

FOOD PELLETS.

SO IT'S ANXIOUS TO OR IT'S

IMPATIENT TO FEED AND ITS

NOVELTY SEEKING AND IMPULSIVE IN

OTHER WAYS ALSO THAT WERE

EVALUATED IN THIS STUDY.

WHICH IS I BELIEVE ONE OF THE

ONES THAT IS ACTUALLY POSTED

ON-LINE IF YOU'RE INTERESTED IN

LOOKING AT IT NOW ANOTHER WAY OF

LOOKING AT THIS WHOLE, WHAT IS

THE PHENOTYPE ISSUE IS TO TAKE

ONE GENE THAT ALTERS BEHAVIOR,

ONE FUNCTIONAL GENETIC VARIANCE

AND THEN TRACE ITS EFFECTS

THROUGH BEHAVIOR ALL THE WAY

FROM THE MOLECULAR LEVEL TO THE

COMPLEX BEHAVIOR.

SO ANOTHER DIMENSION THAT I

MENTIONED THAT'S IMPORTANT IS

EMOTION AND STRESS RESILIENCE,

AND THIS PROTEIN HERE, NEURO

PEPTIDE Y IS A -- PEPTIDE THAT'S

VERY IMPORTANT IN STRESS

RESILIENCE.

FOR EXAMPLE IT'S SHOWN BY

LOOKING AT LEVELS OF NEURO

PEPTIDE Y IN RETURNING WAR

VETERANS WITH THOSE WITH THE LOW

LEVELS ARE MORE LIKELY TO HAVE

PTSB.

SO WHAT'S SEEN AS A VERY STRONG

EFFECT OF GENOTYPE ON THE

EXPRESSION OF THESE MOLECULES,

THE MRNA AND THE PROTEIN.

AN IMMEDIATE EFFECT ON THE

RESPONSE OF THE BRAIN AS SEEN BY

BRAIN IMAGING, AND THEN WEEK --

WEAK EFFECTS ON THE COMPLEX

TRAIT OF ANXIETIES.

IF YOU ASK A PERSON HOW ANXIOUS

THEY ARE OR TRY TO DETERMINE

THAT WITH A QUESTION THERE, YOU

THEN ARE NOT NEARLY AS CLOSE TO

THE LEVEL OF GENE AS YOU ARE IF

YOU FOR EXAMPLE DO THIS BRAIN

IMAGING WHERE HERE THE PERSON IS

SHOWN EMOTION IMAGES.

THEIR EMOTIONAL REACTIVITY IS

DETERMINED BY ACTIVATION OF

THEIR AWE MI MEDULLA -- AND PEOPLE WITH

THE EXPRESSION OF NEURO PEPTIDE

Y GENO TYPES ARE ACTIVATING

THESE EMOTIONAL REGIONS OF THE

BRAIN MORE THAN PEOPLE WHO DO

NOT HAVE THOSE.

SO THEN AWE DECKIONS ARE A CAUSE

AND EFFECT OF RESPONSE TO THESE

SORTS OF THESE EMOTIONAL

TRAUMAS.

IF YOU ARE IMPULSIVE OR THERE

ARE PEOPLE IN YOUR ENVIRONMENT

YOU ARE MORE LIKELY TO

EXPERIENCE A TRAUMA.

YOU MAY ALSO HAVE VARIATION IN

YOUR TRESS RESILIENCY OR

EMOTIONALITY.

AND THEN ADDICTIONS THEMSELVES

IS -- MAY BE DISCUSSING THE --

THEMSELVES CAN CAUSE ALS CAUSE AL CAUSE

A -- ALSO JETTIC -- MEDIATING

THAT LIABILITY.

SO NOW JUST IN THE VERY END,

TURN TO PHARMACOGENETIC

PREDICTORS.

IN ADDITION TO GENE THAT MAY

MAKE US MORE VULNERABLE OR LESS

VULNERABLE IN THE FIRST PLACE

IT'S IMPORTANT THAT WE MOVE

TOWARDS PERSONALIZED MEDICINE TO

FIND GENETIC PREDICTORS OF

RESPONSE TO PARTICULAR DRUGS.

THOSE DRUGS MAY NOT BE INVOLVED

IN THE INITIAL MECHANISM OF

VULNERABILITY BUT NEVERTHELESS

MAY HELP US.

AND SO FOR EXAMPLE IN TREATMENT

TO DICK TINA DICTION, IT'S

DEVELOPING THE GENETIC VAPORS OF

CYP2A6 A CYTOCHROME GENE

PREDICTING NICOTINE METABOLISM

AND ARE HELPING TO PREDICT FROM

THE CO-GENETIC RESPONSE TO

NICOTINE TREATMENTS SUCH AS

NICOTINE PATCH AND --

I ALREADY DISCUSSED THE EXAMPLE

OF THE ALCOHOL METABOLIC GENES

WHICH IS A GOOD EXAMPLE A

PHARMACOGENETIC PREDICTOR.

AND ALCOHOLISM TREATMENT NOW FOR

EXAMPLTREKSO MANY -- OF THE OPIOID

RECEPTOR ACTUALLY IN A FAIRLY

STRONG WAY WITH MODULATE THE

RESPONSE NOW THIS IS THE

FUNCTIONAL VARIANCE HERE, I

WON'T GO INTO ANY DETAIL BUT THE

RECEPTOR VARIANCE ALTERS THE

AFFINITY TO ENDO MORE FIN AND

THEN THE TREATMENT EFFECTIVE

THAT IF YOU'RE TREATED WITH

PLACEBO, GENOTYPE IS IRRELEVANT

TO GOOD CLINICAL OUTCOME.

NOW THE TREXONE GROUP

APPROXIMATELY ONE QUARTER OF THE

POPULATION WHO CARRY THIS

PARTICULAR GENOTYPE ARE VERY

LIKELY TO HAVE GOOD CLINICAL

OUTCOME AFTER FOR EXAMPLESOME

OME THAT'S THE WAY PEOPLE ARE

TRYING TO MOVE FORWARD TOWARDS

PERSONAL EYED MEDICINE OF THE

ADDICTION OTHER THAN BETTER

DIAGNOSIS IN THE FIRST PLACE.

THE ADDICTIONS ARE HIGHLY

INHERIT SO THERE ARE GENES WORTH

SEEKING EVEN THOUGH INITIALLY IT

WOULD SEEM THAT THIS WOULDN'T BE

VERY FERTILE GROUND FOR GENETIC

ANALYSIS.

HERITABILITY IS TO BEHAVIORAL

DIE MENTIONS AND RESPONSE TO

ADDICTION AGENTS.

THERE ARE A FEW WEAK GENETIC

PREDICTORS OF ADDICTION AND

TREATMENT RESPONSE THAT HAVE

BEEN IDENTIFIED SO FAR.

BUT WE HOPE THAT IN THE FUTURE

THAT IT'S MUCH, IT'S GOING TO BE

MUCH MORE FRUITFUL.

AND ALTHOUGH IT'S NOT YET

FEASIBLE, THOSE MARKERS AS THEY

ARE DISCOVERED ARE LIKELY TO BE

USED IN THE SORT OF COMPLEX

CLINICAL CONTEXT THAT WE HEARD A

LOT ABOUT EARLIER.

THANK YOU ALL.

[APPLAUSE]

>> THANK YOU VERY MUCH DAVID.

WE HAVE TIME FOR SOME QUESTIONS.

COULD YOU REPEAT THE QUESTION

WHEN YOU HEAR IT BECAUSE THERE

ARE A LOT OF PEOPLE TUNED IN.

>> DELIGHTED.

YES, BACK HERE.

>> [INDISCERNIBLE]

I WA>> HE WAS WONDERING IF WE MIGHT

PASS THE MICROPHONE AFTER THIS

FIRST ONE.

NOT LIKE PHIL DONAHUE.

>> I'M NOT A SCIENTIST SO BEAR

MA WITH ME.

IN CONVERSATION WITH A SCIENTIST

LAST WEEK HE MENTIONED THE RISK

ALLELE.

NOW THIS IS RESUS MONKEYS A

POLYMORPHISM CALLED RISK ALLELE.

THEY GAIN DOMINANCE NOT THROUGH

AGGRESSION BUT THROUGH SOCIAL

INTERACTIONS.

THEY ARE SCHMOOZERS, THIS IS HOW

THEY PHENOTYPICALLY EXPOSE THERE

RISK ALLELE.

BUT IN RHESUSES MONKEYS.

THEY DRINK LIKE CRAZY.

>> IT'S A MARVELOUS QUESTION.

THERE ARE SEVERAL POINTS, ONE

PARTICULARLY THE COMMON VARIANCE

VERY OFTEN HAVE COUNTERBALANCING

ADVANTAGES AND ONE OF THEM SKHUL

BE THOUGHT OF THE MUTATION OR

THE BAD GENE BECAUSE WHETHER

IT'S BAD OR NOT CAN BE

COMPLETELY CONTEXT DEPENDENT.

SECOND, GREAT VALUE OF THE SORTS

OF ANIMAL MODELS WHERE SOME OF

THESE  EXPOSURES COULD BE

CONTROLLED, IN PARTICULAR

THESE -- MODELS HAVE BEEN QUITE

VALUABLE.

THEY ARE EVEN PARALLEL GENETIC

VARIANCE THAT WORK MUCH THE SAME

WAY IN SOME OF THESE OTHER

SPECIES.

BUT I THINK THAT THE POINT IS

VERY WELL TAKEN THAT WE

SHOULDN'T THINK OF THESE

ALLELES, IT'S JUST RISK ALLELES.

THEY EXIST FOR OTHER PURPOSES,

MANY OF THEM.

YES, AL KINGMAN.

>PLEASURE TO SEE YOU, AL.

>> COULD YOU COMMENT, DAVID, ON

THE DIFFERENCE BETWEEN THE

ADDICTION TO ALCOHOL AS OPPOSED

TO COCAINE.

IT SEEMS LIKE PEOPLE CAN DRINK

AND DRINK AND DRINK AND NOT

BECOME ADDICTED TO ALCOHOL BUT

THEY CAN'T TAKE COCAINE VERY

OFTEN.

WITHOUT BECOMING ADDICTED.

>> YES.

I THINK PERHAPS THAT MIGHT EVEN

BE MORE OF -- DOMAIN.

I WOULD CALL THAT IT'S

WELL-KNOWN THAT THERE'S A

DIFFERENCE IN ADDICTIVE

LIABLITY.

FOR A SERIES OF DIFFERENT AGENTS

TO WHICH PEOPLE CAN BECOME

ADDICTED.

AND THAT ALSO THAT THE TYPICAL

CLINICAL COURSE MAY VARY FOR

THESE AGENTS.

BUT I THINK I WOULD RESERVE ANY

OTHER RESPONSE BECAUSE WE'RE

GOING TO HEAR MORE ABOUT THE

NEUROSCIENCE IN A FEW MINUTES.

>> VERY BRIEFLY YOU MENTIONED

LESS THAN 5% OF THE VARIANCE IS

ACCOUNTED FOR BY GENETIC

FACTORS.

I WONDER IF YOU WOULD COMMENT ON

WHAT THE OTHER 95% MIGHT BE

ACCOUNTED FOR.

>> THANK YOU.

JUST TO CLARIFY THAT, SO THIS

NICOTINIC AWE SEE TOE CHOLINE

VARIANCE IS ONE VARIANT

ACCOUNTING FOR LESS THAN 5% OF

THE GENETIC VARIANCE.

BUT WE KNOW THAT THERE MUST BE

MANY OTHER UNDISCOVERED GENETIC

VARIANCE THAT ACCOUNT FOR MORE

THAN HALF OF THE VARIATION AND

VULNERABILITY THAN NICOTINE

ADDICTION BECAUSE THE

HERITABILITY OF NICOTINE

ADDICTION.

SO THE HERITABILITY OF NICOTINE

ADDICTION IS OVER 50%.

SO FROM THAT WE KNOW THAT THERE

MAY BE A LARGE CONSTELLATION OF

GENES OF WHICH WE'VE ONLY FOUND

ONE THAT ARE CONTRIBUTING TO

LIABILITY.

SO IT'S, YOU KNOW, IT'S A VERY

FRUSTRATING POINT IN THE SCIENCE

WHERE YOU MIGHT BE POINTING TO

WHAT YOU KNOW IS SOME HUGE

CONTINENT OF INFORMATION.

AND IN THAT CONTINENT IS ONE

LITTLE AREA THAT'S BEEN

ILLUMINATED TO THIS POINT.

>> DAVID YOU TALKED ABOUT THE

IDENTICAL TWIP STUDIE TWIN STUDIES SORT OF

THE GOLD STANDARD.

WHAT HAPPENS WHEN WIDE SPREAD

GENOMIC STUDIES ARE DONE OF SAY

POPULATIONS THAT HISTORICALLY

ARE ASSOCIATED WITH HIGHER

DEGREES OF ALCOHOLISM.

THIS SORT OF CULTURAL

ASSOCIATION IF THAT'S A FAIR

WORD FOR IT.

>> I THINK IT'S VERY FAIR.

I THINK THAT FIRST OF ALL THE

TWIN STUDIES HAVE BEEN THE GOLD

STANDARD AND WHAT WAS THE

QUANTITATIVE GENETIC ERA.

WHEN WITHOUT THE TOOLS TO FIND

THE GENES, SO MUCH OF THE ENERGY

WAS FOCUSED ON QUANTIT QUANTITATING THE

ROLES WITHOUT BEING ABLE TO SEE

THEM.

IT'S A LITTLE BIT LIKE SEEING

THE SHADOW OF THE GENES ON THE

WALL.

WE CAN SEE THEY ARE SHADOW BUT

WE DON'T SEE THEM.

ON THE OTHER HAND FOR ACTUAL

GENE DISCOVERY TO HONE IN ON

WHAT THOSE GENES ARE.

IT PROVES TO BE EXTREMELY

POWERFUL JUST TO HAVE MANY

THOUSANDS OR TENS OF THOUSANDS

OF CASES AND CONTROL.

IT'S VERY POWERFUL TO HAVE

FAMILY CONSTELLATION.

AND I DIDN'T MENTION THIS BUT

ACTUALLY IN THAT STUDY THAT WE

DID WHERE WE FOUND THE STOP

CODON LEADING TO IMPULSIVITY, IT

CAN BE HELPFUL TO HAVE CERTAIN

POPULATIONS THAT HAVE

CHARACTERISTICS THAT MAKE THEM

UNIQUELY POWERFUL FOR GENE

DISCOVERY.

THAT STUDY WAS DONE IN FINS WHO

ARE A FOUNDER POPULATION.

THE STOCK COLD ON IT WE FOUND

HAD THE FREQUENCY OF OVER 1% IN

FINS BUT SO FAR IT'S ABSENT IN

ALL THE OTHER POPULATIONS THAT

WE'VE LOOKED AT WORLDWIDE.

SO YOU'RE ABSOLUTELY RIGHT THAT

WE COULD LOOK AT THE TWIN

STUDIES IN ONE WAY, AND LOOK AT

THESE OTHER STUDIES IN ANOTHER

BUT I MUST SAY ALSO THAT THE

TWIN STUDIES ARE COMING BACK IN

THE CONTEXT, FOR EXAMPLE, TO

LOOK AT EPI GENETIC EFFECTS AND

TO LOOK FOR DENOVO MUTATIONS AND

LOTS OF OTHER THINGS.

>> LOOK AT THE DATA OF THE

CONSUMPTION OF THE TWO SCAFNED

ANYWAYIAN -- SCANDINAVIAN

NEIGHBORS [INDISCERNIBLE]

>> WELL, I DON'T HAVE THE SLIDE

UP NOW.

YES, I GUESS THE QUESTION THAT

YOU'RE ASKING IS, YOU COULD ASK

THIS QUESTION TWO WAYS.

WHAT ARE THE DIFFERENCES

CULTURALLY THAT CAN CAUSE TWO

COUNTRIES THAT ARE SO CLOSE

TOGETHER TO HAVE SUCH VARIATION

IN ALCOHOL CONSUMPTION.

YOU COULD ALSO ASK WHAT'S GOING

ON GENETICALLY FROM MY WARD IN

AMERICAN INDIAN POPULATIONS.

THERE'S A LAW THAT'S BEEN DONE

WORLDWIDE.

THERE'S A CULTURAL EFFECT FAR

MORE PROFOUND THAN ANY GENETIC

DIFFERENCES THAT ARE

DISTINGUISHING TWO POPULATIONS.

I MEAN, PEOPLE ON A INDIVIDUAL,

THE GENETIC VARIATION THAT

PEOPLE HAVE IS 90%

INTERINDIVIDUAL AND ABOUT 10%

BETWEEN PAW POPULATIONS.

THERE ARE THESE HUGE CHANGES IN

THE USE OF SUBSTANCES IN THE

FREQUENCY OF ADDICTIONS THAT ARE

OCCURRING OVER TIME AND THE

GENOTYPE ISN'T CHANGING.

SO WE KNOW THAT ISN'T IMPORTANT.

THE TWIN STUDIES THAT ARE DONE

ARE ALWAYS DONE IN A POPULATION

AND AT ONE POINT IN TIME.

AND SO SOME CONSIDERABLE EXTENT,

WE JUST GET RID OF A LOT OF THAT

CULTURAL VARIATION THAT IS

OCCURRING.

SO IF I HAD TO GUESS, I WOULD

SAY THAT THERE'S SOMETHING VERY

DIFFERENT BETWEEN THOSE TWO

COUNTRIES.

>> ANYWAY WAY TO ACTIVATE THE

NEURO PEPTIDE Y?

>> THERE ARE.

THERE ARE.

THERE ARE PEOPLE WHO ARE TRYING

TO DESIGN TRAIMENTS AR TREATMENTS AIMED AT

THE WHOLE STRESS ACCESS CRH

NEUROPEPTIDE Y.

>> I WAS JUST GOING TO SAY IN

NORWAY FOR MANY YEARS IT'S BEEN

ONE CASE OF DRUNK DRIVING LOSE

YOUR LICENSE FOR LIFE ONE YEAR

ARE IN JAIL, NO OUTS.

>> THANK YOU VERY MUCH.

SO WERE WE READY TO TRANSFER THE

BATON HERE.

>> YES.

I WANTED TO MENTION THAT THOSE

OF YOU WHO ARE INTERESTED, DAVID

HAS A NEW BOOK COMING OUT FROM

AL SEVERE SHORTLY.

DEALING WITH GENES AND I GUESS

ENVIRONMENT.

WHAT'S THE TITLE OF IT, I

FORGOT.

>> OUR GAINS OUR CHOICES.

 -- OUR GENES OUR

CHOICES.

>> THANK YOU FOR MENTIONING

THAT.

I COULDN'T HAVE.

>> I KNOW.

[LAUGHTER]

>> DAVID, WONDERFUL JOB.

I AGREE WITH YOU, AND THANK YOU

FOR INVITING ME.

I AGREE WITH YOU EVERYONE HERE

AS A VERY DIFFERENT DIMENSION TO

OUR SMALL SCIENCE SOMETIMES

WHICH IS NOT AS INTERESTING AS

HEARING A PERSON'S STORY.

THAT'S WHY I LOVE SEEING

PATIENTS.

BRINGS ME BACK TO EARTH TO

REALITY.

I NEVER AS SCARED AS WHEN I TALK

TO A PERSON THAN, YOU KNOW,

PAPERS, NATURE THAT CAN BE

REJECTED.

A PATIENT IF YOU SCREW UP.

IT'S A DIFFERENT STORY.

SO THANK YOU.

AND NOW WE'RE TAKING A JOURNEY

ON SYNAPTIC -- ON THE FUTURE OF

NEUROSCIENCE AND THE DISCLAIMER.

THIS IS A GROSS

OVERSIMPLIFICATION RIGHT THAT WE

NEED TO HAVE MODEST SIMPLE

MODEST -- OF THE Y.

WE WILL NEVER GO ANYWHERE

ESPECIALLY WITH OUR RO MODEL.

DAVID EXPLAIN VERY CLEARLY WHAT

IS THE STATE OF THE ART IN TERMS

OF THE GENETICS AND HOW THEY

INFLUENCE SUBSTANCE ABUSE.

AND HE MENTIONED PREVIOUSLY

ABOUT ENVIRONMENTAL STIMULI.

WHAT I'M GOING TO TELL YOU ABOUT

IS THAT NO MATTER WHAT, AT THE

END OF THE DAY IF YOU WANT TO

CREATE SUBSTANCE ABUSE IN A

RODENT OR A HUMAN YOU NEED TO

SHIFT BRAIN ACTIVITY IN THE

EMOTIONAL SYSTEM, THE LIMBIC

SYSTEM FROM A CERTAIN STATE A TO

A STATE B.

IF THERE IS NO BRAIN ACTIVITY

CHANGES, THERE'S NO AWE DECKION.

THAT'S MY ASSUMPTION AS SYNAPTIC

RESULTS.

I'M NOT TALK BIG THE ACUTE

EFFECTS OF SUBSTANCE ABUSE.

WHAT I STARTED WITH PEOPLE IN MY

INSTITUTE IS WHAT WE CALL THE

MEMORY.

MEMORIES ARE THAT ARE CREATED

BECAUSE I DO BELIEVE THAT THOSE

MEMORIES, THE VERY LONG TERM

CHANGES ARE THE ONE THAT

ACTUALLY CAUSE PEOPLE TO RELAX.

EVEN NEAR, THEY HAVEN'T FIT A

DRUG OR ALCOHOL.

SO THE IDEA OF STUDYING MEMORY

IS CENTRAL TO WHAT I STUDY.

WE STUDIED MEMORY IN DI DOPAMINE --

THESE ARE IN THE BIG BRAIN --

THEY ARE FUNDAMENTAL TO A HUGE

LIST OF CONDITIONS.

AND THE CLAIM TO FAME OF

DOPAMINE IN TERMS OF ADDICTION

IS THAT EVERY DUG OF ABUSE THAT

YOU CAN -- DRUG OF ABUSE THAT

YOU CAN THINK OF ALCOHOL,

NICOTINE, MORE MEAN, COCAINE,

PSYCHO STIMULANTS ANYTHING,

CREATES VERY PROFOUND CHANGES IN

DOPAMINE USE.

SO THIS IS WHY DOPAMINE BECAME

SO CONNECTED TO THE IDEA THAT

REALLY MODULATES THE BIG PORTION

OF GENETIC YOU CAN BEHAVIOR.

THE TECHNIQUE I WILL SHOW YOU

VERY SIMPLY ABOUT IS IT'S

CALLED -- SO BASICALLY WE SPEAK

IN MICRO -- INTO ONE DOPAMINE AT

A TIME, THIS IS CALLED MY SECOND

WIFE BECAUSE I STUDIED THESE

CELLS FOR ABOUT 21 YEARS.

MORE THAN MY WIFE.

I HAVEN'T FIGURED OUT MY WIFE OR

THIS.

SO THIS TECHNIQUE ALLOWS YOU TO

RECORD ON REAL TIME BRAIN

ACTIVITY BASICALLY.

SINGLE CHANNEL ACTIVITY, ION

CURRENT AND WHATNOT.

AND THE MECHANISM THAT I WILL BE

REFERRING TO VERY QUICKLY TOO IS

SGT.

THIS IS A FUNDAMENTAL MECHANISM

THAT PEOPLE HAVE TODAY IN THE

HIPPOCAMPUS AND OTHER REGIONS

THAT HAVE BEEN RELATED TO

LEARNING AND MEMORY PROCESSES.

NCP IS SIMPLY AN INCREASED

ACTIVITY OF THIS EXCITATORY

RECEPTORS BY -- BASICALLY WHEN

YOU CREATE THIS MEMORY, IT'S

SYNAPTIC MEMORY.

YOU HAVE CHANGES IN ACTIVITY OF

THIS RECEPTOR THAT DON'T LAST

FOR A FEW MILLISECONDS AS THE

BRAIN USUALLY COMMUNICATES

BETWEEN.

BUT THEY LAST FOR HOURS, DAYS

WEEKS OR EXAMPLES EVEN MONTHS.

SO THE FIRST EXPERIMENT OF

MANY -- FIRST OF ALL ARE DRUGS

ABUSE ABLE TO PERFORM THIS FORM

OF CELLULAR MEMORY.

YES OR NO.

THAT'S THE FIRST FUNDAMENTAL

QUESTION.

AND THE ANSWER IS YES.

THERE'S A SINGLE INJECTION OF

COCAINE THAN THE DAYS BEFORE OF

THIS MEASURE OF CELLULAR MEMORY

WHICH IS A RATIO BETWEEN THOSE

AMPA RECEPTORS THAT I TALKED TO

YOU ABOUT.

THE BOTTOM LINE OF THESE FIGURES

IS THE DAY AFTER SINGLE EXPOSURE

TO COCAINE OR EVEN FIVE DAYS

AFTER EXPOSURE TO COCAINE THERE

IS A CELLULAR MEMORY RETAINED ON

THESE AMPA RECEPTORS.

ON TO THE -- COCAINE WAS PRESENT

FOR ABOUT TWO TO THREE HOURS AT

THIS DOSE.

YET YOUR BRAIN REMEMBERS IT.

SO THIS IS ON MEMORY ALMOST A

WEEK LATER.

THEN IT'S GONE AFTER TEN DAYS,

OKAY.

THIS IS A PASSIVE SINGLE COCAINE

INJECTION.

WHAT ABOUT MORE BEHAVIORS.

WHAT IF YOU -- WHAT HAPPENED TO

THIS MEMORY.

IS IT GOING TO BE CREATED AT

ALL?

IS IT PRESENCE OR NOT?

SO THE TRAINING THAT WE DID WAS

TO BASICALLY MAKE SURE THAT THIS

WOULD BECOME ABLE TO -- CO-AND

THEN WE WAITED A DAY, FEW WEEKS

OR A FEW MONTHS.

AND WE WENT BACK TO MEASURE THAT

CELLULAR MEMORY.

HERE'S WHAT HAPPENED.

IF YOU MEASURE THIS FORM OF --

THE CELLULAR MEMORY THE DAY

AFTER TRAINING, YOU HAVE TWO

GROUPS THAT SHOW THIS MEMORY.

THE DEEP -- COCAINE AND AS A

CONTROL HAVE ADMINISTERED --

THIS IS THE NEXT DAY AFTER

TREATMENT.

SEE WHAT HAPPENS HERE.

THIS LINE RIGHT HERE IS CALLED

COCAINE CONTROL.

THEY RECEIVE THE SAME AMOUNT OF

COCAINE AS THE OTHER, OKAY.

SAME TIME, SAME AMOUNT.

THE ONLY DIFFERS BETWEEN THOSE

TWO GROUPS IS THAT THEY NEVER

KNEW WHEN COCAINE WAS COMING.

IT WAS PASSIVELY INJECTED.

THEY HAD NO CUE AND NO CLUE THAT

COCAINE WAS COMING TO THEM.

AND THEY DIDN'T HAVE TO PRESS A

LEVER FOR IT.

THEY JUST RECEIVED IT EVERY

SINGLE TIME THAT THEY CHOSE TO,

OKAY.

WHAT THIS IS TELLING YOU IS THIS

IS NOT JUST ABOUT TAKING

COCAINE, IT'S ABOUT LOOKING FOR

COCAINE, PRESSING A LEVER,

ENGAGING THE WHOLE LIMBIC SYSTEM

SO THAT YOUR BRAIN CREATES THIS

PLASTICITY, THIS MEMORY.

AND THEN YOU SEE THEM.

NOW THE MOST INTERESTING PART,

YOU WAIT THREE WEEKS FOUR WEEKS,

THREE MONTHS OF COMPLETE ABSENCE

OF COCAINE.

ONLY THE RED THE DEEP SENSE OF

COCAINE, THIS GROUP HERE

RETAINED THIS LONG TERM MEMORY

RIGHT HERE.

FULL -- CONTROLS AS BEFORE, NO.

THESE ARE THE PHYSIOLOGICAL

TRAITS WHICH WE DON'T NEED TO

GET INTO.

SO THE BOTTOM LINE IS THAT FIRST

OF ALL -- KIND OF THE EQUIVALENT

TO YEARS FOR A HUMAN, RIGHT.

LIFE SPAN IS MUCH SHORTER.

AND YOU DO SEE THAT THESE TRAITS

SEEM TO BE VERY PERSISTENT.

SO WHY AM I TALKING ABOUT THESE

RECEPTORS, THESE PRONE

EXCITATORY RECEPTORS.

THERE ARE MANY CLINICAL TRIALS

THAT PEOPLE HAVE RUN OVER THE

PAST SEVERAL YEARS WITH AMPLE

ANTAGONISTS.

THEY ARE NOT CLINICAL TRIALS

WHEN THEY ARE SUBSTANCE ABUSE.

IT'S NOT REALLY IMPORTANT TO

READ, IT'S JUST TELLING YOU THAT

AT RECEPTOR ANTAGONISTS HAVE

BEEN USED FOR CHRONIC PAIN

TREATMENT, FOR MIGRAINE, FOR

SEIZURE FOR DEGENERATION

PROCEDURES AND WHATNOT.

THE BOTTOM LINE IS IF YOU HAVE

AN ACCESSIVE ACTIVITY OF THESE

EXCITATORY RECEPTORS MAYBE YOUR

DOPAMINE SYSTEM IS

OVERAMPLIFIED, OVER ACTIVE.

THIS IS NOT THE REASON WHY

PEOPLE ARE ADDICTED BUT THIS IS

CERTAINLY PHARMACOLOGICAL EFFECT

AND PHYSICAL, FUNCTION EFFECT.

THERE IS -- COCAINE EXPOSURE

THAT WOULD LIKELY FACILITATE THE

EXPRESSION OF THE BEHAVIORS,

RIGHT.

SO THE IDEA OF TUNING DOWN THIS

AMPLE RECEPTOR ANTAGONIST TO

BRING THEM BACK TO A MORE NORMAL

ACTIVITY, AND WE WILL RUN SOME

PRELIMINARY EXPERIMENTS, CLEARLY

REDUCES THE RODENT MODELS

COCAINE ADMINISTRATION.

AND WHAT I'M SUGGESTING HERE IS

THAT AMPLE RECEPTOR ANTAGONIST

MIGHT BE ONE OF THE WAYS THAT WE

CAN TRY TO CONTROL THIS URGE OF

COCAINE CRAVING FOR EXAMPLE.

THIS IS CERTAINLY SOMETHING THAT

IS AVAILABLE.

THE SPECIFICITY OVER ANTAGONIST

IS NOT FANTASTIC BUT IT'S AN

IDEA THAT I VALUE VERY

INTERESTED IN AND I -- AM VERY

INTERESTED IN AND OTHER PEOPLE

ARE PURSUING AND HOPEFULLY WE

WILL KNOW SOMETHING ABOUT IT

PRETTY SOON.

SO THE SUMMARY OF THIS IS THAT

IF YOU GIVE A SINGLE INJECTION

OF COCAINE, YOU CREATE A MEMORY

INTO THIS LIMBIC DOPAMINE CELLS

WHICH LASTS FOR ABOUT A WEEK,

OKAY.

IF YOU TRAIN -- THAT THIS MEMORY

IS VERY LONG LASTING.

IT'S LASTING FOR MONTHS.

THE WHOLE IDEA AND WE ARE

WORKING ON ANOTHER GROUP IS TO

TRY AND REMOVE THIS.

YOU COULD CORRELATE SYNAPTIC

RIGIDITY.

THESE ARE STUCK IN THE AMPLIFIED

MODE.

WHAT WE ARE TRYING TO DO IS

REMOVE THE PRESENCE OF LONG TERM

PROPENSE INFORMATION OF THESE

AMPA RECEPTORS AND BY REDUCING

IT.

WE BASICALLY REDUCE THE

LIKELIHOOD OF THIS TO RELAPSE

THAT BASICALLY WHERE WE'RE GOING

WITH THIS.

AND I DON'T WANT TO MENTION OR

TAKE THE TIME BUT IF YOU TRAIN

AND LEARN PHYSIOLOGICAL

REWARDS -- THEN YOU JUST SEE

THIS FORMAL PLASTICITY, THIS

MEMORY JUST ONE DAY WHERE THEY

LEARN TO ASSOCIATE A CUE WITH

THIS NEWLY PRESENTED REWARD.

SO THEY ARE QUICK IN LEARNING

WHAT'S GOOD FOR THEM.

BUT PLASTICITY DOESN'T LAST.

THERE'S NO MEMORY WHATSOEVER.

JUST PRESENT FOR ONE DAY.

SO THIS IS TELLING YOU IN A

NUTSHELL THAT LET'S SOMETHING

DEEPLY WRONG WITH COCAINE.

IT TAKES OUT THIS AMPA

RECEPTORS.

IT CREATES A MEMORY BUT UNLIKE

NATURE, ARE PHYSIOLOGICAL

REWARDS, FOOD, SEX AND WHATNOT,

IT MAINTAINS A PRESENCE OF

AMPLIFICATION OF THESE AMPA

RECEPTORS WHICH WE THINK IS ONE

OF THE MECHANISMS THAT IS THE

UNDERLYING BEHAVIORS.

NOW THAT'S THE PRESENT AND THIS

IS WHAT WE'RE DOING.

BUT WHAT ABOUT THE FUTURE.

WHERE ARE WE GOING.

ONE OF THE MAJOR LIMITATIONS

OF -- IS THAT YOU CAN STUDY

REGIONS IN GENERAL BUT ESSEX

TREMELY DIFFICULT TO SELECT

GROUP OF SITES INTO YOUR BRAIN

AND SAY I WANT TO TURN ON OR

OBVIOUS DOPAMINE OR I JUST WANT

TO TURN OFF FIBER FROM THE PRE

FRONTAL CORTEX TO THE --

AREA -- THE

DOPAMINE SETS ARE VERY IMPORTANT

FOR SUBSTANCE ABUSE.

I WANT TO TURN THEM ON AND OFF

AND LEAVE THE BRILLIANT

ABSOLUTELY UNTOUCHED.

IT CAN BE DONE, THANKS TO PAIR

DAKSAL AND SEVERAL OTHER GROUPS

NOW.

BECAUSE A FEW YEARS AGO

DISCOVERED THIS NEW REVOLUTION

FOR NEUROSCIENCE WHICH IS CALLED

OPTOGENETICS.

I MENTIONED THIS BECAUSE ANYONE

WHO IS INTERESTED IN ANY DISEASE

RELATED TO THE CENTRAL NERVOUS

SYSTEM CAN REALLY PICK AND

CHOOSE A WAY TO USE UP THE

GENETICS.

THAT DOESN'T REALLY MATTER IF

YOU STUDY SUBSTANCE ABUSE.

YOU WILL SEE IN A SECOND WHY IS

THIS SO IMPORTANT.

AUNT NO GENETICS MEAN THAT YOU

HAVE A VIRUS WITH A PROMOTER

WHICH THIS SELECTIVITY FOR A

CERTAIN CLASS OF BRAIN SPACE,

THE PROMOTER COULD TARGET

DOPAMINE -- FOR EXAMPLE OR --

AND THEN YOU HAVE THIS LIFE

SENSITIVE PROTEIN WHICH ARE

CALLED -- AND A CERTAIN

WAVELENGTH WILL STIMULATE THESE

PROTEINS RIGHT HERE.

AND THE STIMULATION OF THESE

PROTEIN WILL EXCITE ALL THAT

HAVE BEEN INFECTED WITH THIS

VIRUS.

SO YOU INJECT THE VIRUS INTO THE

BRAIN.

YOU HAVE A SELECTIVE PROMOTER

AND YOU HAVE A -- WHICH ALLOWS

YOU LATER ON TO SHINE THE LIGHT

AND CHOOSE TO SELECTIVELY

ACTIVATE THOSE BRAIN CELLS AND

NOT ALL THE OTHERS.

IS THAT CLEAR?

SIMPLE IN GREAT.

SO THE PROJECT THAT WE DID

RELATE THE -- THIS WAS CONNECTED

ALSO TO WHAT DAVID IS SAYING

ABOUT THE PREFRONTAL CORTEX.

WE FIRST OF ALL -- I DIDN'T DO

MUCH, CREATED AND DEVELOPED A

COMPOSITE OW COCAINE -- WHICH I

WILL EXPLAIN IN A SECOND.

AND THE IDEA BECAUSE OF OWE CANE

ADMINISTRATION, WE THOUGHT

PRODUCES -- HUMAN STUDIES HAVE

SHOWN IN A SELECTIVE MANNER TO

CORRECT THE HYPER FRONT TALITY.

IMAGINE THE PACEMAKER IN YOUR

HEART.

YOU HAVE A SLOW BEATING HEART.

YOU TURN ON YOUR -- YOU RESTORE

NORMAL ACTIVITY OF YOUR

PREFRONTAL CORTEX AND HOPEFULLY

YOU REMOVE PSYCHOLOGICAL

BEHAVIORS.

THAT'S IT IN A NUTSHELL.

SO MOTIVE WAS USED YEARS AGO.

THIS ADMINISTRATION MOTIVE IN A

NUTSHELL HAS TWO STAGES.

A SIXTH STAGE WHERE THE RATHER

HAD TO PRESS A LEVER TO GET

COCAINE.

BUT THAT'S NOT ENOUGH.

YOU HAVE A PRESS A SECOND LEVER,

THE TAKE LEVER IN ORDER TO

REALLY GET COCAINE.

THIS IS TAILORED TO MAKE SURE

THAT THE RAT HAS ENOUGH TIME TO

DECIDE IN BETWEEN THE TWO LEVER

PRESSES IF THEY REALLY WANT TO

TAKE CO-TAIN OR NOT.

AND THERE IS ANOTHER TWIST IN

THIS.

WE WOULD WANT TO MAKE SURE THAT

THIS RAT REALLY WAS -- SO WHAT

DID HE DO?

AFTER A LONG ADMINISTRATION

TRAINING FIRST SESSION IN THE

PINK AREA WHERE RATS WERE

EXPOSED TO PUNISHMENT -- SHOW.

WHAT DOES THAT DO OVER THE LAST

FOUR DAYS AFTER YOU TRAIN THEM

FOR MANY WEEKS, TO ADMINISTER

LOTS OF COCAINE.

THE FOOD SHOCK SEGREGATES THEM

INTO TWO SEPARATE GROUPS.

THAT'S CALLED THE SENSITIVE RED,

70% OF THEM.

THEY STAYED I'M GIVING UP.

IF YOU SHOCK ME I'M NOT GOING TO

TAKE COCAINE ANYMORE.

NOT THAT IMPORTANT TO ME.

AS YOU CAN SEE HERE THE LEVER

PRESSES AND IT GOES DOWN.

THEY JUST TONIGHT CARE ENOUGH

ABOUT COCAINE TO KEEP THEM

PRESSING IF YOU SHOCK THEM.

OKAY.

PLAIN AND SIMPLE.

BUT THERE IS A SENSE OF THEM

ADMINISTERING COCAINE DESPITE

FOOD SHOCK.

I DON'T CARE, I REALLY WANT

COCAINE, EVEN IF YOU SHOCK ME,

I'LL KEEP ON TAKING IT.

AND HERE THEY ARE.

THE VIDEO HAS MUCH MORE THAN TOO

MANY.

THIS GUY WHO IS A -- RESISTENT

GUY, HE'S WAITING TO BE ABLE TO

PRESS RIGHT THERE TO GET

COCAINE.

YOU SEE HERE THE BACK ONE IS FOR

COCAINE.

THE TWO FRONT ONES ARE BECAUSE

OF SURGERY WAS MADE BEFORE WE

THOUGHT THAT THE WHOLE PROCEDURE

AND -- WERE INJECTED BILATERALLY

INTO THE PREFRONTAL CORTEXES TO

KNOW THIS EXPERIMENT IN THE

MIDDLE.

YOU WILL SEE IN A SECOND HE IS

REALLY ANXIOUSLY WAITING TO BE

ABLE TO PRESS FOR COCAINE AND HE

WILL GET SHOCKED.

HE RUNS AROUND, HE KNOWS WHERE

HIS COCAINE IS WAITING WAILING

WAITING.

I NEVER REMEMBER WHERE THIS ONE

SHOULD BE.

NO.

IT'S GOING TO BE THE NEXT ONE.

I WANT TO IF I ISSUE ON TIME.

THERE YOU GO.

SEE HE JUMPED BACKWARD JUST A

SHOCK THAT HE DOESN'T CARE.

HE REALLY WANTS COCAINE.

SO IS THIS -- AND STRESS?

YES THERE IS.

YOU SEE THE BOTTOM TRACES.

THIS IS TRACES OF PREFRONTAL

CORTEXES FROM THE CHRONIC

COCAINE DURING REST.

THEIR ACTIVITY IS HIGHLY REDUCED

IN VIVO COMPARED TO THE

CONTROLS, OKAY AND SO MUCH MORE

IN THE PUNISHMENT RESISTENT

ONES.

THEY ARE REALLY REALLY HYPO

ACTIVE.

WE MEASURE THAT.

AS YOU CAN SEE HERE IT CONTROLS

PRETTY GOOD ACTIVITY IN THEIR

PFC PUNISHMENT SENSITIVE.

THEY WERE -- COCAINE FOR WEEKS.

THEY HAD RULES THE ACTIVE TO BUT

NOT AS REDUCED AS THE PUNISHMENT

RESIST EMPT ONES.

SO THOSE ARE THE TARGETS THAT

WE'RE GOING TO SEE AND THIS IS

THE SUMMARY OF THE DATA.

SO WHAT IF NOW WE TURN ON, WHAT

IF NOW WE TURN ON THIS LIGHT

STIMULATION TO ACTIVATE

SELECTIVELY BOTH PREFRONTAL

CORTEXES TO THIS BEHAVIOR.

THE INJECTION AS I MENTIONED

BEFORE WAS DONE AT THE VERY

BEGINNING OF THE EXPERIMENT.

YOU ARE TO WAIT FOR VITAL

EXPRESSION BACK INTO YOUR -- AND

THEN RECORD FROM THEM.

AND IT HAS TO BE TESTED WITH

ACTION POTENTIAL AND ACTIVITY.

SO IT'S INTO THE PFC, IT'S

THERE, IT'S ACTIVATING ACTION

POTENTIAL THAT YOU STIMULATE.

AND GENERAL HAVE BEEN TURNED ON

DURING FOR A VERY LONG TIME SO

IT'S KIND OF A STABLE CON STUNT

STIMULATION TO ALLOW THEM TO

DECIDE WHETHER THEY WANT TO GO

FOR THE TAKE LEVER AND THE SICK

LEVER OR NOT.

AND THAT IS WHAT HAPPENS.

FIRST OF ALL WHAT HAVE YOU

NOTICED?

NO MAJOR CHANGES IN ACTIVITY BUT

LESS ACTIVE.

ALSO JUST VERY LESS OBSESSED

ABOUT THAT CORNER OF THE CAGE.

HE'S LOOKING AROUND.

HE'S ON THE OTHER SIDE ACTUALLY.

I DON'T KNOW WHAT HE IS LOOKING

BUT NOT REALLY INTERESTED

ANYMORE INTO THESE CORNERS.

SO THAT'S WHAT HAPPENS, OKAY.

THESE ARE VERY IMPORTANT

CONTROL.

IF YOU TURN ON THOSE GENERAL --

BEFORE YOU MAKE THIS RESISTENT,

THEY DIET FEE DON'T FEEL ANY SHOCK YET.

DON'T DO ABSOLUTELY ANYTHING.

OFF OR ON, THERE'S NO EFFECT ON

BEHAVIOR.

ONLY AFTER YOU MAKE THEM

PUNISHMENT RESISTENT.

NOW TURNING ON GENERAL -- MAKES

THEM LESS INTERESTED IN

ADMINISTERING COCAINE.

IT TAKES OFF THE EDGE SO TO

SPEAK.

THIS IS A SUMMARY OF THE DATA.

YOU CAN SEE HERE LONGER LATENCY

TO LEVER PRESS.

IT GOES WAY UP AND THE BOTTOM

LINE WAY WAY LESS LEVER PRESSES

WHEN YOU RESTORE IN A MORE

REGULAR ACTIVITY BILATERALLY IN

THE PREFRONTAL CORTEX IN THE

RESISTANCE.

SO THE SUMMARY OF THIS IS THAT

YOU CAN USE THIS PUNISHMENT

PROCEDURE TO CREATE TWO

DIFFERENT GROUPS LIKE PUNISHMENT

RESIST EVEN, PUNISHMENT

SENSITIVE.

NOW THE PERCENTAGE OF RED THAT

BECOMES PUNISHMENT RESISTENT IS

NOT RELATED AT ALL WITH HUMANS

IN MANY WAYS, RIGHT.

IF YOU TWEAK THE PROCEDURE, IF

YOIF -- THIS IS A VERY IMPORTANT

POINT.

IF YOU TWEAK THE PROCEDURE YOU

CAN GO DOWN TO 20% RESISTENTS OR

80%, IT JUST DEPENDS ON WHAT YOU

WANT TO DO.

BUT JUST A WAY TO DIVIDE THEM.

AND NEURONS IN THIS PART OF THE

PREFRONTAL CORTEX ARE LESS

ACTIVE FOLLOWING THIS COCAINE

ADMINISTRATION PARTICULARLY THE

PASSION RESISTENT ONES.

AND YOU CAN USE THIS SPACE, MAKE

LIKE AN APPROACH TO NOW RESTORE

A REGULAR ACTIVITY INTO THE PFC

AND BASICALLY YOU SEE THAT

CRAVING.

NOW THIS IS A BIG WORD BUT YOU

SEE LESS COCAINE ADMINISTRATION

CLEAR AND SIMPLE.

OKAY.

SO I AM GOING TO STOP HERE.

FORGET ABOUT SUBSTANCE ABUSE.

OF -- YOU CAN MENTION THE FLIP

SIDE -- YOU CAN INJECT THROUGH

THE SAME VIRUSES THE OPPOSITE

OF -- YOU CAN INJECT A -- WHICH

WHEN ACTIVATED WITH LIGHT WILL

SHUT DOWN ALL THE CELLS THAT

HAVE BEEN INFECTED.

AND YOU CAN PLAY WITH EXCESSIVE

ACTIVITY IN OTHER PARTS OF THE

BRAIN, RIGHT.

AND YOU CAN PLAY -- EPILEPSY FOR

EXAMPLE OR ANY OTHER DISEASES

WHERE YOU NOW WANT TO MODULATE

DOWN EXCESSIVE ACTIVITY.

SO YOU CAN CROSS THE NUMBER OF

REGIONS BY CONDITIONS AND

DISEASES AND SEE HOW MANY

APPLICATIONS YOU CAN FIGURE OUT

FOR THIS APPROACH WHICH IS

REALLY THE FUTURE.

THIS IS WHY IT'S SO BEAUTIFUL.

AND GEORGE IS USING THAT AT

TRIPLE A.

WE HAVE COLLABORATIONS WITH HIM

IN MANY OTHER INSTITUTES SO THIS

IS LIMITLESS OPPORTUNITIES FOR

NEW PROJECT.

I'M STOPPING HERE AND TAKE

QUESTIONS.

[APPLAUSE]

S.

>> [INDISCERNIBLE]

>> IF WE DID THIS -- WHAT'S

GOING TO HAPPEN TO THIS MEMORY

IN TERMS OF -- THE ACUTE EFFECT

IDENTICAL THE SINGLE INJECTION

OF NICOTINE AND COCAINE AND

WHATNOT PRODUCES THE SAME FORMAL

CELLULAR MEMORY.

THE LONG TERM CHANGES WHICH GOES

BACK TO THE TITLES OF THIS WHOLE

THING ARE DIFFERENT.

SO THE IDEA OF CREATING MEMORIES

THROUGH IRON CHAMPS THROUG CHANNELS THROUG
H

MANY DIFFERENT WAYS IS COMMON TO

ABUSE.

THE TARGET CHANGES.

WITH COCAINE CLEARLY ALPHA

RECEPTORS ARE THE CENTER OF THE

UNION FIRSUNIVERSE FOR NOW.

WE STARTED A YEAR AGO SHOWING

THERE ARE CERTAIN POTASSIUM

CHANNELS THAT UNDERGO VERY LONG

MEMORY.

THEY ARE CHANGED AND AFFECT

ACTIVITY IN THE LIMBIC SYSTEM

FOR SEVERAL WEEKS.

SO THE COMMON THEME IS COMMON TO

MANY DIFFERENT DRUGS, MEMORY

PRODUCED BY THESE DRUGS.

HUGH IT'HOW IT'S PRODUCED IS NOT

HOMOGENOUS.

>> [INDISCERNIBLE]

>> WE DON'T KNOW YET.

GEORGE'S PEOPLE AND OUR PEOPLE

ARE DOING THOSE EXPERIENCE.

WE HAVE SOME STUDIES BUT THIS IS

A NEW TECHNIQUE.

SO WE DON'T KNOW YET.

IT DEPENDS WHERE YOU LOOK AND

WHAT YOU LOOK AT.

>> [INDISCERNIBLE]

>> DOES LONG TERM POTENTIAL

INFORMATION CHANGE THE LEVEL OF

THESE AMPA RESOAR OR MDA

RECEPTORS AND OTHER RECEPTORS IN

OTHER -- FACTORS.

THERE ARE A LOT OF STUDIES, THE

ONE THAT DAVID WAS MENTIONING

BEFORE ABSOLUTELY YES.

THE PREFRONTAL CORTEX THE AWE THE AWE

MIX LAW IS AFFECTED WELL WITH

DIFFERENT BEHAVIORS.

ES LONG TERM GENETIC STIMULATION

KRRKZ THE PRESENCCORRECTS THE PRESENCE OF 
-- WE

DON'T KNOW YET.

GREAT QUESTION.

>> I GUESS A LOT OF WITH A

YOU'RE TALKING ABOUT APPLIES TO

PURELY PSYCHOLOGICAL ADDICTIONS

LIKE ADDICTION TO GAMBLING WHERE

THERE'S NO ACTUAL PHYSICAL

SUBSTANCE INVOLVED.

>> THERE'S NO SUCH THING AS

PSYCHOLOGICAL ADDICTIONS FIRST

OAF ALL.

ANY ADDICTION HAS TO HAVE THAT

BRAIN BASE, RIGHT.

>> WHAT ABOUT ADDICTION TO

GAMBLING.

>> NOW VERY GOOD EXAMPLES ARE

PARPARKINSONIAN PATIENTS WHO TAKE

CERTAIN -- AGONISTS AND THEY DO

BECOME HEAVY GAMBLERS, RIGHT.

SO THAT'S A TRIGGER.

THERE'S A CHEMICAL TRIGGER TO

GAMBLING IN THESE PATIENTS.

EVEN IF YOU DON'T HAVE A

SUBSTANCE OF ABUSE IN YOUR BODY

BUT YOU HAVE THE FORM OF

ADDICTION, YOU COULD IMAGINE

JUST A THEORY, I'M JUST

SPECULATING.

YOU COULD IMAGINE THAT YOUR

BRAIN, YOUR LIMBIC SYSTEM MIGHT

BE OR MIGHT HAVE UNDERGONE

CHANGES THAT ARE SIMILAR PERHAPS

TO PEOPLE WHO HAVE BEEN EXPOSED

TO ABUSE.

AGAIN JUST A SPECULATION BUT

WHAT I DO BELIEVE IS THAT FOR

ANY BEHAVIOR THERE HAS TO BE A

CHEMICAL BASIS FOR ANY BEHAVIOR

WE DO BRAINS CELLS ARE

ACTIVATED.

THERE'S NO WAY OUT OF IT.

DOESN'T MEAN YOU NEED TO HAVE

THE SUBSTANCE IN YOUR BODY TO

CHANGE.

>> ONE OTHER QUESTION DAVID,

MAYBE YOU COULD GET IN THE ACT

HERE TOO.

WHEN PEOPLE ARE STUDYING THE

EFFECT ON THE CENTRAL NERVOUS

SYSTEM BEFORE GENES WERE

DISCOVERED THE MAJOR THOUGHT

WERE THESE WERE INTERFERENCE IN

LIPID METABOLISM IN MEMBRANE.

I MEAN ALCOHOL HAS THIS WIDE

RANGE OF AC ACTIVITY AND CERTAINLY

BRAINS ARE AFFECTED IN

MITOCHONDRIA AND EVERYTHING

ELSE.

WHEN YOU START LOOKING FOR

GENETIC ABNORMALITIES WITH

SOMETHING AS YOU THINK AS

ALCOHOL WHICH AFFECTS ALL THESE

OTHER SYSTEMS, TWO QUESTIONS.

ONE, HOW DO YOU GO ABOUT

DISCERNING WHAT IS GENETIC AND

WHAT IS EPI GENETIC AND ISN'T IT

MORE LIKELY GIVEN THIS MULTIPLE

EFFECTS OF ALCOHOL THAT EPI

GENETIC CONSIDERATIONS ARE GOING

TO BE MORE POWERFUL THAN PRIMARY

MANDELIAN GENES.

>> IT'S A TERRIFIC QUESTION.

 COULD HAVE ANSWERED THIS

QUESTION MUCH BETTER.

THERE'S A HISTORY IN ALCOHOL

RESEARCH OF PUTTING FORWARD MANY

DIFFERENT CANDIDATES AS THE

TARGET FOR ALCOHOL'S ACTION ON

THE BRAIN.

AND PROBABLY THERE ARE MANY

TARGETS FOR ALCOHOL WHICH IS A

MOLECULE THAT CAN BOTH ALTER

MEMBRANE STRUCTURE AND ALSO

INTERACT SPECIFICALLY TO MODIFY

THE FUNCTION OF A VARIETY OF

DIFFERENT IMPORTANT ION CHANNELS

FOR EXAMPLE GAB AWE URGIC

CHANNELS AND OTHERS.

ONE OF THE STRENGTHS OF THE

GENETIC APPROACH IF YOU'RE

IDENTIFYING VARIATIONS IN

MOLECULES THAT ALTER RESPONSE,

IS THAT YOU CAN DO AN OBJECTIVE

HYPOTHESES-FREE GENOME-WIDE

SURVEY TO FIND THE MOLECULES

THAT HAVE VARIATIONS THAT ARE

ALTERING RESPONSE.

AND THAT'S BEING DONE SO FOR

EXAMPLE THERE ARE GENETIC ANIMAL

MODELS WITH LOW AND HIGH

SENSITIVITY.

BOTH IN THE MOUSE AND ALSO --

THERE'S BEEN PROGRESS TOWARDS

IDENTIFYING SOME OF THE

MOLECULES THAT ARE INVOLVED.

NOW AS YOU ALSO SAY, THERE ARE

MOLECULAR CHANGES AT THE DNA

LEVEL WHICH ARE NOT INHERITED

CHANGES BUT THAT ARE LONG

LASTING EVEN E GENETIC CHANGES.

THESE ARE CHANGES IN DNA

METHYLATION IN CHROMATIN

STRUCTURE.

THERE ARE PRELIMINARY PAPERS AND

STUDIES -- FOR EXAMPLE WE HAD A

PAPERPNAS LASTING THESE EPI

GENETIC CHANGES IN THE BRAINS OF

ALCOHOLICS AND COCAINE ADDICTS

AND THEY ARE LONG LASTING AND

THEY INVOLVE SYSTEMS OF GENES.

THIS IS A PAPER HODGKINS -- IF

ANYBODY WAS REALLY INTERESTED

YOU COULD E-MAIL ME, I WOULD BE

GLAD TO SEND YOU A REFERENCE.

THAT'S WORK THAT I THINK IS VERY

COMPLEMENTARY TO THE WORK SUCH

AS ANTONELLA WAS DESCRIBING

LOOKING AT THE MODIFICATION OF

CIRCUITS BY THESE DRUGS.

THEY ARE MODIFICATIONS OF

MOLECULES AND THEN MODIFICATIONS

OF CIRCUITS.

>> CAN I ASK YOU ONE OTHER ONE.

>> REALLY SIMPLE QUESTION THERE.

>> THERE SEEMS TO BE I THINK HER

NAME IS -- AT UC SAN FRANCISCO

HAS DONE THIS MARVELOUS STUDIES

IN -- WHICH ARE FANTASTIC SYSTEM

FOR LOOKING AT DRO -- ALCOHOL OF

COURSE FROM ROTTED FOODS AND

FRUITS AND EVERYTHING ELSE.

AND THEY MAKE ACID ALDEHYDE.

BUT SHE'S IDENTIFIED A WHOLE

SERIES I FORGOT -- NAMES OF

GENES ARE ALWAYS VERY ROMANTIC

AND I FORGOT.

>> HANGOVER OR HANGOVER.

ONE OF THE NICE THINGS ABOUT

STUDYING DROA SAW LAW, STUDYING

THE GENE YOU CAN GIVE IT A

COLORFUL NAME.

I BELIEVE ONE OF THE MOST

PROFOUND LESSONS FROM THE DROA

SAW LAW WORK IS THAT THESE FRUIT

FLIES WHICH DON'T HAVE A CULTURE

OF DRINKING OR DRUG USE, WHEN

THEY SHOW A DIFFERENCE, YOU CAN

BE PRETTY SURE IT'S DUE TO A

DIFFERENT SCENARIO IN THE

GENETIC MAKE UP.

OVER AND OVER, RICKY AND A

COUPLE OTHERS HAVE BEEN ABLE TO

IDENTIFY GENES THAT ACTUALLY

ALTER DIFFERENCES IN RESPONSE.

IT'S A VERY WELL-KNOWN PAPER

JUST RECENTLY PUBLISHED IN

SCIENCE WHICH YOU MIGHT WANT TO

LOOK AT I IT SHOWS THE MAIL

PRODA LAW -- MALE DROA SAW

LAW -- THEM IT'S PRONE TO

DRINKING.

NOW SOME OF THE THINGS THAT IT

JUST SHIFTED FROM ONE --

BEHAVIOR MATING TO ANOTHER DRAW

SAW LAW BEHAVIOR SEEKING FOOD.

BUT WE'RE NOT EXPERTS ON DRAW

SAW LAW LIKE -- WHO -- WORKED

WITH.

>> THAT SOUNDS LIKE SHAKESPEARE,

I THINK.

ALCOHOL DOES THREE THINGS,

INCREASES THE DESIRE, DIMINISHES

THE PERFORMANCE AND PROMOTES THE

FLOW OF URINE, RIGHT?

[LAUGHTER]

>> EXACTLY.

>> ARE THERE ANY OTHER

QUESTIONS?

YES, LAST QUESTION.

QUESTION REGARDING THE MEMORY

EFFECT.

YOU'RE MEASURING THE -- RESOAR

TO THE MD RECEPTOR.

SO WHAT IS IT AFFECTING THIS

LONG TIME RETENTION EFFECT.

IS THAT THE PRODUCTION OF THE --

AND THE RATIOS.

WHAT IS IT AFFECTING BY THIS

EFFECT OF THE DRUG OF ALCOHOL

ADDICTION.

>> THAT'S THE HOLY GRAIL.

THAT'S A BEAUTIFUL QUESTION.

WE DON'T KNOW.

WE HAVE NO IDEA YET PLAIN AND

SIMPLE.

>> I WANT TO THANK YOU ALL,

THANK YOU VERY VERY MUCH.

[APPLAUSE]