>> WELCOME TO THE WEDNESDAY

AFTERNOON LECTURE SERIES.

OUR SPEAKER, DR. MARINA

PICCIOTTO IS CURRENTLY A CHILD

MURPHY PROFESSOR IN PSYCHIATRY

AND PROFESSOR OF NEUROBIOLOGY

AND PHARMACOLOGY AT YALE

UNIVERSITY.

SHE IS ALSO SERVES AS ASSISTANT

CHAIR FOR THE BASIC SCIENCE

RESEARCH FOR THE DEPARTMENT OF

PSYCHIATRY AND AN ASSOCIATE

DIRECTOR OF THE NDPH PROGRAM FOR

YALE UNIVERSITY SCHOOL OF

MEDICINE.

SHE IS SENIOR EDITOR OF THE

JOURNAL OF NEUROSCIENCE, SERVED

ALSO AS SCIENTIFIC COUNSELOR FOR

THE SOCIETY FOR NEUROSCIENCE AND

NIDA.

SO SHE KNOWS THE INS OF NIH.

DR. MARINA PICCIOTTO RECEIVED

HER Ph.D. OR HER BACHELORS

FROM -- AND THEN HER Ph.D.

FROM ROCKEFELLER UNIVERSITY

WHERE SHE WORKED IN THE

LABORATORY OF DR. PAUL

GREENBERG.

SHE WENT ON TO CONDUCT

POSTDOCTORAL RESEARCH IN FRANCE,

IN PARIS AND A DIVISION OF

DR. -- [ INDISCERNIBLE ] BEFORE

JOINING THE FACULTY AT YALE

UNIVERSITY IN 1995.

DR. MARINA PICCIOTTO'S RESEARCH

IS ON ANIMAL MODELS OF

PSYCHIATRY WITH A PARTICULAR

EMPHASIS ON THE ROLE OF NICOTINE

ACETYLCHOLINE RECEPTORS IN

BEHAVIORS RELATED TO ADDICTION,

DEPRESSION, LEARNING AND

APPETITE.

SHE IS GOING TO TELL US ABOUT

SOME BEAUTIFUL WORK AND VERY

IMPORTANT WORK THAT SHE RECENTLY

PUBLISHED IN "SCIENCE" AND

PREFERABLE SOMETHING ELSE, BUT I

WANTED TO SPECIFICKY MENTION

THIS WORK IN WHICH SHE UNCOVERED

POTENTIAL MECHANISMS FOR

NICOTINE ACTING ON PEOPLE'S

RESPONSE IN NEURONS AND DECREASE

IN APPETITE.

AND IF YOU'RE LUCKY ENOUGH,

YOU'RE ABLE TO HEAR ABOUT THAT

ON NPR, WHICH IS WHAT HAPPENED

TO ME ONE EVENING GOING BACK

HOME LAST YEAR.

THAT'S HOW I LEARNED ABOUT HER

WORK.

IT'S REALLY A PLEASURE TO HAVE

YOU HERE AND TELL US MORE ABOUT

THAT.

[ APPLAUSE ]

IS.

>> SO MUCH FOR THE INVITATION

FOR BEING HERE THIS AFTERNOON.

IT'S A PLEASURE TO TALK TO YOU

AND I WILL BE TALKING TODAY

ABOUT NICOTINE ADDICTION AND I

DID MY DEGREE AS A GRADUATE

STUDENT ON THE PHOSPHORYLATION

OF THE CYSTIC FIBROSIS

TRANSDUCTION REGULATORS.

SO I GOT MY DEGREE WORKING ON A

PROTEIN THAT ISN'T EVEN

EXPRESSED IN NEURONS.

IT WAS VERY HARD TO TALK ABOUT

IT ON THE TRAIN, ON THE AMTRAK

TRAIN AND NOW, WHEN PEOPLE ASK

ME WHAT I DO, I SAY, I WORK ON

WHAT NICOTINE DOES TO THE BRAIN.

AND FRANKLY, EVERYBODY HAS A

STORY.

SO EVERYBODY KNOW WAS NICOTINE

DOES TO THE BRAIN WHERE THEY ARE

A CURRENT OR FORMER SMOKER OR A

RELATIVE OF A SMOKER, EVERYBODY

KNOW THAT IS NICKSTEIN ADDICTIVE

AND HAS MANY OTHER EFFECTS ON

BEHAVIOR.

AND OF COURSE IT'S A HUGE PUBLIC

HEALTH PROBLEM.

IT'S STILL THE MAJOR PREVENTIBLE

CAUSE OF MORTALITY IN THE UNITED

STATES, MORE THAN 300,000 PEOPLE

DIE EVERY YEAR AS A CONSEQUENCE

OF NICOTINE ADDICTION.

SO UNDERSTANDING THE BASIC

NEUROSCIENCE OF THIS ONE

SUBSTANCE COULD MAKE AN ENORMOUS

DIFFERENCE FOR HUMAN HEALTH.

AND FROM THE STANDPOINT OF BASIC

NEUROSCIENCE, WE DIDN'T EVOLVE

NICOTINE ACETYLCHOLINE RECEPTORS

SO WE COULD ROLE UP A PLANT LIFE

AND STICK IT IN OUR MOUTH AND

SET IT ON FIRE.

THESE RECEPTORS ARE IN THE BRAIN

FOR A REASON.

SO IN ADDITION TO UNDERSTANDING

NICOTINE ADDICTION AND THE

BEHAVIORS RELATED TO NICOTINE

ADDICTION, IS TO UNDERSTAND WHAT

THESE MOLECULES DO TO THE

FUNCTION OF THE NORMAL BRAIN,

THE FUNCTION OF A NORMAL

INERTIA.

I'LL TRY TO TAKE YOU 32 SOME OF

OUR WORK AND SEE HOW WE TRY TO

MAKE LINKS BETWEEN THE BASIC

MOLECULAR BIOLOGY OR THE

MOLECULAR DESCRIPTION OF THESE

RECEPTORS THROUGH THE LEVEL OF

WHAT THEY DO TO CELLS, TO

CIRCUITS AND THEN TO BEHAVIORS.

SO HERE IS WHAT I'M GOING TO

TALK TO YOU ABOUT.

HERE IS THE PROBLEM.

WE KNOW A LOT ABOUT THE

MOLECULAR BIOLOGIES OF NICOTINE

ACETYLCHOLINE RECEPTORS.

IT'S A GIANT FAMILY.

YOU CAN SEE THERE ARE ABOUT 15

SUBUNITS AND THESE COMBINE

TOGETHER TO CAUSE AN ENORMOUS

DIVERSITY OF NICOTINE RECEPTORS

IN THE BRAIN.

AND NICOTINE RECEPTORS IS A

SHORT HAND.

THERE ARE NAMES FOR THE

PHARMACOLOGICAL SIB STANCE,

NICOTINE THAT ACKIVATES THEM AND

THEY TRANSDUCE A NORMAL

NEUROTRANSMITTER ACETYLCHOLINE.

WE KNOW A LOT ABOUT THE BRAIN

AREAS IN WHICH THESE ARE

EXPRESSED.

SO, THIS IS ACTUALLY AN MRI OF A

HUMAN BRAIN AND THIS IS A SPEC

STUDY DONE BY COLLEAGUES WITH A

RADIO LABEL, NICOTINE-LIKE

MOLECULE, THAT SHOWS THESE ARE

EXPRESSED THROUGHOUT THE BRAIN

AND IN FACT, ALMOST EVERY NERVE

CELL.

AND, WE KNOW A LOT ABOUT THE

BEHAVIORAL CONSEQUENCES OF

NICOTINE'S EFFECT ON THE BRAIN

BECAUSE WE HAVE BEEN DOING THIS

BIOASSAY ON OURSELVES AS A

POPULATION FOR THOUSANDS OF

YEARS.

WE KNOW THAT PEOPLE REPORTS THEY

SMOKE FOR MANY, MANY DIFFERENT

REASONS, AND WE CAN GET CLUES

ABOUT THE EFFECTS OF NICOTINE

AND NICOTINIC ACETYLCHOLINE

RECEPTORS ON BEHAVIOR FROM WHAT

PEOPLE REPORT WHEN THEY CHOOSE

TO SMOKE AND WHEN THEY HAVE

TROUBLE QUITTING.

SO OUR PROBLEM IS TO LINK THIS

LARGE BIOCHEMISTRY MOLECULAR

BIOLOGY KNOWLEDGE BASE WITH THIS

ANATOMICAL DATABASE AND THIS

BEHAVIORAL DATABASE.

SO WE'LL TRY TO PUT THEM

TOGETHER.

THIS IS THE MOLECULE.

THE RECEPTORS ARE SITTING IN THE

MEMBRANE OF NERVE CELLS AND I'LL

BE TALKING ABOUT THE BRAIN

TODAY.

THEY ARE ION CHANNELS WITH A

CORE THAT OPENS WHEN A LIGAND

N-THIS CASE, I'M DIAGRAMMING

ACETYLCHOLINE, BINDS AT THE

INTERFACE BETWEEN TWO SUBUNITS.

SO SUBUNITS ARE THE STAGE OF A

BARREL AROUND WHICH THEY

SURROUND A PORE THAT ALLOWS IONS

TO FLOW ACROSS MEMBRANES.

THIS TYPE HERE, WHICH WE KNOW

THE MOST ABOUT.

H., IS THE TYPE AT THE

NEUROMUSCULAR JUNCTIONS EVER ALL

COMMUNICATION BETWEEN NERVE AND

MUSCLE GO THROUGH THIS TYPE.

WE KNOW ABOUT IT'S STRUCTURE AND

PHARMACOLOGY.

THERE IS ONE TYPE HERE THAT YOU

CAN SEE THAT HAS OF FIVE

SUBUNITS THAT ARE ALL THE SAME

AND SO IT HAS DIFFERENT

PROPERTIES FROM THESE TWO

HETEROMAKER SUBTYPES THAT HAVE

AT LEAST ONE KIND OF ALPHA AND

AT LEAST ONE KIND OF BETA IN

ORDER TO BE FUNCTIONAL AND SO

EACH OF THESE SUBTYPES HAVE

DIFFERENT PROPERTIES.

WHEN THE LIGAND BINDS AT THE

INTERFACE, IF YOU HAVE FOUR

DIFFERENT INTERFACES YOU COULD

HAVE FOUR DIFFERENT PROPERTIES.

HOW TIGHTLY IT BINDS, THE

AFFINITY, HOW LIKELY THE

RECEPTOR IS TO OPEN.

THE OPEN PROBABILITIY AND HOW

LIKELY THE RECEPTOR IS TO THE

REFRACT REESE OPENING AGAIN, THE

DESENSITIZATION KINETICS.

THAT VARIABILITY GIVES RISE TO

THE DIFFERENT PROPERTIES OF

NICOTINE AT DIFFERENT CELL TYPES

AND AT DIFFERENT RECEPTORS.

SO IN THE BRAIN, WE HAVE GREAT

DEAL OF INFORMATION ABOUT HOW

THESE DIFFERENT SUBUNITS ARE

EXPRESSED.

SO HERE IS JUST A PANEL OF

INSIGHTUE HYBRIDIZATION AT TWO

DIFFERENT LEVELS IN THE MOUSE

BRAIN SHOWING YOU IF YOU TAKE

NINE OF THOSE SUBUNITS, YOU CAN

SEE THERE IS SEVERAL DIFFERENT

TYPES OF PATTERNS OF EXPRESSION.

SO I'LL GO THROUGH THIS MORE IN

DETAIL ON A LATER SLIDE.

WHAT CAN YOU SEE IS THERE ARE

TYPES THAT ARE VERY WIDELY

EXPRESSED.

SO THESE TWO ARE PARTNERS.

AND TYPE THAT IS ARE VERY

SPECIFICALLY EXPRESSED IN

PARTICULAR BRAIN AREAS.

AND SO THEY HAVE OBVIOUSLY

DIFFERENT CONSEQUENCES WHEN YOU

ACTSIVATE THEM.

AND THE OTHER POINT THEY WANT TO

MAKE IS THAT THE PATTERN OF

RECEPTOR EXPRESSION, ALTHOUGH

DIFFERS SOMEWHAT BETWEEN MOUSE

AND HUMANS, IT'S REALLY PRETTY

HIGHLY CONSERVED.

HERE YOU'RE LOOKING AT A HUMAN

SCAN WITH A SECTION LIKE THIS,

RIGHT THROUGH THE BRAIN, AND

THIS IS THE THALAMUS, THIS IS

THE RELAY STATION FOR SENSORY

INFORMATION FROM THE PERIPHERY

UP TO THE CORTEX FOR ACTION.

AND THIS IS THE MOUSE BRAIN AND

IT'S CUT LIKE THIS.

BUT WHAT CAN YOU SEE IS THAT IN

BOTH CASES, HERE IS THE

THALAMUS, THIS IS A HOTSPOT FOR

EXPRESSION OF RECEPTORS.

I'M NOT GOING TO TALK ABOUT THAT

BRAIN AREA TODAY.

BUT IT'S AN EXAMPLE OF HOW THERE

IS CONSERVATION OF THE OVERALL

PATTERN OF EXPRESSION BETWEEN

MOUSE AND HUMANS.

SO NOW I'M GOING TO GO THROUGH

SOME OF THE DIFFERENT REASONS

PEOPLE REPORT THAT THEY SMOKE.

NOW CLEARLY ONE THING THAT IS

KNOWN DESPITE THE FACT THAT

TOBACCO COMPANY EXECUTIVES CAN

GET UP AND SAY, IT'S NOT

ADDICTIVE.

IT'S A HABIT.

IT'S A CHOICE.

NICOTINE AND TOBACCO IS

ADDICTIVE AND DRIVES ON-GOING

SMOKING.

IF YOU TAKE NICOTINE OUT OF

TOBACCO AND ALLOW PEOPLE TO

SMOKE, THEY WILL SMOKE LESS OVER

TIME.

SO THE NICOTINE THAT IS IN

TOBACCO IS REINFORCING LIKE

OTHER DRUGS, LIKE COCAINE AND

AMPHETAMINES.

IT ACTS ON SIMILAR PARTS OF THE

BRAIN.

I'LL TELL BUT THAT IN A MINUTE.

AND IT'S IMPORTANT FOR ONGOING

SMOKING.

SO, THE PART OF THE BRAIN THAT

IS REALLY IMPLICATED MOST

STRONGLY IN THE ADDICTIVE

PROPERTIES OF ALL DRUGS OF ABUSE

THAT ARE USED BY HUMANS TODAY IS

STILL THE DOPAMINE SYSTEM.

IT'S NOT THE ONLY PART OF THE

BRAIN WHERE THESE SUBSTANCES

CONVERGE, BUT IT'S A PART OF THE

BRAIN WHERE WE KNOW QUITE A BIT

ABOUT THE TRANSITION OF LIKING

SOMETHING TO USING IT

HABITUALLY.

AND WHAT CAN YOU SEE HERE AGAIN

NOW THIS IS A BLOW UP OF THE

PANEL OF IN SITU HYBRIDIZATION

OF NINE DIFFERENT SUB UNITS S

THAT THEY ARE EXPRESSED QUITE

HIGHLY AND QUITE SELECTIVELY IN

THE CELL BODIES OF THESE

DOPAMINE NEURONS.

I'LL DIAGRAM IT HERE.

THIS MUSTACHE HERE IS THE --

REPRESENTS THE VENTRAL TEGMENTAL

AREAS, THE CELL BUSINESS

IMPORTANT FOR ADDICTION-RELATED

BEHAVIORS AND THE TAIL HERE IS

THE DOPAMINE CELL BUSINESS THAT

GENERATE IN PARKINSON'S DISEASE

AND RESULT IN THE INABILITIES

TOW PERFORM INVOLUNTARY

MOVEMENT.

THERE IS SOME SUBTYPES THAT ARE

HIGHLY SELECTIVELY EXPRESSED

HERE IN THE DOPAMINE NEURONS.

ALPHA 6 AND BETA 3 ARE EXPRESSED

HERE AND ALSO IN NEW APP NERGIC

NEURONS.

THERE IS SOMETHING SPECIAL ABOUT

THESE SUBUNITS IN NEURONS THAT

EXPRESS CAT COAL MEANS LIKE

DOABA MEAN AND NEUREPINEPHRINE.

AND THEN BETA TWO AND ALPHA 4

ARE WIDESPREAD.

STILL HAVE THAT MUSTACHE EVEN

THOUGH THEY EXPRESSED IN MANY

SUBTYPES.

YOU CAN SEE THAT THERE ARE ALSO

SELECTIVELY EXPRESSED HERE IN

THE DOPAMINE CELL BODIES.

AND THEN AN AVRILA 5 IS VERY

IMPORTANT BECAUSE THERE IS A

HUMAN -- ALPHA 5 -- IT'S

PROBABLY ONE OF THE GENES OF

GREATEST EFFECT ON BOTH SMOKING

BEHAVIORS AS WELL AS OTHER

BEHAVIORS INCLUDING ALCOHOLISM.

THAT IS EXPRESSED QUITE HIGHLY

IN THIS BRAIN AREA AND EVEN

THOUGH YOU CAN'T SEE VERY MUCH

HERE, THERE IS EVEN SOME OF THIS

HOMOMERIC 7.

SO YOU CAN SEE THERE IS A LOT OF

DIFFERENT SUBTYPES CAN CONTROL

THESE DOPAMINE NEURONS.

AND WHEN WE LOOK AT VERY

SIMPLIFIED BRAIN, THIS IS MY

QUITE SCALED-UP BRAIN.

I USED TO HAVE A ONE NEUROBRAIN.

NOW I HAVE FIVE NEURON BRAINS.

YOU CAN SEE THAT NICOTINIC

RECEPTORS ARE VERY GOOD AT

MODULATING A CIRCUIT.

SO THERE ARE NICOTINE RECEPTORS

ON THE CELL BODIES OF THESE

DOPAMINE NEURONS.

THEY ARE EASY TO UNDERSTAND.

WHEN NICOTINE OR ACET COLEAN

BINDS, YOU INCREASE THEIR

ACTIVITY AND INCREASE THE

DOPAMINE RELEASE FROM THE OTHER

SIDE.

BUT THAT'S NOT ALL.

BECAUSE IF YOU CUT OFF THE

TERMINALS OF THESE NEURONS AND

YOU SIMPLY PUT THEM IN A TEST

TUBE IN THE SYNAPTIC ZONE AND

PUT NICOTINE ON THOSE TERMINALS.

NICOTINIC RECEPTORS ARE ON THEIR

OWN ENOUGH TO CAUSE DOPAMINE

RELEASE.

AND IF THAT WEREN'T ENOUGH,

THERE ARE ALSO NICOTINIC

RECEPTORS ON THE NEURONS THAT

DRIVE THE FIRING OR INHIBIT THE

FIRING OF THESE CELL BODIES.

SO IT'S NOT UNCOMPLICATED LIKE

MANY THINGS TO DO WITH NICOTINE,

NICOTINE CAN DO SOME THINGS.

I'LL EXPLAIN WHY THIS IS

ANYTHING A MINUTE.

SO GLUTAMATE, THE PRIMARY

EXCITATORY NEUROTRANSMITTER IN

THE BRAIN, DRIVES THE FIRING OF

THESE DOPAMINE NEURONS.

THERE ARE RESEPSORS ON THEIR

TERMINALS AND NICOTINE STIM

LIGHTS ITS DRIVE ON THIS

CIRCUIT.

AT THE SAME TIME, AT BASELINE,

GABA NEURONS, THE PRIMARY

INHIBITORY NEURONS IN THIS

CIRCUIT OR IN THE BRAIN V

NICOTINE RECEPTORS ON THEIR

TERMINALS AND SO BASELINE YOU

HAVE A MIXED EXPECTATION

INHIBITION OF DOPAMINE NEURONS.

ONE LABORATORY OR A FEW

LABORATORIES NOW THAT

PARTICULARLY THE LABORATORY OF

DAN McGEE IN CHICAGO SHOWS

THAT ALTHOUGH THIS HAPPENS AT

BASELINE, IF YOU LEAVE NICOTINE

ON A SLICE FOR ABOUT HALF HOUR

TO AN HOUR, THESE RECEPTORS KEEP

DRIVING EXCITATION ON TO THESE

DOPAMINE CELL BODIES WHEREAS THE

NICOTINE RECEPTORS ON THESE

NEURONS DESENSITIZE MORE

RAPIDLY.

SO YOU GO FROM A MIXED

EXPECTATION AND INHIBITION TO

UNMIXED EXCITATORY DRIVE ON THIS

CIRCUIT, WHICH CAN CONTINUE TO

GET THIS CIRCUIT ACTIVATED FOR A

LONGER PERIOD OF TIME THAN YOU

MIGHT THINK FROM RECEPTORS THAT

DESENSITIZE.

SO NICOTINE IS VERY GOOD AT

GETTING DOPAMINE NEURONS TO FIRE

AND TO GET DOPAMINE RELEASE.

SO, WHAT WE DID WHEN WE STARTED

OUT WAS TO ACTUALLY ASK THE

QUESTION OF THAT LARGE GROUP OF

NICOTINIC ACETYLCHOLINE

RECEPTORS, WHICH ARE ESSENTIAL

FOR THESE PROPERTIES OF NICOTINE

TO DRIVE THE DOPAMINE CIRCUIT?

THE FIRST ONE WE PICKED WAS THIS

BETA 2 SUB UNIT BECAUSE IT WAS

EXTREMELY RIDE SPREAD AND IT WAS

A PARTNER WITH ALPHA 4.

WE DIDN'T KNOW THAT AT THE TIME

BUT IT IS TRUE.

SO WHEN WE KNOCKED OUT THIS

SUBUNIT IN MICE, WE WERE

SURPRISED TO FIND OUT THAT ALL

THE HIGH AFFINITY, TIGHTEST

BINDING SITES FOR NICOTINE WERE

GONE IN THE MOUSE FRAME.

SO IT TURNED OUT WE ACTUALLY

WERE LUCKY IN THAT WE CHOSE THE

RECEPTOR THAT WAS MOST LIKELY TO

TRANSDUCE THE SIGNAL FROM THE

SMALL AMOUNTS OF NICOTINE THAT

GET INTO THE BRAIN FROM

CIGARETTE SMOKING.

AND WHAT WE SAW WAS THAT WITHOUT

THAT ONE SUBUNIT, NORMALLY

NICOTINE COULD CAUSE THESE --

THIS IS A SLICE THROUGH THE

DOPAMINE CELL BODY REGION,

PATCH-CLAMP EXPERIMENT WHERE WE

MEASURED THE FIRING OF

INDIVIDUAL DOPAMINE NEURONS.

WHAT CAN YOU SEE IS THAT

NICOTINE NORMALLY EXCITES THESE

NEURONS IN EACH LINES AND ACTION

POTENTIAL WHEN NICOTINE IS GONE,

YOU GET MORE ACTION POTENTIAL

AND THESE NEURONS FIRE.

IF YOU KNOCK OUT THE BETA 2

SUBUNIT, THAT GOES AWAY.

SO YOU NEED THE BETA 2 SUBUNIT

ENOUGH TO TAKE AWAY ONE OF THOSE

SUBUNITS TO GET RID OF THE

ABILITY OF NICOTINE TO CAUSE

THESE DOPAMINE NEURONS TO FIRE.

AND OF COURSE AS I TOLD YOU,

NICKSTEIN GOOD AT STIMULATING

THIS WHOLE CIRCUIT.

SO WE DID AN EXPERIMENT WHERE WE

LOOKED AT PROLIFERALLY

ADMINISTERED NICOTINE IN THE

WHOLE BRAIN IN NICOTINE AND

BODY.

AND IF YOU PUT A PROBE INTO THE

TERMINAL FIELDS OF THOSE

DOPAMINE NEURONS, YOU MEASURE

HOW MUCH DOPAMINE IS RELEASED AS

A RESULT OF STIMULATING EVERY

NEURTHINK IN THE BRAIN.

WHAT CAN YOU SEE IS NORMALLY

NICOTINE AS A DOSE DEPENDENT

ABILITY TO STIMULATE DOPAMINE

RELEASE AND THAT'S GONE DESPITE

THE MANY AREAS WHERE NICOTINIC

RECEPTORS CAN ACTIVATE THE

CIRCUIT.

THAT'S GONE COMPLETELY IF YOU

TAKE AWAY THIS ONE SUBUNIT.

AND WE CAN EVEN LOOK AT THE

TERMINALS IN A PREPARATION.

YOU CAN SEE THAT THAT IS ALSO

COMPLETELY GONE WITH THIS ONE

SUBUNIT KNOCK OUT.

SO THIS WAS THE FIRST STEP IN

TRYING TO CONNECT TO THIS BODY

OF MOLECULAR BIOLOGY, FAMILY OF

NICOTINIC RECEPTORS W A

PHYSIOLOGICAL FUNCTION BUT MORE

IMPORTANT, WITH A BEHAVIORAL

FUNCTION.

SO I TOLD YOU THAT SOME OF THE

HALLMARKS OF DRUGS OF ABUSE IS

THEY ARE PSYCHOSTIMULANTS, NOT

ALL BUT MANY OF THEM.

AND THEY INCREASE DOPAMINE IN A

MOUSE BUT IT MEANS YOU INCREASE

MOVEMENT AND EXCITATION AND YOU

CAN IMAGINE FOR EXAMPLE, COCAINE

AND AMPHETAMINE ARE AROUSING.

PEOPLE SPOKE BECAUSE THEY WANT

TO BE AWAKE.

THEY WANT TO BE ENGAGED.

AND WE CAN USE A PROXY OF THAT

IN THE MOUSE WHERE WE LOOK AT

SIMPLY MOVEMENT IN A FAMILIAR

ENVIRONMENT.

IN THIS CASE, WHAT WE SEE IS

THAT NORMALLY IF WE ADMINISTER

NICOTINE TO A NORMAL MOUSE, THEY

MUTUAL MORE THAN A MOUSE WITH

JUST GETTING A VEHICLE.

IN THIS CASE IT'S A SACCHARIN

SOLUTION.

AND IF WE KNOCK OUT THIS ONE

SUBUNIT, THAT ACTUALLY IS

COMPLETELY ABOLISHED.

SO THIS STIMULANT IS AROUSING

COMPONENT WHICH WE THINK IS

ASSOCIATED -- WE HAVE SHOWN

PHARMACOLOGICALLY ASSOCIATED

WITH DOPAMINE SYSTEM AND GOES

AWAY WITH THIS KNOCKOUT AND WE

CAN MEASURE WHETHER OR NOT THE

MOUSE FINDS THE NICOTINE

REWARDING BY GIVING IT A CHOICE

BETWEEN A ENVIRONMENT THAT IS

IMPAIRED WITH SALINE SOLUTION OR

AN ENVIRONMENT THAT IS IMPAIRED

WITH NICOTINE.

SO IF EVERY TIME YOU CAME INTO

THIS AUDITORIUM I LET YOU SMOKE

AND DRINK AND EVERY TIME YOU

WENT INTO THE ROOM NEXT DOOR,

YOU WERE ASKED TO LISTEN TO ME

SPEAK AND THEN AFTER THAT, I

GIVE YOU A CHOICE, WHICH

AUDITORIUM YOU WANTED TO BE IN.

YOU WOULD POTENTIALLY COME TO

THE AUDITORIUM WHERE YOU'RE

HEARING ME SPEAK BECAUSE I'M

VERY REWARDING.

SO WE GO THIS WITH NICOTINE IN A

MOUSE.

AFTER TRAINING, THE MICE EXPLORE

MORE.

THEY SPEND MORE TIME IN THE

ENVIRONMENT IMPAIRED WITH

NICOTINE THAN THEY DO IN THE

ENVIRONMENT IMPAIRED WITH SALINE

AND IF YOU KNOCK OUT THE BETA 2

SUBUNITS THAT GOES AWAY.

WE INTERPRET THIS AS SAYING THEY

CAN'T LEARN TO PAIR AN

ENVIRONMENT WITH A REWARDING

EXPERIENCE THEY HAVE WITH

NICOTINE.

AND FINALLY, THE GOLD STANDARD

FOR DRUGS OF AINTUSE WHETHER

ANIMAL WILL REALLY WORK TO GET

THAT DRUG OF ABUSE.

AND THE PARADIGM THAT HAS BEEN

USED IN SOME OF THE PEOPLE IN

THIS ROOM ARE USING IT TO GOOD

EFFECT, IS CALLED SELF

ADMINISTRATION.

WILL ANIMAL DO A FUNCTION N-THIS

CASE, POKING ITS NOSE INTO A

HOLE TO GET INFUSIONS OF THE

DRUG INTO ALMOST DIRECTLY INTO

THE BRAIN BECAUSE IT GOES

THROUGH THE JUGULAR AND GOES

DIRECTLY TO THE BRAIN.

AND WHAT CAN YOU SEE HERE IS

THAT MICE THAT ARE WILDTYPE

MICE, WE TRAIN THEM TO SELF

ADMINISTER COCAINE AND THEN

SWITCH THEM FROM COCAINE TO

NICOTINE.

AND THOSE NORMAL MICE WILL KEEP

POKING THEIR NOSE FOR NICOTINE.

IF WE TAKE THE NORMAL MICE AND

SWITCH THEM TO SALINE, THEY WILL

ACTUALLY EXTINGUISH AND STOP

BOTHERING TO POKE THEIR NOSE.

IT'S NOT WORTH IT.

THEY ARE NOT GETTING ANYTHING.

THAT'S EXTINCTION.

IF WE TAKE THE KNOCKOUT MICE AND

SWITCH THEM FROM COCAINE TO

NICOTINE, THEY LOOK LIKE THEY

GOT A SALINE SOLUTION.

SO WHAT WE HAVE DONE IS WE HAVE

GOT A BATTERY OF BEHAVIORS.

WHENEVER WE DO BEHAVIOR IN A

MOUSE, THERE IS A LOT OF REASONS

THAT A MOUSE CAN CHANGE ITS

BEHAVIOR.

IF YOU TAKE A NUMBER OF

DIFFERENT BEHAVIORS THAT ARE

ASSOCIATED WITH THE PROPERTIES

THAT ARE IMPORTANT IN HUMANS,

THEY CAN COME CLOSER TO MODELING

A HUMAN BEHAVIORAL DISEASE.

IN THIS CASE, WE HAVE ALL OF THE

COMPONENTS THAT WE LOOKED AT

THAT ARE ASSOCIATED WITH

ADDICTION AND HUMANS ARE ALTERED

WHEN WE TAKE AWAY THIS ONE

COMPONENT OF NICOTINIC RECEPTOR

THIS IS THE START OF THIS

RESEARCH AND NOW A NUMBER OF

DIFFERENT GROUPS HAVE BEGUN TO

ASK MUCH MORE SPECIFIC

QUESTIONS.

THIS IS A CONSTITUTIVE KNOCKOUT.

THESE GENES OR THIS GENE HAS

GONE FROM THE FIRST MOMENTS OF

DEVELOPMENT THROUGHOUT THE

LIFESPAN OF THE ANIMAL.

IT'S GONE IN EVERY CELL.

WE HAVE CORRELATIONS HERE BUT

DON'T HAVE CAUSATION.

THERE IS A NUMBER OF EXPERIMENTS

THAT HAVE BEEN DONE OVER THE

LAST PROBABLY 10 YEARS, IN ORDER

TO GET MORE SPECIFICALLY AT

WHICH CELLS AND WHICH TIMES DO

WE NEED THESE RECEPTORS.

SO ONE EXPERIMENT I WILL TELL

YOU ABOUT RIGHT NOW, BECAUSE WE

DID IT IN OUR LAB, INVOLVED A

TRANSGENIC SYSTEM IN WHICH WE

WERE ABLE TO RESCUE THE BETA 2

SUBUNIT EXPRESSION SELECTIVELY

IN A PARTICULAR CELL TYPE AND TO

DO THAT UNDER THE CONTROL OF AN

INDUCIBLE PROMOTOR SO WE COULD

GET CELL TYPES AND TEMPORAL

SPECIFICITY.

I'M GOING SHOW YOU ONE BEHAVIOR

HERE AND THIS SYSTEM MAY BE ONE

THAT IS FAMILIAR TO ALL OF YOU,

PARTICULARLY CHEN CHEN WHO IS IN

THE AUDIENCE AND DEVELOPED THE

FIRST MICE OF THIS KIND THAT WE

USED.

AND THESE MICE ARE BITRANSGENIC.

THEY HAVE A GENERAL NEURON

SPECIFIC PROMOTOR THAT IS

MINIMAL, THAT DRIVES THE

SYNTHETIC TRANSCRIPTION FACTOR

THAT TRANSACT VARIATE AND THAT

TRANSACT VARIATE THEN BINDERS TO

A PROMOTOR THAT IS DRIVEN BY THE

ONLY -- TRANSACTIVATOR -- IN THE

MOUSE BRAIN BECAUSE THERE IS

NOTHING ELSE TO DRIVE IT.

AND IT DRIVES IN THIS CASE, THE

BETA 2 SUBUNIT.

WHEN TET PSYCHE LEAN BINDS TO

THAT TRANSCRIPTION FACTOR, IT

CAN'T CAUSE TRANSCRIPTION OF THE

BETA 2 SUBUNIT.

WELL THEN A LOT OF BREEDING

HAPPENS.

LUCKILY WE DON'T HAVE TO DO IT.

THE MICE DO, BUT THE TIME IT

TAKES TO MAKE THESE TRIPLE

TRANSGENIC MICE IS CONSIDERABLE

AND A POSTDOC DID THIS.

SHE WAS HEROIC.

SHE CROSSED TWO TRANSGENES ON TO

THE HOMOZYGOUS BETA 2 KNOCKOUT

BACKGROUND AND RESCUE THE BETA 2

SUBUNIT EXPRESSION SO ALL THE

BETA 2 SUBUNIT EXPRESSION IN THE

BRAIN CAME ONLY FROM THIS

INDUCIBLE TRANSGENE.

AND WE DID THIS WITH A NUMBER OF

MICE THAT OTHERS DEVELOPED AS

WELL AS A LINE THAT WE GOT FROM

MARK.

AND WE GOT MANY DIFFERENT

PATTERNS OF EXPRESSION.

SO HERE IS, I'M SHOWING YOU

RADIO LABELED NICOTINE BINDING

IN THE BRAIN.

YOU CAN SEE THAT PATTERN, THAT

IS THE NORMAL WILDTYPE PATTERN.

AND THERE IS A KNOCKOUT ALL GOES

AWAY.

WE CAN EXPOSE THIS AS LONG AS WE

AND WANT THERE IS NO BINDING

THERE.

AND THEN HERE THERE ARE

DIFFERENT LINES.

IN THIS LINE WE FOUND WE ARE

RESCUING THE CORTICOFLAMMIC

NEURONS.

THEY ARE EXTREMELY IMPORTANT FOR

UNDERSTANDING WHAT NICOTINE DOES

TO THE CONNECTION BETWEEN

NEURONS AND THE CIRCUIT DURING

DEVELOPMENT.

AND WE HAVE BEEN ACTIVELY USING

THOSE MICE FOR THAT EXPERIMENT.

ONE TURNED OUT TO BE EXPRESSING

PREDOMINANTLY INDIVIDUAL NUCLEI

IN THE RETINA AND PROJECTION

NEURONS IN THE BRAIN AND ANOTHER

LAB AT YALE USED THAT TO EXAM

THE DEVELOPMENTS OF RETINAL

WAVES DURING VISUAL SYSTEM

DEVELOPMENT.

THIS ONE TURNED OUT TO BE THE

HIGHEST EXPRESSING AND WE NEVER

USED IT BECAUSE THE MICE LOOKED

SORT OF STRANGE.

THEY CIRCLED.

AND SINCE WE DIDN'T WANT TO DO

SOMETHING NONSELECTIVE, WE

HAVEN'T STUDIED THESE FURTHER

BUT THIS LINE HERE, THERE IS

THAT MUSTACHE.

WE WERE ABLE TO SELECT OF

EXPRESSION IN THESE BCA NEURONS

AND IN PROJECTIONS HERE IN THE

GROUP OF THE STRATUM BUT MORE IN

THE NUCLEUS ACCUMBENS.

WE USED THAT LINE TO ASK, IF WE

ONLY HAVE BETA 2 SUBUNIT

EXPRESSION IN THE VTA NEURONS,

CAN WE RESCUE THOSE BEHAVIORS?

IT TURNS OUT, YES.

SO HERE IS I'M SHOWING YOU LOCO

MOTOR ACTIVITY.

IT INCREASES ACTIVITY.

THE KNOCKOUT DOESN'T SHOW THAT

ACTIVITY.

AND WHEN WE RESCUE ONLY THE VTA,

THAT'S ENOUGH TO RESCUE THIS

DOPAMINE DEPENDENT BEHAVIOR.

SO NOW WE ARE ON THE WAY TO

CONNECTING A BRAIN REGION TO THE

EFFECTS OF THE PARTICULAR

SUBUNIT IN THESE BEHAVIORS.

AND NOW, A WHOLE FIELD HAS

ACTUALLY CONVERGED TO DO REALLY

CAREFUL WORK TO IDENTIFY WHAT

ARE THE DIFFERENT SUBUNIT AND

THE BRAIN AREAS THAT ARE

INVOLVED?

SO REALLY ELEGANT WORK WAS DONE

BY COLLEAGUES WHERE THEY USED A

LENGTHY VIRAL EXPRESSION TO

REEXPRESS THE BETA 2 SUBUNIT

FIRST IN THE VTA AS A WHOLE.

AND THEY SHOWED THAT COULD

RESCUE NICOTINE SELF

ADMINISTRATION.

THAT IS A VERY IMPORTANT

BEHAVIOR RELATED TO ADDICTION.

AND THEN CALL TECH DID A SERIES

OF BEAUTIFUL RESCUE

EXPERIMENTS -- KNOCKIN

EXPERIMENTS, WHERE THEY PUT

POINT MUTATIONS INTO EITHER A

PARTNER BETA 2, ALPHA 4, OR ONE

OF THOSE SUBUNITS THAT IS REALLY

SELECTIVE FOR DOPAMINE NEURONS,

ALPHA 6.

IF THEY MADE THOSE RECEPTORS

REALLY HYPERSENSITIVE TO

NICOTINE, THEY COULD SHOW

BEHAVIORS LIKE PLACE PREFERENCE

AT DOSES OF NICOTINE THAT WERE

SO LOW THEY WERE COMPLETELY

IGNORED BY A NORMAL MOUSE.

SO HERE IS FIRST WE HAD ENOUGH

SUFFICIENT TO DRIVE THE REWARD

FOR NICOTINE.

AND TO TOGETHER, WHAT THIS

SHOWED -- I DIDN'T SHOW IT HERE

AND I SHOULD HAVE.

I'M SORRY.

TK BOOKER IN THE LAB SHOWED JUST

LAST YEAR THAT IF THEY MADE A

SELECTIVE KNOCKOUT OF THE ALPHA

4 SUBUNIT, ONLY IN DOPAMINE

NEURONS THAT WAS ALSO SUFFICIENT

TO ABOLISH NICOTINE PLACE

PREFERENCE.

SO TOGETHER AS A FIELD, WE COME

UP WITH A CONSENSUS.

THESE ALPHA 4, ALPHA 6, BETA 2

NICOTINIC RECEPTORS IN DOPAMINE

NEURONS OF THE VTA ARE NECESSARY

AND SUFFICIENT FOR A WHOLE PANEL

OF BEHAVIORS THAT ARE RELATED TO

NICOTINE REWARD AND NICOTINE

REINFORCEMENT, THE HALMARK

BEHAVIORS WITH ADDICTION.

SO THAT IS NOW STARTED TO FILL

IN SOME OF THE BLANKS OF OUR

DIAGRAM HERE.

WE THAN WE HAVE A NICOTINIC

RECEPTOR SUBTYPE.

WE KNOW THIS ONE IS THE

ESSENTIAL ONE FOR THE ADDICTIVE

PROPERTIES OF NICOTINE AND WE

ALSO HAVE A BRAIN AREA.

SO IT'S DOPAMINE NEURONS

PARTICULARLY THAT ARE ESSENTIAL

FOR THESE BEHAVIORS.

AND NOW LOOKING BACK, IT ALL

SEEMS LOGICAL AND NOT VERY

SURPRISING BUT WHEN YOU STARTED

THIS, IT WAS NOT AT ALL CLEAR

THAT WITH THIS EXTREMELY BROAD

EXPRESSION PATTERN OF NICOTINIC

RECEPTOR SUBUNITS AND THE LARGE

NUMBER, IT COULD POINTED AND

FIGURE OUT WHICH RESEPTEMBERRORS

IN WHICH BRAINIERS WERE

ESSENTIAL.

ALL OF THAT HAS BEEN PUBLISHED

AND THE BACKGROUND FOR THE NEXT

PART OF THIS TALK.

AND WHAT IS ANOTHER REASON WHY

PEOPLE SAY THEY SMOKE?

I FIND THIS TRAGIC BECAUSE WHEN

YOU GO OUT AND YOU ASK PEOPLE

WHY THEY SMOKE, SOME PEOPLE SAY,

WELL, I WANT TO.

I LIKE IT.

I DON'T WANT TO STOP.

AND THAT'S GENERALLY A HALMARK

OF REINFORCEMENT OF ADDICTION.

BUT THE GROUP THAT REPORTS THAT

THEY SMOKE TO CONTROL THEIR

APPETITE IS LARGELY TEENAGED

GIRLS.

SO ONE OF THE PRIMARY REASONS

TEENAGE GIRLS SAY THEY START

SMOKING, NOT EVEN CONTINUING TO

SMOKE, IS IN ORDER TO CONTROL

BODY WEIGHT.

IN ADDITION, A LOST PEOPLE SAY,

YOU ASK PEOPLE WHY DON'T YOU

QUIT?

AND THEY SAY I'M AFRAID TO GAIN

WEIGHT.

NOW, ON AVERAGE, ACROSS THE

POPULATION, WE KNOW THAT SMOKERS

ARE ACTUALLY LEANER FROM

EPIDEMIOLOGICAL STUDIES THAN

NONSMOKERS BUT IT'S ABOUT 2.5

KILOGRAMS.

A LITTLE MORE THAN 5 POUNDS.

YET SOME PEOPLE GAIN A LOT MORE,

SOME OBVIOUSLY HAVE TO GAIN LESS

FOR THIS TO BE ON AVERAGE.

AND YET IT IS A BARRIER TO

HAVING PEOPLE STOP SMOKING.

SO, WE WANTED TO ASK, WHAT IS

THE LENGTH -- WHAT IS THE LINK

BETWEEN SMOKING AND BODY WEIGHT?

AS I MENTIONED ON AVERAGE,

SMOKERS ARE LEANER AND THAT

QUITTING LEADS TO -- I SAID ALL

OF THIS.

LEADS TO WEIGHT GAIN AND

REPORTED TO BE A MAJOR REASON

SOME PEOPLE START SMOKING.

AND THERE HAD BEEN A PRETTY GOOD

BEHAVIORAL LITERATURE, IN

PARTICULAR THIS IS WORK FROM

NEIL GRUN BERG'S LAB WHO IS JUST

ACROSS THE STREET WHO HAD SHOWN

THAT IS POSSIBLY THE NICOTINE IN

TOBACCO IMPORTANT FOR APPETITE

CHANGES.

AND WE USED RAT MODELS AND SHOWN

THAT NICOTINE ITSELF OF THE 4000

CONSTITUENTS IN TOBACCO IS

ENOUGH TO DECREASE FOOD IN TAKE

IN RATS.

AND SHOWED THERE IS A SEX

DIFFERENCE.

SO FEMALE RATS ARE MORE

SENSITIVE TO THIS EFFECT THAN

MALE RATS.

AND ALSO A LITERATURE AROUND THE

EFFECT OF WITHDRAWAL ON BOTH

METABOLIC AND BRAIN SYSTEMS THAT

ARE ASSOCIATED WITH FOOD IN

TAKE.

AND IN THIS CASE, ZOLI SHOWED

THAT AFTER NICOTINE WITHDRAWAL,

IF YOU TREAT CHRONICALLY IN

RATS, THAT THERE IS A INCREASE

IN BODY WEIGHT BUT ALSO

INCREASES IN EXPRESSION OF

MOLECULES IN BROWN AND LIGHT

ADIPOSE TISSUE AND IN THE BRAIN

THAT ARE ASSOCIATED WITH

METABOLIC REGULATION.

SO, PROBABLY COMPLEX PROCESS.

AND SO, THE QUESTION THAT WE'RE

REALLY ASKING HERE IS, WHAT ARE

THE NEUROBIOLOGICAL MECHANISMS

THAT UNDERLIE THESE OBSERVATIONS

THAT HAVE BEEN AROUND FOR QUITE

A WHILE?

FIRST WE HAD TO SEE IF WE COULD

REPRODUCE THESE BEHAVIORAL

STUDIES IN MICE.

AND SO WHAT WE DID WAS TO JUST

TREAT EVERY DAY WITH ONE

INJECTION, NORMAL MICE WITH

INCREASING DOSES OF NICOTINE.

SO WHAT CAN YOU SEE IS THAT EVEN

AT THE LOWEST DOSE, WHICH IS 100

MICOGRAMS PER KILOGRAM, WE SEE A

DECREASE IN THE WEIGHT GAIN OVER

TIME OF THESE MICE WHEN WE TREAT

DALEY WITH NICOTINE.

AND WHAT CAN YOU SEE IS TWO

THINGS, ONE IS THAT THERE IS A

DESENSE STATION OF THIS EFFECT.

THIS IS CONTINUOUS  --

THERE IS NO DESENSITIZATION.

SMOKERS MAINTAIN WHATEVER WEIGHT

DECREASE THEY HAVE UNTIL THEY

QUIT SMOKING AND THEN THEY GO

BACK UP TO WHERE THEY WOULD

HAVE.

THE OTHER THING IS, IT'S NOT

RELEVANT TO OUR TALK TODAY SAID

THAT MICE TON GAIN WEIGHT OVER

TIME LIKE HUMANS DO AS WE AGE.

JUST A LITTLE FUN FACT FOR YOU.

AND AS WE INCREASE THE DOSE OF

NICOTINE, THE ANIMALS LOSE

WEIGHT BEFORE THEY GO BACK TO A

TRAJECTORY OF GAINING WEIGHT BUT

AT A SLOWER RATE OF OTHER MICE,

CONTROL MICE.

VERY HIGH DOSE OF NICOTINE, I'M

NOT SURE THAT IS SELECTIVE BUT

THESE I'M CONVINCED ARE

SELECTIVE EFFECTS OF NICOTINE ON

FOOD INTAKE.

AND THEN WE STARTED TO USE MORE

SELECTIVE PHARMACOLOGICAL AGENTS

TO SEE IF WE COULD ASK QUESTIONS

ABOUT WHAT SUBTYPES OF NICOTINIC

RECEPTORS MIGHT BE INVOLVED.

AND WE WERE LUCK NETHAT WE HAD A

PLANT ALKALOID AND CYTOSIN, THAT

IN MICE IS A PARTIAL AGONIST OF

NICOTINIC RECEPTORS.

SO IT OPENS THEM BUT NOT NEARLY

AS MUCH AS NICOTINE DOES.

SO HERE IS OUR NORMAL ADDICTION

RELATED RECEPTOR.

THE ALPHA 4 BETA 2 RECEPTORS.

YOU CAN SEE NICOTINE CAUSES AN

INWARD CURRENT THROUGH THESE

RECEPTORS.

BUT CYTOSIN IS A LOW EFFICACY

PARTIAL AGONIST.

IT OPENS THEM BUT NOT VERY MUCH.

THAT MEAN IF ACETYLCHOLINE, THE

NORMAL LIGAND COMES HERE AND

STITEO SEEN IS AROUND, IT'S

GOING TO BLOCK THE EFFECTS OF

SIGHT SEEN.

IT'S OPENING A LITTLE BIT BUT

NOT FULLY.

AND IN MICE, THIS LIGAND IS ALSO

A FULL AGONIST OF ANOTHER

RECEPTOR IN THE AUTONOMIC

GANGLIA.

AND THAT'S EXPRESSED IN THE

BRAIN BUT IN VERY LOCALIZED

AREAS INTO A LESSER EXTENT THE

OTHER SUBTYPES.

I'LL TELL THAT YOU AGAIN AT THE

END.

BUT UNFORTUNATELY, THESE

PROPERTIES ARE SPECIFIC FOR

MOUSE RECEPTORS.

IF YOU LOOK AT CYTOSIN ON ALPHA

THREE BETA 4 RECEPTFURORS HUMAN

AND OCYTES, IT LOOKS LIKE THIS.

IT'S NOT A FULL AGONIST IN

HUMANS.

WHICH IS A CAUTIONARY THEY'LL

YOU'RE DOING DRUG DEVELOPMENT,

YOU NEED TO DO SELECTIVE

EXPRESSION OF THE HUMAN SUBTYPES

AND NOT THE MOUSE SUBTYPES.

SO WE DID USE THESE IN MICE TO

SEE WHETHER CYTOSIN HAD THE SAME

EFFECT OF NICOTINE.

YOU CAN SEE HERE THAT IT HAD

EXACTLY THE SAME EFFECT ON BODY

WEIGHT GAIN IN MICE THAN AS

NICOTINE.

THAT SUGGESTS THAT WHATEVER IS

HAPPENING HERE THE PROPERTY IS

SHARED BY SIGHT SEEN AND

NICOTINE AND IT'S LIKELY IT'S

ACTING AS THIS RECEPTOR.

BUT THAT'S JUST A HINT.

WE ALSO WANTED TO KNOW WHETHER

THERE WAS REALLY AN EFFECT ON

BODY FAT PERCENTAGE OR WHETHER

IT WAS A SELECTIVE EFFECT.

MAYBE THEY DON'T DRINK AS MUCH.

WE NEEDED TO MAKE SURE THESE

WERE LEANER MICE.

ONE WAY WE DID THIS WAS TO

COLLABORATE WITH COLLEAGUES AND

DO A LITTLE MRI OF THESE MICE

AND WE WERE ABLE TO MEASURE

TOTAL BODY FAT CONTENT.

WHAT CAN YOU SEE IS THAT BOTH

SIGHT SEEN AND NICOTINE DECREASE

THE FAT CONTENT OF MICE.

IT'S NOT JUST THAT THEY DECREASE

FOOD INTAKE.

THEY ARE LEANER AFTER THESE

TREATMENTS.

SO HERE WE HAVE OUR RECEPTORS

AGAIN.

WE HAD A HINT FROM PHARMACOLOGY

THEY THIS SUBTYPE MIGHT BE

IMPORTANT.

BUT WE REALLY JUST STARTED.

AND THEN, BECAUSE THIS SUBTYPE

WAS KNOWN AS GANGLIONIC

RECEPTOR, INCREASE OF FUNCTION,

WE THOUGHT MAYBE THIS COULD BE

WORKING IN A PERIPHERAL NERVOUS

SYSTEM JUST TO ACTIVATE THE

MICE.

AND THAT'S WHY THEY ARE LEANER.

SO, WE HAD TO START BY ASKING,

DOES THIS HAPPEN IN THE BRAIN OR

DOES IT HAPPEN IN THE PERIPHERY?

WHAT WE USED WAS A SELECTIVE

ANTAGONIST THAT CAN'T CROSS THE

BLOOD-BRAIN BARRIER.

ANYTHING IN THE BODY WOULD BE

BLOCKED WHAT CAN YOU SEE IS THAT

THAT ANTAGONIST ON ITS OWN HAD

NO EFFECT AND IT DIDN'T BLOCK

THE ABILITY OF CYTOSIN TO

DECREASE FOOD INTAKE EITHER.

THIS GAVE US THE CLUE THAT THIS

IS HAPPENING IN THE BRAIN AND

NOT IN THE BODY.

SO WHERE IS THIS HAPPENING?

WELL, THERE HAS BEEN AN

EXPLOSION OF NEURONIC ATOM CALL

AND PHYSIOLOGICAL STUDIES THAT

IMPLICATED THE VENTRAL

HYPOTHALAMUS REGULATES A LOT OF

COMMUNICATION BETWEEN THE BRAIN

AND BODY AS A CRITICAL CENTER

FOR MATCHING YOUR NEED FOR

CALORIES WITH YOUR BEHAVIOR.

AND SO WE THOUGHT, THIS IS

PROBABLY A GOOD PLACE TO LOOK.

COLLEAGUES HAD ALREADY STARTED

TO DO SORT OF INVESTIGATIONS OF

THE ABILITY OF NICOTINE TO CAUSE

FIRING IN DIFFERENT CELL TYPES

IN THE HYPOTHALAMUS AS A WHOLE.

AND IN PARTICULAR, TWO GROUPS OF

NEURONS IN THE VENTRAL

HYPOTHALAMUS AND THIS IS THE ARK

NUCLEUS, ONE THAT IS VISUALIZED

BY A PEPTIDE CALLED PRO OPEN LOW

MA LANA COURT IN.

WHEN THESE CELLS FIRE, IT

SIGNALS, I HAVE ENOUGH CALORIES,

I CAN DO SOMETHING MORE

INTERESTING THAN FORAGE FOR

FOOD.

PERHAPS I CAN LISTEN TO A

LECTURE BY MARINA PICCIOTTO AND

IN THIS POPULATION OF NEURONS,

THIS SIGNALS, I DO NOT HAVE

ENOUGH CALORIES.

PLEASE FEED ME NOW.

SO IF YOU STIMULATE THESE

NEURONS, YOU STOP EATING.

IF YOU STIMULATE THESE YOU

FORAGE FOR FOOD.

RECENT EXPERIMENTS WHERE YOU CAN

USE LIGHT TO MAKE PARTICULAR

NEURONAL TYPES FIRE, YOU CAN

SHOW THAT JUST USING LIGHT, YOU

CAN CAUSE THESE CELLS TO FIRE,

CAUSE DECREASES IN FEEDING,

CAUSE THESE CELLS TO FIRE AND

CAUSE INCREASES IN FEEDING.

SO SINCE NICOTINIC RECEPTORS

GENERALLY EXCITATORY, WE THOUGHT

MAYBE IF THEY ARE ON THESE CELLS

THAT ARE IMPORTANT FOR THE

ABILITY EF NICOTINE TO DECREASE

APPETITE.

WEATHER I SAY WE, I MEAN OTHERS

WHO ARE THE POSTDOC IN THE

ASSOCIATE RESEARCH

| DID THESE STUDIES.

SO WHAT WE SECTIONED THROUGHOUT

VENTRAL HYPOTHALAMUS AND WE DID

DOUBLE STAINING FOR A MARKER OF

NEURONAL FIRING, WHICH IS C-FOS

AND FOR THE PRO OPEN MONTH LANO

PEPTIDE AND ASKED IS THERE

COLOCALIZATION STAINING OF POMC?

WHEN WE LOOKED FOR OVER ALL

FIRING IN THE CELLS, WE DIDN'T

SEE ANY DIFFERENCE AFTER EITHER

CYTOSIN OR NICOTINE.

OR AFTER THE BLOCKER OF

NICOTINIC RECEPTORS.

AND THAT IS INTERESTING BECAUSE

HE HERE WE HAVE THE POM C

NEURONS AND THE NPY NEURONS SO

MAYBE WE'RE AVERAGING ACROSS

THOSE.

BUT WHEN WE LOOKED AT CELLS THAT

WERE DOUBLE STAINED FOR POM C,

AND ACTIVITY MARKERS, YOU CAN

SEE CYTOSIN AND NICOTINE COULD

INCREASING C PHOS EXPRESSION AND

POM C NEURONS.

THIS IS TRUE ACUTELY AND JUST

LIKE THE BEHAVIOR, WHICH LASTED

OVER TIME, IF WE TREATED

CONICALLY EVERY DAY, WE STILL

SAW A BIG INCREASE IN THE CFOS

EXPRESSION IN THE POM C NEURONS

AFTER CYTOSIN TREATMENT.

THAT WAS A PRETTY GOOD IDEA THAT

DESPITE THE FACT THAT WE HAD A

LOST DIFFERENT NICOTINIC

RECEPTORS IN A LOT OF DIFFERENT

NEURONAL CELL TYPES, WHEN YOU

TREAT PROLIFERALLY, YOU GET A

SUM OF ALL OF THE CONVERGENCE OF

THOSE NICOTINIC RECEPTOR

ACTIVITIES ON THE ACTIVITY OF A

PARTICULAR NEURONAL SUBTYPE N

THIS CASE, THE POM C NEURONS.

HOWEVER, THAT WAS AGAIN A WHOLE

ANIMAL EXPERIMENT.

AND WHAT WE WANTED TO KNOW IS

ARE THERE NICOTINIC RECEPTORS ON

THE POM C NEURONS THAT CAN CAUSE

THEM TO FIRE?

HERE WITH OUR COLLABORATORS WE

MADE SLICES THROUGH THE VENTRAL

HYPOTHALAMUS AND PUT NICOTINE OR

CYTOSIN ON THE SLICES AND

MEASURED AND IN THIS CASE, THE

POM C NEURONS WERE GREEN BECAUSE

WE USED MICE IN WHICH THE POM C

PROMOTOR DROVE THE GREEN

FLORESCENT PROTEIN.

SO IF YOU SEE GREEN NEURONS, YOU

SEE NICOTINE CAUSES THEM TO

FIRE.

CYTOSIN DOES TOO.

YOU CAN SEE THERE IS A DOSE

DEPENT END INCREASE IN THE

FIRING RATE OF THESE NEURONS AND

IT WASHES OUT AND WE CAN BLOCK

IT WITH THE ANTAGONIST MECCA

MELAMINE.

ON THOSE NEURONS DIRECTLY THERE

WERE RECEPTORS THAT CAUSED THEM

TO FIRE.

AND SO, WHAT THAT GAVE US WAS

THE POSSIBILITY THAT NICOTINIC

RECEPTORS COULD BE ACTING

THROUGH THESE NEURONS BUT DIDN'T

GUARANTEE THAT WAS THE MECHANISM

THAT WAS ESSENTIAL FOR NICOTINE

EFFECT ON APPETITE.

SO FIRST WE TOOK KNOCK-OUT MICE

THAT AGAIN WERE THE CONSTITUTIVE

KNOCKOUT MICE LACKED POM C

THROUGHOUT DEVELOPMENT AND WE

ASKED, CAN CYTOSIN STILL CAUSE

DEGREES FOOD INTAKE IF WE GET

RID OF THE POM C PRO 17 YOU CAN

SEE IN NORMAL MICE, WE STILL

HAVE THIS -- PROTEIN -- YOU CAN

SEE WE HAVE DEGREES FOOD INTAKE

BUT IF WE KNOCKED OUT POM C, IT

WAS GREATLY BLUNTED.

THESE MICE ARE NOT NORMAL MICE.

THEY ARE OBESE.

THEY ARE DIABETIC AND HAVE A THE

OF OTHER THINGS WRONG WITH THEM.

WE WERE NOT HUGELY SATISFIED

WITH THIS EXPERIMENT.

LIKE THE BEHAVIOR, WE WANT TO

GET TAT FROM EVERY DIFFERENT

DIRECTION.

SO WHAT WE DID WAS TO SAY, HERE

IN THIS CIRCUIT, THE POM C

NEURONS SIGNAL UP TO THE

VENTRICULAR NUCLEUS OF THE

HYPOTHALAMUS, THE NEXT PART OF

THE CIRCUIT, THROUGH THE MC4

RECEPTORS IN ORDER TO SAY, HERE

YOU'RE STATED.

THIS IS THE CIRCUIT.

SO WE THOUGHT IF WE COULD

KNOCKOUT OUT THEIR RECEPTOR, MC4

RECEPTOR, AND GET THE SAME

EFFECT, WE WOULD BE MORE

CONFIDENT THAT THIS ACTIVITY,

THIS PARTICULAR CIRCUIT WAS

ESSENTIAL FOR NICOTINE'S EFFECT

ON FOOD INTAKE.

SO WE PACKAGED A SMALL HAIR PIN

RNA TARGETING THE MC4 RECEPTOR.

WE TAGGED THEM WITH GF.

AND PUT IT IN THE NUCLEUS.

WE GET PRETTY GOOD KNOCK DOWN

AND WE THEN TESTED AGAIN THE

ABILITY OF CYTOSIN TO DECREASE

FOOD INTAKE.

IF WE DELIVERED EITHER SCRAMBLED

HAIR PIN OR GFP, WE STILL GOT

DECREASE IN FOOD INTAKE BY

CYTOSIN AND IF WE KNOCKED OUT

ARE DOWN THE MC4 RECEPTOR, WE

GOT SIGNIFICANTLY BLUNTED FOOD

INTAKE RESPONSE.

SO THIS ADJUSTS -- WE HAVE A

CIRCUIT.

SO, THE PROBLEM WAS THAT WE

WEREN'T CONVINCED THERE WAS

ACTUALLY ANY OF THIS BETA 4

SUBUNIT CONTAINING NICOTINIC

RECEPTOR IN THESE NEURONS.

IT HAD NEVER BEEN REPORTED.

IT WAS NOT SOMETHING THAT WE

CONSIDERED CONVENTIONAL WISDOM.

THIS IS A HIGHLY-EXPRESSED IN

THE GANGLIA.

IT'S ALSO IN A VERY IMPORTANT

BRAIN AREA CALLED THE MEDIAL HA

BEN LA IMPLICATED AS A REWARD

SYSTEM BUT NOT SO MUCH IN THE

HYPOTHALAMUS.

WE TOOK THOSE GFP, POM CGFP MICE

WHERE THE PC NEURONS ARE GREEN,

WE LASER CAUGHT MICROSCOPY TO

ISOLATE THOSE GREEN NEURONS.

TO ISOLATE THE RN FLORIDA.

THOSE NEURONS AND THEN WE DID

RTPCR TO SEE IF IN THOSE POM

Cs WE COULD FIND THE BETA 4

TRANSCRIPT.

AND SURE ENOUGH, HERE ARE THE

CONTROLS SHOWING THAT THESE

NEURONS DO HAVE THE POM C

TRANSCRIPT.

THEY HAVE THE BETA 4 TRANSCRIPT.

AND IF WE DO THIS IN BETA 4

KNOCKOUT MICE THAT BETA 4 GOES

AWAY.

IT IS SELECTIVE AND IT DOES

SUGGEST THAT YES, IT TURNS OUT

BETA 4RNA IN THESE POM C

NEURONS.

WHO KNEW?

THAT WAS A LITTLE SURPRISING.

I HAD NOT BEEN EXPECTING THAT.

BUT IT DID NOW GUIDE US TO THE

NEXT STEP, WHICH IS IF THIS IS

THE RECEPTOR SUBTYPE THAT IS

IMPORTANT FOR FEEDING, WE SHOULD

BE ABLE TO KNOCK IT DOWN AND WE

SHOULD BE ABLE TO BLUNT THAT

EFFECT OF CYTOSIN OR NICOTINE ON

FOOD INTAKE.

SO THAT'S WHAT WE DID.

AND AS A CONTROL, WE KNOCKED

DOWN THE BIG 2 SUBUNIT

IMPLICATED IN THE ADDICTION

EFFECTS OF NICOTINE AND WE DID

BOTH OF THESE IN THE VENTRAL

HYPOTHALAMUS, SITE OF THE POM C

CELL BODIES.

YOU CAN SEE THAT WITH THESE

SMALL HAIR PIN RNAs WE COULD

KNOCK DOWN THE BETA 2 SUBUNIT OR

THE BETA 4.

WE COULD SEE A DIFFERENCE IN

NICOTINE BINDING WHEN WE KNOCK

DOWN THE BETA 2 SUBUNIT

CONSISTENT WITH IMPORTANT AS THE

HIGH AFFINITY BINDING SITE.

AND WE LOOKED, WHEN WE LOOK AT

THE ABILITY OF CYTOSIN TO

DECREASE FOOD INTAKE AND STILL

HAVE DECREASE IN FOOD INTAKE,

VERY ACUTELY, ONLY TWO HOURS

AFTER THE INJECTION OF CYTOSIN,

BETA 2 KNOCKDOWN NOTHING.

I WAS SURPRISED.

IF WE KNOCKED DOWN THE BETA 4

SUBUNIT IT IS COMPLETELY GONE.

A NICE CONFIRMATION OF THE

PHARMACOLOGY.

GOOD CONFIRMATION WHAT WE SAW

WITH MOLECULAR CELL BIOLOGY AND

GIVES US A LOCATION IN THE BRAIN

OF CIRCUIT AS WELL AS A

PARTICULAR MOLECULE THAT IS

IMPORTANT FOR THIS BEHAVIOR.

SO HERE IS THE CIRCUITSA WE ARE

LOOKING AT.

WE THINK THAT NORMALLY THESE ARE

NEURONS, THE POM C NEURONS IN

THE VENTRAL HYPOTHALAMUS CONTAIN

ALPH 3, POTENTIAL THEY IS THE

USUAL PARTNER SUBUNIT OF BETA 4.

WE DON'T KNOW FOR SURE.

IT'S EXPRESSED HERE SO THAT'S

WHY WE ARE GOING NEXT.

BUT AT LEAST BETA 4 CONTAINING

RECEPTORS ON THE CELL BODIES, IT

CAUSES THESE NEURONS TO RESPOND

TO ACETYLCHOLINE.

WHERE IS IT COMING FROM?

ANOTHER AREA THAT WE ARE VERY

INTERESTED IN PURSUING.

AND IN THIS CIRCUIT ALTHOUGH

ACTUALLY ANOTHER LABORATORY AT

THE SAME TIME, SHOWED THAT IN

ISOLATED NEURONS, YOU CAN GET

NEURONS EITHER THAT HAVE POM C

OR NPY THAT FIRE IN RESPONSE TO

NICOTINE.

WHEN WE TAKE THE WHOLE ANIMAL,

THIS EFFECT ON THE POM C NEURONS

PREDOMINATES AND IT DOESN'T

DESENSITIZE.

I THINK THAT MAY BE WHY IT IS

POSSIBLE TO SEE OTHER SUBTYPES

ON THE NPY THAT ARE MORE

SUSCEPTIBLE TO SENSITIZATION.

AND TONY'S LAB SHOWED THERE WAS

A GREATER LIKELIHOOD FOR THAT

RESPONSE NOT TO PERSIST.

SO WHEN YOU STIMULATE WITH

NICOTINE OR IN THE MOUSE

CYTOSIN, YOU WHAT GET IS

STIMULATION OF THESE POM C

NEURONS, THEY SIGNAL UP TO THE

PARAVENTRICULAR NUCLEUS AND

ACTIVATE MC4 RECEPTORS AND THAT

IS THE BEGINNING OF THE PATHWAY

THAT SIGNALS SAFETY.

BACK TO OUR SCHEME.

WE KNOW THAT THESE RECEPTORS

CONTAIN BETA 4.

WE DON'T KNOW THEIR ALPHA

PARTNER.

WE KNOW THAT THERE IS A BRAIN

AREA.

THE POM C NEURONS WHERE THIS

HAPPENS AND WE HAVE THE LINK

BETWEEN THE ARE A PARTICULAR

NICOTINIC SUBUNIT AND ROLE IN A

PARTICULAR SET OF EXPELS THIS

BEHAVIORAL EFFECT ON FOOD

INNERTAKE.

SO IN THE LAST FEW MINUTES THAT

I HAVE, I'M GOING TO COVER ONE

LAST BEHAVIOR THAT IS IMPORTANT

FOR WHY PEOPLE REPORT THAT THEY

SMOKE AND THAT IS IN PARTICULAR,

THAT PEOPLE REPORT THAT THEY

SMOKE TO TREAT THEIR SYMPTOMS OF

DEPRESSION AND ANXIETY.

EVEN MY OWN DAD WHO SMOKED FOR

YEARS AND HAS FINALLY QUIT, SAID

THAT ONE TIME HE EFFECTIVELY

QUIT SMOKING AND HE WAS SO

DEPRESSED THAT HE FORCED

HIMSELF, PERHAPS A LITTLE BIT OF

JUSTIFICATION, TO GO BACK TO

SMOKING IN ORDER NOT TO FEEL SO

DEPRESSED.

HE IS NOT ALONE.

THERE ARE DRUGS THAT TREAT

DEPRESSION THAT ARE USED FOR

SMOKING CESSATION THAT ARE

EFFECTIVE IN A NUMBER OF PEOPLE.

AND SO WE ARE INTERESTED IN HOW

DOES THIS REFLECT THE ROLE OF

NICOTINIC RECEPTOR AND IN

PARTICULAR, THE BRAIN THAT IS

IMPORTANT FOR MOOD AND AFFECT.

SO WE KNOW THAT PEOPLE WHO ARE

DEPRESSED ARE MORE LIKELY TO

SMOKE.

ABOUT 25% OF THE GENERAL

POPULATION THAT HAS GONE DOWN TO

22%.

22% OF GENERAL POPULATION SMOKE.

ABOUT 40-60% OF PATIENTS WITH

MAJOR DEPRESSIVE DISORDERS

SMOKE.

MUCH HIGHER.

AT LEAST DOUBLE.

AND WE KNOW THAT NICOTINE ITSELF

WHEN JUST ADMINISTERED ON ITS

OWN CAN HAVE EFFECTS ON MOOD.

HOWEVER, IT IS QUITE PARADOXICAL

BECAUSE DEPENDING ON HOW YOU

ADMINISTER THE NICOTINE, YOU CAN

EITHER INCREASE OR DECREASE

SYMPTOMS OF DEPRESSION.

SO FOR EXAMPLE, PAUL NEW HOUSE

BACK IN THE 80's SHOWED THAT

IF HE GAVE INTERVENOUS NICOTINE

TO SUBJECTS, THEY ACTUALLY

REPORTED GREATLY INCREASED

ANXIETY AND SOME DEPRESSION

SYMPTOMS.

AND YET, COLLEAGUES IN MEXICO

HAVE DONE A SUCCESSFUL CLINICAL

TRIAL WHERE THEY PUT NICOTINE

PATCH ON NONSMOKERS WHO ARE

DEPRESSED AND THEY CAN GET A

SIGNIFICANT ANTIDEPRESSANT

EFFECT ON THE PATCH.

HOW CAN THEE TWO THINGS COEXIST?

IF YOU KNOW SOMETHING ABOUT THE

PHYSICAL PROPERTIES OF THE

NICOTINIC ACETYLCHOLINE

RECEPTORS YOU CAN HAVE A HINT.

ONE IS THAT IV NICOTINE GETS

INTO THE BRAIN QUICKLY.

IT'S CLEARED QUICKLY AND IT'S

FAST AND IT ACTIVATES RECEPTORS.

A PATCH WHICH DELIVERS A LOWER

LEVEL OF NICOTINE TO THE BRAIN

IT KEEPS IT STEADY FOR A LONG

PERIOD OF TIME.

IT IS MORE LIKELY TO ACTUALLY

DESENSITIZE OR TURN OFF THE

NICOTINE RESEPTEMBERRORS IN THE

BRAIN.

SO OUR ORIGINAL HYPOTHESES

BASED -- RECEPTORS -- BASED ON

DATA THAT PERHAPS IT'S TURNING

OFF RECEPTORS ESSENTIAL FOR

REGULATING SYMPTOMS OF MOOD.

MAYBE THE PATCH ANTIDEPRESSANT

NOT BECAUSE IT'S ACTIVATING

THESE RECEPTORS BUT BECAUSE IT'S

DECENT TIEING THEM.

WE ARE LUCKY AND THEN THE

FURTHER COROLLARY OF THAT,

SMOKERS ARE LIKELY TO BE GOING

THROUGH CYCLES IN WHICH THEY ARE

ACTIVATING THE RECEPTORS AND

DESENSITIZING THEM THROUGHOUT

THE DAY AND PARTICULARLY

RESENSITIZING THEM OVERNIGHT

WHEN THEY SLEEP.

AND THAT IS PROBABLY EXPLAINING

WHERE SMOKERS REPORT THEY SMOKE

TO TREAT THEIR DEPRESSIVE

SYMPTOMS.

FIRST THEY ARE PROBABLY CREATING

DEPRESS EVERY SYMPTOMS WHEN THEY

ACTIVATE THEIR RECEPTORS AND

THEN INVOLVING IS THAT BY

DESENSITIZING RECEPTORS IN THE

LARGE PORTION OF THE DAY.

THAT IS ALSO SUPPORTED BY HUMAN

DATA WHEN YOU GIVE A POM PILOT

TO PEOPLE WHO ARE SMOKING

ACTIVELY AND YOU ASK THEM TO

ENTER THEIR ANXIETY AND

DEPRESSION SYMPTOMS, COLLEAGUES

SHOWED THAT THEY WOULD SAY I'M

SMOKING TO RELIEVE MY DEPRESSION

SYMPTOMS BUT IF YOU GIVE THEM A

PALM PILOT AGAIN AFTER THEY QUIT

AND THEY ARE DREW WITH

WITHDRAWAL.

THE NUMBER OF SYMPTOMS THEY

REPORT ARE LOWER AFTER THEY QUIT

THAN WHILE THEY ARE ACTIVELY

SMOKING.

SO IT'S PROBABLY TRUE THAT

SMOKERS ARE CREATING SOME OF THE

SYMPTOMS THEY ARE FEARING.

SO WE HAVE A WAY TO TEST THIS

BECAUSE WE HAVE A

PHARMACOLOGICAL AGENT THAT IS IN

THE MOUSE IS ABLE TO BLOCK THE

CORE OF PRETTY MUCH ALL THE

NICOTINIC ACETYLCHOLINE

RECEPTORS.

WE ASKED SIMPLY, CAN WE USE THIS

TO CHANGE SYMPTOMS OF AS AN

ANTIDEPRESSANT-LIKE DRUG IN

MOUSE MODELS?

I'M CAREFUL CALL THESE MOUSE

MODELS ANTIDEPRESSANT EFFICACY

BECAUSE THEY ARE VALIDATED BY

USE THE PHARMACOLOGICAL AGENTS

THAT HUMANS USE TO TREAT

DEPRESSION.

THEY CHANGE BEHAVIOR IN THESE

MOUSE MODELS MOD IN A PREDICTABLE WAY

BUT WE CAN'T TELL FOR SURE IF

THE MOUSE DEPRESSED OBVIOUSLY.

THEY REALLY DON'T VERY OFTEN GO

SEE MICE PSYCHIATRISTS.

SO WHAT WE SAW WAS THAT IN ONE

OF THESE MODELS I'M SHOWING YOU

ONE OF MANY TESTS WE HAVE DONE,

WE HAVE DONE A LOT OF THEM.

AND THIS TEST IS THE TEST WHERE

THE MORE A MOUSE SWIMS IN A BEAK

THEY'RE IT CAN'T GET OUT OF, THE

MORE WE CALL DID -- ALL RIGHT.

LET ME BACK UP.

THESE ARE TESTS WHERE WE WE ARE

MEASURING MOTIVATION.

THIS IS A CORE SYMPTOM IN SOME

CASES OF DEPRESSION WHERE IF

ANIMAL IS MORE MOTIVATED TO MOVE

MORE, AND IF IT GIVES UP AND IT

DOESN'T MOVE AND MAKES THE

MOVEMENTS IT NEEDS TO DO STAY

AFLOAT, THIS THEN THAT SAY

MEASURE OF GIVING UP OF LESS

MOTIVATION, OF BEHAVIORAL ASSAY

OF A MOTIVATIONAL SYMPTOM OR

SYNDROME.

SO THE MORE IMMOBILE THAT ANIMAL

IS, THE LESS ANTIDEPRESSANT

EFFICACY THERE IS AND THE MORE

AN ANTIDEPRESSANT WORKS THE LESS

IMMOBILE THEY WILL BE.

THE MORE SECONDS HERE AND MORE

DEPRESSION-LIKE AND LESS SECONDS

HERE MORE ANTIDEPRESSANT LIKE.

WE SAW THAT THIS CAN INCREASE

THE MOVEMENT OF THE ANIMALS AND

DECREASE IMMUNOABILITY AND ACTED

IN THIS TEST LIKE THINGS LIKE

PROZAC OR OTHER ANTIDEPRESSANTS

USED BY HUMANS.

THIS SOUR FIRST HINT THAT IT

COULD ACT SIMILARLY TO CLASSICAL

ANTIDEPRESSANTS.

WE NOW HAVE DONE THIS WITH TESTS

THAT HAVE MORE VALIDITY FOR

HUMIDITY EXPRESSION.

SO TESTS LIKE NOVELTY FEEDING

SENSITIVE TO CHRONIC

ADMINISTRATION OF NICOTINIC OR

OF ANY ANTIDEPRESSANTS.

AND OUR QUESTION WAS, IS THIS

SOMETHING THAT WE CAN IDENTIFY

AS A EFFECT OF NICOTINIC

RECEPTNURSE A PARTICULAR BRAIN

AREA?

AND SO WHAT WE FIRST DID WAS TO

SEE WHETHER THIS EFFECT IS STILL

THERE WHEN WE GOT RID OF ONE OF

THE NICOTINIC RECEPTORS.

WE DID THE ALPHA 7 SUBTYPE AND

THE BAIT 2 SUBUNITS AND I'M

SHOWING YOU HERE.

YOU SEEN THESE BEFORE.

HERE IS THE BINDING OF NICOTINIC

RECEPTORS IN THE PRESENCE OR

ABSENCE OF THE BETA 2 SUBUNIT.

AND WHAT CAN YOU SEE HERE AGAIN

IS THAT MACK MELAMINE DECREASES

BLOWABILITY.

ANTIDEPRESENT LIKE IN NORMAL

MICE.

BUT IT ABSOLUTELY IS NOT

EFFECTIVE IN MICE BLOCKING THE

BAIT 2 SUBUNIT.

WE CAN ALSO SEE AT BASELINE,

THERE IS A DECREASE IN INABILITY

OF THESE MICE.

WE DON'T SEE THIS AS A GENERAL

CHANGE IN LOCOMOTION.

IT DOES SEEM THAT AT FLEET THIS

ASSAY, THERE IS SOME KIND OF

BASELINE EFFECT THAT LOOKS MORE

LIKE THEY HAD AN ANTIDEPRESSANT

ONBOARD.

AND I'M RELUCTANT TO GO TOO FAR

ON THIS BUT THIS IS SOMETHING WE

HAVE SEEN CONSISTENTLY.

AND IT SUGGESTS THAT IT IS

BLOCKING THIS RECEPTOR, THAT IS

IN THISSEST AND IT'S IMPORTANT

FOR THE ANTIDEPRESSANT PROPERTY

OF MEC MILL MEAN.

SO IT TURNS OUT THAT IN FACT IN

HUMANS AND PARTICULARLY TONY

GEORGE AND A COMPANY, THEY WERE

ABLE TO PERFORM SMALL TRIALS

USING THIS WHICH HAD BEEN

APPROVED FOR NEWS HUMANS FOR

HYPERTENSION AND IN THESE SMALL

TRIALS THERE WAS SOME INDICATION

THAT IS IT WAS EFFECTIVE.

UNFORTUNATELY THIS DRUG WAS

TRIED IN VERY LARGE TRIALS BY

AFFIDAVIT SENECA AND IT DOESN'T

SEEM TO BE EFFECTIVE AT THIS

POINT  --

ASTRO SENECA.

THERE WAS INDINDICATION THAT

THERE ARE COULD BE

TRANSERATION -- TRANSLATION OF

THIS MOUSE DATA TO HUMANS.

SO THE QUESTION IS, WHERE IN THE

BRAIN IS THIS HAPPENING?

AND WE ONCE AGAIN ASKED USING

TWO DIFFERENT DRUGS, CYTOSIN IN

THIS CASE MEC MILL MEAN WHERE

SIGHT SEEN SHOULD BE BLOCKING

THE BETA 2 SUBUNIT CONTAINING

RECEPTORS AND MECCA MILL MEAN IS

BROCKING OUGHT THE RECEPTORS.

WHERE DO WE SEE A DECREASE IN

CFOS TREATMENT?

IT WAS AT BASAL LATERAL

AMYGDALA.

IT'S A PART OF THE BRAIN THAT IS

ESSENTIAL FOR FEAR-BASED

BEHAVIORS, FOR EMOTIONALITY AND

A PLACE THAT HAS BEEN, A BRAIN

AREA THAT IS CONSISTENTLY SHOWN

AS BEING HYPERACTIVE IN PATIENTS

WITH MAJOR DEPRESSIVE DISORDER.

SO THE IDEA THAT NICOTINE COULD

BE BLOCKING ACTIVITY HERE OF

NICOTINIC RECEPTORS THAT ARE

TRANSDUCING A SIGNAL OF

ACETYLCHOLINE THAT MAY INCREASE

DURING STRESS OR DURING

CONDITIONS THAT LEAD TO

DEPRESSION WAS VERY ATTRACTIVE.

WHAT WE DID IS DO TWO

EXPERIMENTS.

I'M SHOWING YOU MALL MILL MEAN

AND I'M NOT GOING TO SHOW YOU

THE KNOCKDOWN STUDIES.

THEY LOOK THE SAME.

WE DID LOCAL INFUSION, THE

BLOCKER OR OF A SMALL HAIR PIN

R-NA TARGETING THE BAIT 2

SUBUNITS AND THEN WE AGAIN

LOOKED FOR IMMUNOBUILT NEEITHER

THE TAIL SUSPENSION TEST OR THE

SWIMMEST AND WHAT WE SAW THAT

WAS LOCALLY INFUSED BASAL

LATERAL AMYGDALA MACAMILL MEAN

WAS ANTIDEPRESENT LIKE JUST LIKE

IF IT WAS GIVEN PERIPHERY.

IT WAS ENOUGH TO PUT THIS INTO

THE BASAL LATERAL AMYGDALA OR

KNOCK DOWN THE SUBIMMUNITY THIS

NUCLEUS TO SEE AN

ANTIDEPRESSANT-LIKE EFFECT.

WE WANTED TO SEE IF THERE WAS

RELEVANCE TO MOVEMENTS AND SO WE

COLLABORATED WITH -- REL

VIOLENCE TO HUMANS  --

WE COLLABORATED WITH A COLLEAGUE

AT YALE TO ASK THE QUESTION,

COULD WE SEE EVIDENCE OF THIS IN

HUMAN SUBJECTS?

LET ME TELL YOU ABOUT WHAT OUR

THINKING IS IN TERMS OF THE

CIRCUIT.

SO THIS IS BASED A LOT ON MEYER

AND SELL IG MAN WORKING AT THE

UNIVERSITY OF COLORADO.

HIS IDEA IS THAT EVOLUTIONARILY

WE EVOLVED THE AMYGDALA IN ORDER

TO PROTECT US FROM THREATS IN

THE ENVIRONMENT AND IN A MOUSE,

WHAT THAT MEANS IS THAT WHEN YOU

GET A THREAT, YOU ACTIVATE YOUR

AMYGDALA AND WITHDRAW BEHAVIOR

AND FREEZE.

SO THE WILFINENT A HUMAN IS THAT

IF YOU'RE IN A THREATENING

SITUATION, YOU WITH WOULD

WITHDRAW TO A SAFE PLACE AND

THAT SHOULD BE EVOLUTIONARY

FAVORABLE.

AS WE EVOLVE, WE WERE LUCKY AND

GOT THIS HUGE PREFRONTAL CORTEX

THAT DISTINGUISHES US FROM ALL

OF THE OTHER SPECIES, INCLUDING

THE HIGHER PRIMATES AND THAT

CORTICAL AREA SENDS A MASSIVE

PROJECTION, EXCITATORY

PROJECTION TO A PART OF THE

AMYGDALA WHICH IS GABBERERGIC

AND SHUTS DOWN THE ACTIVITY OF

THE AMYGDALA.

SO WHEN YOU KNOW THERE IS A

THREAT, YOU CAN ACTIVATE YOUR

PREFRONTAL CORTEX.

IT WILL SEND A PROJECTION TO THE

AMYGDALA AND SHUT IT DOWN.

WHAT DOES THAT 17 YOU CAN SEE A

THREAT IN THE ENVIRONMENT AND

IT'S NOT THAT DANGEROUS, YOU CAN

OVERCOME THAT ACTIVITY OF THE

AMYGDALA.

WILL YOU HAVE AN EVOLUTIONARY

ADVANTAGE.

SO WHAT THAT MEANS IS THAT IF

YOU CAN CHANGE THE BALANCE

BETWEEN THESE TWO BRAIN AREAS

WHEREAS THE AMYGDALA IS HYPERACT

ENOUGH PATIENTS WITH DEPRESSION,

THE PREFRONTAL CORTEX IS HYPO,

LESS ACTIVE IN PATIENTS

DEPRESSION, THAT MIGHT BE

ANTIDEPRESSANT-LIKE.

SO OUR MODEL IS THAT NORMALLY

STRESS INDUCES ACETYLCHOLINE

RELEASE AND YOU STIMULATE YOUR

NICOTINIC RECEPTORS AND INCREASE

THE ACTIVITY OF THE AMYGDALA AND

THE BALANCE WOULD BE SHIFTED

THIS WAY AND IF YOU BLOCK

NICOTINIC RECEPTORS, YOU SHOULD

COME BACK THIS WAY AND YOU

SHOULD RESTORE NORMAL BEHAVIOR.

AND THERE IS IN LINE WITH THE

WORK OF A PSYCHIATRIST WHO IN

THE 70s SAID, I THINK THAT IF

YOU HAVE TOO MUCH ASSET COALINE

YOU'RE MORE LIKELY TO BE

DEPRESSED.

HE GAVE A BLOCKER OF THE ENZYME

THAT BREAKS DOWN ACETYLCHOLINE

AND SAW IF IF YOU HAVE TOO MUCH,

YOU REPORT MORE DEPRESSION-LIKE

SYMPTOMS.

SO WE DID AN EXPERIMENT WHERE WE

ASKED IF NORMAL ACETYLCHOLINE IS

AT A LOW LEVELS AND YOU NUT A

TRACER, YOU SHOULD HAVE A

SIGNIFICANT AMOUNT OF BINDING 

IN VIVO.

IF YOU HAVE A LOT OF

ACETYLCHOLINE IN YOUR BRAIN AND

WE VALIDATED THIS BY GIVING THIS

TO HUMAN SUBJECTS AND DOING A

TRACER STUDY, YOU COMPETE WITH

THE TRACER AND YOU'LL HAVE LESS

BINDING OF THE TRACER.

THAT'S WHAT HE SAW.

HE SAW IN PATIENTS WITH -- THESE

ARE NONSMOKERS.

NO COMPETITION WITH NICOTINE N

PATIENTS WHO ARE ACUTELY

DEPRESSED, THERE WAS LESS

BINDING OF THESE NICOTINIC

RECEPTORS AND TO VALIDATE THAT

YOU, SEE IT IS NOT A LOCAL

EFFECT.

IT'S A BROAD EFFECT.

SO IT'S LIKELY TO BE SOMETHING

ABOUT A STATE OF ACETYLCHOLINE.

AND IF WE LOOK POST MORTEM AND

MEASURE HOW MUCH NICOTINIC

RECEPTORS THEY HAVE IN THE

BRAIN, THERE IS NO CHANGE IN THE

NUMBER OF RECEPTORS.

THIS DECREASE IN BINDING IS

LIKELY TO BE INCREASE IN

OCCUPANCY BY ACETYLCHOLINE.

WE THINK THERE IS A REASON TO

BELIEVE THAT THESE STUDIES IN

MICE ARE REFLECTED BY A

MEASURABLE EFFECT IN HUMIDITY

PRESSED PATIENTS.

SO NOW WE ARE LACKS RECEPTOR AND

BACK TO OUR ALPHA 4 BETA 2.

WE DON'T KNOW THE ALPHA AGAIN.

WE KNOW BETA 2 IS INVOLVED.

IN THIS CASE, INSTEAD OF

ACTIVATION, WE THINK -- AGAIN WE

HAVE A BRAIN AREA, BASAL LATERAL

AMYGDALA.

INSTEAD OF ACTIVATION, WE THINK

IT'S INHIBITION OF THESE

RECEPTORS THAT IS IMPORTANT FOR

THESE NICOTINIC RECEPTORS.

SO, THAT CONCLUDES THE TALK.

AS I MENTIONED, THE PROBLEM WAS

TRYING TO GET THESE MOLECULAR

DATA, ANG TOM CALL DATA AND THE

BEHAVIORAL DATA INTO A COHERENT

PICTURE EVER HOW CAN WE MAP THE

SPECIFIC EFFECTS OF A WHOLE BODY

BATHING WITH THE PHARMACOLOGICAL

AGENT TO WHAT WE KNOW HAS TO BE

A CIRCUIT-LEVEL REGULATION OF

FUNCTION BY ACETYLCHOLINE

NICOTINIC RECEPTORS.

AND I THINK THE GOOD NEWS IS

THAT AS A FIELD, THE COMBINATION

OF MOLECULAR GENETICSNETICS AND

PHARMACOLOGY IN ANIMAL MODELS

AND HUMANS, THE TWO SYSTEMS

GOING BACK AND FORTH AND

SPEAKING TO EACH OTHER, HAS,

LOUD US TO MAKE GOOD PROGRESS IN

DISSECT COMING NICOTINIC

RECEPTOR SUBTYPES ARE IMPORTANT

IN WHICH BRAIN AREAS FOR THESE

NICK TINE DEPENDENT BEHAVIORS.

NOW OUR CHALLENGE IS THAT

EXISTING PHARMACOLOGICAL AGENTS

NUDES HUMANS DON'T TARGET

SPECIFIC NICOTINIC RECEPTOR

SUBTYPES.

I TOLD YOU EARLY IN THE TALK,

FOR EXAMPLE, THAT AGENTS THAT

ARE SOMEWHAT SELECTIVE IN MICE,

LIKE SIGHT SEEN, HAVE SOMEWHAT

DIFFERENT SPECIFICITY IN HUMANS.

WE NEED TO DO BETTER TARGETING

OF THESE RECEPTORS.

SO IT'S GOING TO BE ESSENTIAL TO

VALIDATE NEW DRUGS ON HUMAN

NICOTINIC RECEPTORS.

HOWEVER, THERE IS A HOPE AND THE

HOPE IS THAT IF WE COULD GET

THESE MORE HIGHLY OF-SELECTIVE

MEDICATIONS AND TARGET THEM TO

SPECIFICALLY DIFFERENT SUBTYPES,

WE COULD DISSECT OUT, FOR

EXAMPLE, EFFECTS EVER NICOTINIC

DRUGS TO HELP MOTIVATE SMOKERS

WHO SMOKE FOR REASONS OTHER THAN

NICOTINE REINFORCEMENT.

FOR EXAMPLE, APPETITE CONTROL OR

CONTROL OF AFFECTIVE SYMPTOMS.

MAYBE WE CAN MOTIVATE THEM TO

QUIT.

MAYBE ONE OF THE LANES THEY ARE

RELUCTANT TO STOP IS BECAUSE

THEY ARE AFRAID THEY ARE GOING

TO GAIN WEIGHT OR DEPRESSED.

AND THEN THE LONG-TERM HOPE, ONE

THAT IS REALLY MORE SPECULATIVE,

THE SAME MEDICATIONS COULD WORK

IN PATIENTS WHO HAVE THESE

DISORDERS EITHER EATING

DISORDERS OR WHO STRUGGLE WITH

DEPRESSION AND THAT THESE

NICOTINIC AGENTS COULD ADD TO

OUR ARSENAL OF MEDICATIONS FOR

THOSE DISORDERS AND NONSMOKERS

AS WELL AS AS WELL.

SO I'LL STOP THERE AND I'D LIKE

TO THANK NIDA THAT HAS BEEN AN

AGENCY THAT HAS BEEN EXTREMELY

SUPPORTIVE OF MY WORK FROM THE

VERY EARLIEST STAGES.

AND ALSO NINH WHO HAS BEEN

FUNDING THE DEPRESSION WORK.

WE DID THE INITIAL WORK ON THE

DEPRESSION PHENOTYPES THROUGH A

TOBACCO CENTER THAT WAS FUNDED

BY NIDA TO YALE.

IN TERMS OF MY LABORATORY, THEY

WERE ESSENTIAL FOR THE FEEDINGS

STUDIES OF DEPRESSION WHICH WERE

INITIATED BY BARBARA WHEN SHE

WAS A POSTDOC AND ASSOCIATE

RESEARCH SCIENTIST IN THE LAB.

THE SELECTIVE EXPRESSION OF BETA

2 WAS LARGELY DONE BY SARAH KING

AND AGAIN I WANT TO THANK CHIN

WHO BEGAN THE GENERATION OF

THOSE ANIMALS WHEN HE WAS AT

YALE AND WE HAD A NUMBER OF

COLLABORATORS ON THE FEEDING

PROJECT INCLUDING THE

LABORATORIES OF THESE HERE.

[ READING ]

AND I WILL STOP THERE WITH A

PICTURE EVER MY LAB AS IT WAS

ACTUALLY A LITTLE WHILE AGO.

THANK YOU VERY MUCH FOR YOUR

ATTENTION.

[ APPLAUSE ]

I WENT OVER A LITTLE BIT.

SO I UNDERSTAND IF YOU ALL HAVE

TO GO.

>> WE HAVE TIME FOR QUICK

QUESTIONS BEFORE THE RECEPTION.

>> HI, JONATHAN.

>> HI.

SO YOU COULD YOU COMMENT WHETHER

AT THE DOSE YOU USE FOR CYTOSIN

WHETHER IT PRODUCES TASTE

DIVERSION?

>> RIGHT.

NOT BY ANY MEANS AT THE LOWEST

DOSES.

SO AT 100 MICOGRAMS PER -- SO

THE LOWEST DOSE WE USED IS .1

MILLIGRAM PER KILOGRAM.

WE DON'T SEE MUCH.

THAT WAS A WARNING TO STAND

BACK.

WE DON'T SEE MUCH EFFECT ON ANY

BEHAVIORS INCLUDING, FOR

EXAMPLE, EFFECTS ON PLACE

PREFERENCE AS FAR AS I KNOW,

THERE IS NOT AN EFFECT ON

CONDITION TASTE DIVERSION,

ALTHOUGH, I'M SURE THAT IF YOU

WENT HIGHER, FOR EXAMPLE, 3

MILLIGRAMS PER KILOGRAM, YOU

WOULD HAVE SOME PROFOUND CASE

DIVERSION.

>> AND ONE MILLIGRAM?

>> ONE MILLIGRAM PER KILOGRAM, I

WOULD GUESS THERE MIGHT BE BUT I

HAVE NOT DONE THAT MYSELF SO I

DON'T KNOW THE ANSWER TO THAT.

>> AND IN HUMAN STUDIES, WITH

CYTOSIN, YOU SEE WEIGHT GAIN.

COULD YOU COMMENT OUTROOTS TRUE.

ALSO WITH VENA QUEEN.

IT'S A PARTIAL AGONIST OF THE

BETA SUBUNIT AND IN MICE, WE SEE

WEIGHT LOSS SO WE SEE DECREASE

INTAKE AND YOU SEE WEIGHT GAIN

IN HUMANS.

SO AGAIN, WHEN WE DO THEO SITE

STUDIES, THE SPECIFICITY OF

THESE AGENTS FOR BETA 4

CONTAINING SUBUNITS DIFFERS

BETWEEN MOUSE AND HUMANS.

WHICH IS TOO BAD BECAUSE IT

WOULD BE REALLY NICE HAVE SOME

AGENTS APPROVED FOR NEWS HUMANS

THAT WE COULD USE FOR THESE

PURPOSES.

BUT WE DO NOT.

>> BLACK TO THE ARGUMENT, IN THE

POM C NEURONS THAT HAVE THE BETA

4, DOES IT IDENTIFY A SUBSET OF

PC?

>> WE DON'T HAVE THE ANSWER TO

THAT.

IT'S A GREAT QUESTION.

WE TOOK ALL OF THE POM C NEURONS

WE COULD FIND AND PUT THEM IN A

TEST TUBE AND HOPED TO GET

ENOUGH RNAs TO DO THE RTPCR.

SO THE WAY TO DO IS IN SITU

HYBRIDIZATION.

I WOULD GUESS IDENTIFIED THE

SUBSET.

HERE IS WHY.

THERE ARE TWO PAPERS THEY KNOW

EVER THAT LOOKED AT MARKERS OF

COLONERGIC SINCE SYTH IN POM C

NEURONS SO THAT'S COLLEEN

TRANSFER FACE AND THERE IS THAT

IN AT SUBSET IN THE PC NEURONS.

NOT ALL.

THIS IS PROBABLY SOME DIVERSITY

IN WHETHER OR NOT THEY ARE

POTENTIALLY COAL NERGIC

THEMSELVES AND NOT ALL OF THEM

LOOK THE SAME.

SO I'LL KEEP YOU POSTED.

>> AND ANOTHER QUESTION, WHAT

ARE THE COAL NERGIC IN PUTS?

>> WE DON'T KNOW.

SO AS I SAID, THERE IS ONE

SUGGESTION THAT THE POM C

NEURONS THEMSELVES COULD BE

COLONERGIC AND COULD BE AN OUGHT

RECEPTOR.

I THINK THAT'S DEFINITELY A

POSSIBILITY AND ONE WE'RE

EXPLORING.

THE OTHER POSSIBILITY SETHAT

BRAINSTEM NUCLEI LIKE THE

LATERAL DORSAL ACTUALLY PROJECTS

TOWARDS THE POM C NEURONS AND

THAT'S ONE I'D BE EXCITED ABOUT.

SO WHAT WE ARE DOING IS

INITIATING STUDIES, TRACING THE

COAL NERGIC PIN PUT USING

TECHNOLOGY IN VIRAL VECTORS

WHERE WE ARE LABELING COAL

NERGIC NEURONS.

WE'LL SEE WHAT HAPPENS.

>> THANK YOU.

>> SURE.

>> YOU PROBABLY KNOW THAT A

GOODGROUP THAT SMOKES EVEN MORE

THAN TEENAGED GIRLS OR DEPRESSED

PATIENTS ARE SKINS PHRENNICS.

DO YOU HAVE SPECULATION?

>> SO I'M GOING REFER TO STUDIES

BY MY COLLEAGUE TONY GEORGE, WHO

HAS DONE BEAUTIFUL WORK ON

VISUAL ATTENTION.

SO THE SPECULATION FOR

SCHIZOPHRENIC SUBJECTS AND THIS

IS REALLY WORK THAT BEGAN WITH

THE PIONEERING STUDIES BY PAT

GOLD MEN, SUGGESTING THAT IF YOU

HAVE A NEURON THAT IS WORKING

OPTIMALLY AND YOU STIMULATE IT

FOR EXAMPLE IN THE PREFRONTAL

CORTEX WITH A D1 AGONIST F THAT

NEURON IS WORKING OPTIMALLY IT

WILL GET WORSE WHEN YOU

STIMULATE IT.

AND IF IT'S NOT WORKING

OPTIMALLY AS IN A SKIT PHRENIC,

IF YOU INCREASE DOPAMINERGIC,

WILL YOU GET OPTIMAL FUNCTION.

SO IN NONSCHIZOPHRENNICS WE HAVE

FAIRLY GOOD COAL NERGIC

REGULATION, PARTICULARLY AT THE

PREFRONTAL CORE SPECS PRACTICE

FLAPS SCHIZOPHRENICS THAT

FUNCTION IS IMPAIRED AND SO THAT

THEIR SMOKING TO GET BACK TO

NORMAL FUNCTION.

SO WHAT WE DID WAS TO TAKE

SCHIZOPHRENIC BUSINESS AND

NONSCHIZOPHRENIC SUBJECTS AND

ASKED THEM TO DO A PATIENT

ATTENTION TASK.

THESE ARE SMOKERS.

SORRY.

THEY WERE ACTIVELY SMOKING.

EVEN SMOKING, THE SCHIZOPHRENIC

DOESN'T NOT DO AS WELL AS THE

NONSCHIZOPHRENIC SUBJECTS.

HERE IS THE COOL PART.

HE ASKED EVERYBODY TO QUIT.

WHAT HE SAW, WHICH IS VERY

SURPRISING, IS THAT THE

NONSCHIZOPHRENIC SUBJECTS ONCE

THEY QUIT SMOKE ASKING WENT

THROUGH WITHDRAW, GOT BETTER AT

THE SPACIAL ATTENTION TASKS

WHEREAS THE SCHIZOPHRENICS GOT

WORSE.

THE IDEA HE WILL IS IF YOU ARE

MEDICATING A DEFICIT IN YOUR

ABILITY TO TUNE YOUR PREFRONTAL

CORTICAL NEURONS SO YOU

CORRECTLY MATCH ENVIRONMENTAL

STIMULI TO COGNITIVE PROCESSES,

IN PREFRONTAL CORTEX, THEN THE

STIMULATION THAT YOU GET FROM

THE FLICK 17 TOBACCO IS

IMPROVING YOUR FUNCTION.

IT'S IMPROVING THE TUNING SO YOU

CAN EITHER TUNE OUT AN ESSENTIAL

SENSORY INFORMATION OR ACTUALLY

FOCUS ON RELEVANT SPACIAL

INFORMATION.

IF YOU DON'T HAVE THAT DEFICIT,

YOU GET WORSE WHEN YOU STIMULATE

THESE CIRCUITS.

AND SO, THE IDEA IS THAT IS IT

SELF MEDICATION AND THAT

SCHIZOPHRENIC INDIVIDUALS ARE

TUNING THEIR NEURONS MORE

EFFECTIVELY WHEN NICKSTEIN

ONBOARD.

AND THAT'S WORK THAT IS ALSO IN

LINE WITH SHERRY LEONARD AND BOB

FRIEDMAN'S WORK AT THE

UNIVERSITY OF COLORADO, WHERE

THEY SUGGEST THAT OVERALL, THE

NICOTINIC SYSTEM IS NOT

FUNCTIONING OPTIMALLY IN

PATIENTS WITH SCHIZOPHRENIA.

SO THEY ARE STIMULATING THOSE

NICOTINIC RECEPTORS MORE

PROFOUNDLY WHETHER THEY SMOKE.

NOT PROBABLY RELATED TO THE

THINGS THEY TALKED ABOUT HERE,

BUT AGAIN, SOMETHING THAT IS

DISSECTIBLE WITH PARTICULAR

TOOLS THAT ASK, IS IT IN

PREFRONTAL CORTICAL NEURONS,

FARM CORTICAL OR CORTICOFLAMMIC

ARMS?

WHICH NICOTINIC RECEPTORS THERE

ARE INDICATIONS THAT ALPHA 7 IS

CRITICAL FOR THOSE KINDS OF

ATTENTIONAL FUNCTIONS.

WHEN DURING DEVELOPMENT IS THIS

IMPORTANT?

THOSE KINDS OF QUESTIONS ARE

UNDER ACTIVE INVESTIGATION BY

PEOPLE LIKE HEIDI, EVELYN, AT

THE UNIVERSITY OF TONS TORONTO

AND OTHERS.

4* THANK YOU VERY MUCH FOR YOUR

ATTENTION.

[ APPLAUSE ]