Alcoholic Human Liver

>> good afternoon. i'm glad to see so much green amongst us this afternoon. that's the best i could do. i didn't have any -- [laughter] . but this one has a green background.

this is the famous quote from the porter mac beth, and it points out how shakespeare was way ahead of his time in understanding the effects of alcohol. at least those effects that were somewhat torlerable, let's say. so he pointed out also on the

thing that it makes you drowsy and sleepy and we'll hear more about that and the central nervous system and promotes the sleep and promotes the flow of urine. finally many years later i think it was shown that it inhibits any /tkaoeurtetic horm oone and

other central effect. but the thing that's attracted much attention, of course, is that as far as sex is concerned, it promotes the desire, but diminishes the performance. and i think we now in today's world, we also have an explanation to account for these

events. so all of these are somewhat within the socially acceptable, but at least liveable. and it's bro the line that it occurs when alcohol becomes associated with many events in our society, which you know. which in /aa cum /hrulativenature

poses a threat to life and injury. and the two areas of major, quote, untox indication that are going to be discussed by our distinguished /kpwefts this afternoon deal with the central nervous effects primarily with respect to addiction, in/tobgs

intoxication with newural,what's going on in the brain. and the second is /the association with sir /ocirrhosisof the liver. for many years, anyone who had yellow eyes was sort of ostra ostracized from society because people said even though they

didn't agree, they must be an alcoholic. it was the thing. but is still is /the thing, and it's prevalent all over /the world and people aren't all -- with it. but they may be dying from it and we're going to hear this

very he wielegant discussion ofthe relationship between alcohol and liver disease. is it reversible? for years people argued that it wasn't the alcohol, it was the calories you were taking and that went on literally for decades.

but we have some answers now, /rarpblargely due due to thework that we're going to hear presented. so let me briefly introduce our two speakers. the first speaker is dr. george koob, who is director of niaaj. he received a ph.d in behavioral fiphysiology at johnskins and

then spent many years /tin san diego at the spritz research in institute, where he was director of the alcohol research in institute, and he was professor and chair of the scripps committee on newurobiology. now anybody who reads anything about mechanisms of alcohol

effects in the central nervous system is bound to come upon dr. koob's papers, several of which we posted on the website, which i bring to your attention, those of you who are not familiar with it. our second speaker is bin gao, who received his medical

training in china a very famous medical school. do any of you know who norman beth /ao*uune was? it's an unusual name fire medical school in china. but the reason is norman bethune is one of the great heroes of chinese history, particularly

during the large -- rong march. he was a thoroughasic surgeon from canada and eventually wound up as /aa very critical part of the success of the communist effort uncedeing /stkpopbg so forth. and he really devoted his life to excellent health measures,

including the introduction of npneumoauthorizthorax with atreatment of pulmon arary, tuberculosis,which he had and was treated in that way, et cetera. a very well-known man in the whole field of the history of authorithoracic surgery and wasa national hero in china and also

in canada, where his home. a museum is visited each year by a distinguished delegation in china. well, this isn't on norman beth bethune, but you might find it interesting to read about him. so perhaps we will begin with dr. koob.

/phra [applause] >> thank you very much, and thanks for reminding me to be part of this. i look forward to any questions you may have, once we get into so what i thought i'd do is tell you a little bit about alcohol

but i am going to use a newuro neurocircuitry percespective rather than just do a farm pharmacology lecture. in fact, as was already pointed out, shakespeare was very good at the discovery of alcohol so we now how it works at /this point.

but the bigger issue really is and the one our institute ded dedicated toward is trying to address the problems of excess excessive drinking and the costs to society. and it's potentially quite pro dij ioious. alcohol costs us about $23 bail

year and we have about 17 million people who are afflicted with an alcohol use disorder of some kind, and many of them meet cry /taoiterion that we call dependence for alcoholism, and i'll talk about that in a second second. drugs and tobacco are combined,

have a similar im/pabpact on oursew society. so it really begs the question and so i am going to just talk a little bit of /aa conceptual framework and /aa little bit ofda data and a little bit of /aa picture of addiction in general, but alcoholism in particular, so

what's that i would /hraoeuliketo convey to you. it really begs the question what really is addiction? what is alcoholism? what is alcohol-dependent, and i could literal spend my whole time going through the history of how we define those terms and

so forth. i think everyone could -- would agree that addiction to alcohol alcoholism is a rererasping disorder characterized by loss of control in limiting drug in intake. and when we talk about loss of control, it doesn't mean that a

drug addicted or alcoholic is not in control of their alcohol they are. but what we mean is they can't stop. and there are many fephenotypesof alcohol use disorder. from binging 18-year-old, a 21 21-year-old to /the dean of the

medical school who is hiding the bottle in his grovel /skpharplt in his desk, in the /tkaefbgt home and seems to be perfectly normal most of the time until they have some event like bin will tell you about in the hospital and go through severe withdrawal.

so it's a large fene fine -- fephenotype. but there is another part to the disorder that is critical for the way -- what i think alcohol douse our brain. and this is what /i call the emergence of the negative emotional date -- state and

access to the drug is /skpreufd call this the dark side of addiction and i've written quite a lot about it and will probably continue to write quite a lot about it because i think it's one of the key stones of the in instability of our emotional systems that drugs convey when

they're taken in excess and i'll explain what /i meant by /ththatin a minute. but to make it even more simple, addiction has 3 components. i als realize that it says one, two, and four. so i will fix the /skwhraoeufpltd but in /tphanyevent

event, addiction is an disorder and i'll explain what that is in a few minutes. addiction is a reward deficit disorder. it's a disorder and it's a neglective dysfunction disorder and i'll explain those terms in succession /stkpw*euplg to link

them an /totom tomically to your brain. but before i do that, i want to make /the argument thataddiction and alcoholism is a moving target. it consists of different stages, and those stages reflect the function /aal changes i was just

talking about. and most of them are obvious and self-splexplanatory, all right? everybody here knows what binge in/tobtoxication means? shakespeare described it very well. and that's when you are engaged in drinking and possibly drink

drinking to /ebexcess. withdrawal negative affect is the withdrawal stage and focus on the negative affect part of that, the emotional part, and i'll explain that later. and basically anticipation may be a little bit dense. it talks about social psychology

and craving, you prefer, but it's a part of all of these addictive-like disorders and you could superimpose path/hropbological gambling if you want and sil that it fits the cycle. now, where does this cycle come from from? i spent years at the university

of california san diego on my own time teaching a class called im/pupulse disorder and one ofthe things i realize realize if you go back in psychiatry you find there are two disorders that comprise the components of addiction. one was an im/pupulse control

disorder and that's in the blue here another and was a compuls compulsive disorder in the red. now the arch typeal disorder is subto mania and the archetypeal case history ways guy who walks into into the supermarket in a trench coat and he's very excite excited and sweat are growing on

his forehead and the tension is getting larger and larger and he's trying to find where they sell the lobster and he finally finds the canned seafood aisle and finds the lobster cans and the urges are just overwhelming and he stuffs his coat full of lobster cans and he exits the

store and /aa great sigh ofrelief comes -- comes over him and huge feeling of reward and and pleasure and he goes home, and he takes the lobster seasons and shows from them in the closet and he doesn't eat seafood and is the that that is the excitement and risk taking that

contributes to this and maybe returns the lobster /kapbtz apthe some later date. there is not a whole lot /of withdrawal in those kinds /of im im/pupulse controlled disorders. but the other disorder, which is obsessive compulsiveive disorder and that's the arch typeal

syndrome, is a great deal of anxioety and stress produced by /tkhraougsz and suppression says and person feels that they have to /relieve that and engage in represeetitive behavior. a great addiction of this is "as good as it gets" and nobody does it better than jack /tpheunicholoolson

/stkpwro*ufpblt don't believe me, then watch the movie "the shining," which is even worse. but if you take an im/pupulse disorder stored and a compulsive disorder and merge them together together, you in effect end up with the addiction cycle. and to make a short story long,

there are two sources of rin reinforcement in addiction. and in these /skwroeufpblgtz one we call positive reinforcement and one we call negative rin reinforcement. and positive reinforcement y'all know about. go to sea world and watch the

dolphin come to the hoop and watch the trainer slip the ball to the fish and every time he jumps through the hoop he gets a fish and that's how he's trained and that's what keeps the behavior motivated. negative reinforcement is something that is really people

don't get their head around very well, even in psychology departments. and it really is where you increase the response by re removing the stimulus. aren't in the case of addiction, we're talking about the removal of that negative emotional state

state, and this becomes critical if you want to understand what i am going to talk about today and how alcohol im/euimpacts your emotional systems. you got to understand the concept of negative rin now, for you in your daily life it could be a boss that yells at

you every time you step in the office. so what's your response to that? you go back to your cubeicle and you play video games, because you don't want /to deal withthis very averseive stimulant. but it increases the probability that you are going to be doing

video games in your office because you don't want /to deal with this boss who just yells at you no matter what you do, right senator, that's negative rin my argument is that addiction is a combination of the two. but as you move through the cycle and it gets worse and

worse, you want mor of what drives your behavior is negative so then we can get even more complicated and argue that these parts of the addiction cycle, and these sources of reinforcement are actually immediamediate bid separatecircuits in the brain and this is color-code

color-coded for those of you who are failuluoroan /toptomically challenged. this is the nose. this is the brain, this is the back of your brain and you can see the blue is /the binge in in/tobtoxication stage. the green is /the/prpreoccupation

anticipation /stkpaeupblgt red is /the withdrawal negative aspect stage. and that goes into a great deal of detail and you don't have to be a scientist to realize that the green on the outside and the blue and red and -- are on the inside.

and the green and blue are your represent tile -- i'm sorry. the red and blue are your represent tile brain and the green is in effect your cortex, which what makes you human and it's cont -- large rifrontal cortex. let's take a little further what

william shakespeare said and note that there is a dose effect function with alcohol. it's a critical one and then we'll talk about this as well, that if you measure blood alcohol levels and they are usually measured in milligram percent of course gram percent,

most you have know the legal limit for drinking is 0.08, which is 80 milligram percent and you can see why when you look at /this curve. gram percent is simply the number of grams in 100 mill millimeters of your blood. and you can measure it with a

breathe analyzer, you can measure it with a blood test. and as low doses, we get re re/hrablaxation, this is anaddiction addiction, as william shakes shakespeare talks about. it's a social lubricant. i like to tell people that probably every cocktail party on

capitol hill has alcohol for its social lubricant property and the research society on alcohol opens its meeting with a cock cocktail party. and so 70% of americans drink and most of them have no problem whatsoever /sofr. but some do.

and one of the things that we're trying to survey -- convey at the alcohol institute is the the fact that binge part of the curve exists. so when you get to 0.08 and you have trouble driving. this is when you are having im impaired peripheral vision.

this is when you think you can drive very well but your reflex reflexes are not quite what they were and as you move up in dose, alcohol can kill you. and there was something on the news two days ago of brazilian students who were playing a drinking game and decided to

drink 21 shots of vodka in one minute and one /of them died and three of them were in serious condition in the hospital because they were, i can till where their blood alcohol was. /stph-ps where around here, all right? you drink a whole bottle of

scotch, you are going to have a blood alcohol level at the effect /kwreuive dose, 50%. which means if 50% of the people in /this room drink a bottle of scotch, will be dead in about an hour. so how does alcohol work? how do -- how does it have all

these myriad of effects from the good, the bad to the ugly? well, alcohol dish call it the two faces of janus, the god of transition for the romans. .^ the god of add /hrolescenceto adulthood. the god of life, death and stood out in door of rome

to protect them frin truders and and -- frin /traoeurdz. and where we think of two pieces of this /ppuzzle that interact strongly -- reward and stress. i talk about reward, which is basically positive reinforcement and stimulus of increase in positive response and has a head

head-donic connotation. a challenge to thehomeo/ststatic processes. some of you know that i small amount of stress can be rewarding, hence sky diving. to some extent you can think of clepto /phaeukleptomania in thatdomain, although it's not culturally

accepted for the over in the part. on the other hand, we also know that excessive reward pleads -- leads to an activation of the brain stress systems and i am going to try to make that point in /aa few minutes here. so unchallenged -- i've been

challenged with telling you how does alcohol work? well, the first place is on this part of your brain that's called the becauseasal gang /hrelia,which is important for moving toward things in the environment that are important. she probed -- probably talked

about sailients but one of the processes that's involved is/the release of dopamine that triggers a leakage between a stimulus in the environment and whatever it's doing to you, the good feelings semi. for /aa honeybee finding nectarin a flower, that probably and

this is a release of ok topmine and that makes the honeybee remember where that flower is and goes back to tell another honeybees it has high sillience because it was loaded with neck nectar. and this is highly conserved function in animals.

and so even honeybees andli s lizards have the system and presume /a*ably get reward from finding objects in the environment that are pleasurable and linked up to stimuli that is -- that are neutral. alcohol releases dop dopamine but alcohol also has another

powerful effect that's like op opiate drugs. u it releases opiate peptides or endeservein. i am going show you an example in a minute. but there has been enormity -- enormous amount of work funded by the national /euinstitutes of

health over /the /hraflast 30years to delineate portion -- the circuit in the brain that makes you feel good. this is the circuit and this is that same area i just showed you. this is the blue part of your basal gang glihe youia.

and you see peptides coming in and you can put your favorite drug wherever you want on the die /kpwrapl. one /of my colleagues -- and alcohol you will notice is pretty much everywhere. so alcohol influences circuits in two major ways.

activates the dopamine system and opiate peptides. in fact, /kwr-rpblgs years ago in /aa glaalaxy far, far away,we actually blocked opiate recept receptors because we stopped drinking, okay? later on, not too long ago, howard fields and jennifer mitch

mitchell at the gallow center at the university of california, san francisco, did a human /stkwroeurbgsd where they did the place you -- displacement of high-potency opoid that was labeled, and they were able to show that when drinking the e equivalent about two to three

drinks, there was an enormous de decrease in the binding of this opoid drug, which suggests that something had to be displacing the /sepsentinel. somebody had to push this label off that receptor. and of course, the argument is that it was endorphins and the

place it was doing it was in the nucleus -- that's the human brain, all right? beautiful study. in a sense proven to me what we'd seen in the studies a decade before. but showing it in the human brain there is a nucleus that --

and it has endorphins. director of the national /euinstituteshowed exactly the same thing in human subjects. so alcoholics actually. so oif you give -- if you give human subjects methyl sal idatate to challenge the dopamine system what you find in controls is

there is a release of /tkphao*eupb. but in alcoholics, there is no release of dopamine. the dopamine system's comprised. there is other data that has been generateed to show that dop dopamine is /kraels -- released in normal subjects, which is

what you see, looking at the control subject and going this direction. there is a decrease in the dop dopamine receptors. but in the alcoholic subjects, this methyl fphenyl atatereleases. and so this is the first indication that something

something's going wrong in the dopamine system when you drink a lot. and this was an he wielegantstudy published some time to go to support that hypothesis. as you excessively drink, the circuitry starts to change and you start to engage the dopamine

system in the /tkortsal part of the striatum, which is another part of the basal gang glia and you say who cares? what's the big deal? well, this is where we form habits up here in the dorsal part of the basal gang glia. this is the part of our brain

that forms good habits, like putting putting on your seatbelts, and part of the brain that engages bad habit. and when you start to think that dopamine release triggers habit formation, you begin to realize that a drug that induces excess excessive dopamine release, you

are laying down habits that are linked to taking the drug. this is particularly dramatic when you are talking about meth methyl le i -- or meth /apl/tpet methamphetamines. but david at the program at niaa showed exactly the same thing for alcohol.

as you get more compulsively involved in the alcohol, you start engaging more and more of the habit to take alcohol. to to to really -- it's really fascinating work. so this is one /of my favorite all-time opinions and i don't want /to spend too much time on

it but basically this lady doesn't look very happy and she's drink inging a drink that contains /khaoeurpb /haoplts -- amounts of alcohol but a drug called fudd ron and that brings me to then what happens? what happens what happens to the brain once you've engaged in

this excessive drinking? and you noticed that i've labeled it now if red and i've added two structures as part of my represent tile brain. and one. things that we know is that the nucleus loses its power to release dop /phrao*eupb and that

slide you showed you shows that dramatically in an imaging study study. but there is something else that goes wrong. i am going skip this. we're going to run recount of time and i want to have -- i want bin to have enough time.

they're couple slides i am going to skip because i spent too much time on the beginning. but i am going to hit on the main points. so what /i told you from norah's work is that when we first take a draig, an and alcohol no exception, you activate the

newurotransmitters. but as we keep taking the drug, there is a compromised function in these newurotransmiters. some of it is decreased release and changes in transcription function effect. some of it is probably other bio biochemical mechanisms being

engaged. but there is another piece to the situation that is critically dependent on those other structures that i added in to the dark side there, the red. and that has to do with engage engagement of your brain stress system and this is a little --

snap shot of it but i am going to talk quickly about a couple of newurotransmiters that get recruited when you excessively drink alcohol. and this all comes from really pioneering basic research that was done initially at the sulk institute.

i was there at the sulk in institute when mayry veil discovered the factor. many of you probably accept the fact that it is well-known to activate the pituitarya/tkrepdrenal access. but what we didn't know at the time when it was discovered in

1981 was that it also draws your simp /thympathetic to stress anddrives your behavioral response to stress in that a/pheug/tkemygdala that i was talking about. and so in /aa study one /-of mypost postdocs did a rong time ago now now, we -- to alcohol, shown here and a 30-minute session.

but the animals were made dependent and i am not going to go into the details. but the dependent rats drink -- drank four times as much alcohol as /aa non-dependent rat. so these are the non-dependent social drinkers, rats, they are drinking the equivalent of a

glass of wine in 30 minutes. but the dependent animals in 30 minutes, in 30 minutes we're /pauputting away 4 drinks, okay? they were mellow when they came out /-of the cage. if we could reverse that over overdrinking by administering selectively why the dependent

group an /ttag /stkpheuft that's why i'm actually show you data here. and you can see there was no effect on the an /ttagonist inthe non-dependent drinkers but a huge effect in the -- in the delinquent -- dependent drinkers drinkers.

many others have gone on to show that the c /r-fprs an/tatagonist can show alcohol dependence in rodents. but at the same time, again a long time ago and one of the messages from my make it is that things in /sraoeupbs to incubate a little bit. they have to grow and be picked

up and reexamined. it's almost like if you are -- pardon the pun, a good bottle of wine, okay? that has to age. and this was a story that was developed by bill carlozan at harvard, where they speculateed and high /poypothesized, that ifyou ex

excessively took opiates or co cocaine and we know now alcohol fits the same picture -- you act activated cocaine and the response binding protein, we can activate another peptide, a pep peptide called binor -- dinor finn, which binds to capoopoid rereceptors, which make you miz

mizrable. they relieve your pain and make you high and very re/hrablaxedand block your memory of pain /tin particular. but capoopen oidoid receptors make you disfphoric when they're activated. and this was about 10 years in

the literature. this overactivation of the reward system drove this process of excessive activation of bi-- dinor fin. i'd like to say that we /tkphaeupl on a silver horse, but it wasn't us. one /of my postdocs did the

experiment, who is now a profess professor at the university of washington -- at washington state university in pullman, washington state. but during this period, bill carlozan picked up /sand /k-pbd-- continued it and so did charl and now they've been having

regular ckappa meetings for the last four years. but when they absolutely insistd that we we had to look at a capo capoan /ttagonist and i kind of yawn and i had finally said if you want to do the /stkwroeurbgsd go ahead and do the study.

rats ats are drink drinking a rot of alcohol that are dependent and here is his controls. his controls are drink inging a little bit more than in the previous slide. he gave a capaan /ttagonist and repeat ed ed it increasing thedose

and eventually got to a dose consider -- where it completely he wieliminated the excessivedrink drinking, again, selectively and not touching to social drinking. so yet another peptide that makes you feel lousy and if you block that feeling lousy, you stop excessive drinking.

so i think you can see why i personally am a big /afadvocateof negative reinforcement and /skpwr-p i think it's critically important to the process of mis misuse use of alcohol that we talk about. so i'd like to argue with you

that when you excessively drink alcohol, you shut off your reward system, but you recruit your brain -- system and that's tat argument. and that's my /phmy passion. i have a lab at nida right now, where we're pursuing some of these questions.

we still want /to know moreabout the circuitry and how they inter interact. for example, we know that gluco glucocort choids can drive some of them -- this and we want /to know how you and we've get a lot of questions we'd like to answer before i hang up mye/hrelectrode.

those of you who have actually -- who actually know that there are a lot /of transmiters in the it's not just c /r-fprs anddinor fin but there is a whole herd of newurotransmiters that we now know are involved in emotional processing to make you feel feel lousy.

and believe it or not, we have a growing group of transmiters, one /of which are hav havonoids and could probably mellow out your stress system. so you have reward, stress and anti-stress, all built into our central nervous system to regulate what we call homo/kwrio

stasis. actually i want to touch on very quickly is that i told you that there was a green bit and i told you that it was largely frontal cortex and here is a blow occupy --up that have and we now know that the frontal cortex system controls your stress system and

im/pupulse system. it controls both of them. you can call it whatever you want. you can call it your souper ego. you can call it executive function. you can call it decision making. you can call it a stop system.

but we know that this part of our horm -- cortex is critical for controlling these excessive /pwraeufrbz, eth stress /tkoeupltd or im/pupulse/tkoeupltd /tkoeupltd. and another part that you young people should realize is -- and those of you who are parents of

young people should realize perhaps even more importantly is that unfortunately, this part of our brain doesn't fully develop until the age of about 25. and one of the big thrusts of our work /sand currently also of nida is to /traotry andunderstand how drugs of abuse are affectng

the development of this frontal cortex system. but we know now that this may be a key trigger in the process of addiction and this is a study that the group published fairly recently in the /pheramerican be journal of psychiatry showing that the more gray matter

deficits in alcohol-dependent patients because alcohol affects your frontal cortex and reduces function in your frontal cortex and may actually ultimately kill newurons in your frontal cortex. and this is an image of the frontal cortex. and imaging the amount of gray

matter, the more of a deficit, the faster you re/hralapse in/aea recovery program. so it not only impacts on the beginning of the addiction process. it gets you into the system, where you have moreim/pupulsivity and more stress that i spent all

this time telling you about. but we also think that, as the cycle continues, it may impair your executive function and im impair and slow down your recovery process. so frontal cortex is more and more important in the effects of so i am just going to finish up

now and turn it over to bin. but -- i think i've given you a pretty good explanation of how alcohol fits into this addiction rue r. b. i. . obviously, i focused on my love, which is the fact that alcohol impairs your reward system when it's taken in excess.

but also triggers an -- an act activation of your brain stress system, maybe better than other drug of abuse. that's a question that remains to be determined, but i can tell you that alcohol's effects on cr f are probably the most dramatic of all the drugs i've looked at.

and so here is what /i said. now, alcoholism is a syndrome of compulsive alcohol composed of moleable stages and hijacking of moleable sources of rin i'd argue that there are explanations for this within the binge in/tobtoxication stage. there are run away reward

circuits and basal gang glia and habit formation and activation of the dopamine and opoid pep peptide system. and withdrawal negative affect stage, brain anti-reward systems systems. we find brain anti-reward system that deficits decreases peptide

function and brain stress system recruitment in cases of dinor fin and the extended a/pheumigdilla are driving this and finally i didn't go into great detail. but the executive function deficit that's we associate with the frontal cortex, we are now learning that these contribute

to im/pupulsivity andcompulsivity and i didn't talk about the newurotransmiters involved but there is a lot /of work in the literature red by a number of investigators, suggesting that this is deficit, glutam aate is one of the major transmiters in these newurons that project from

the frontal cortex to /thebrain. and thank you very much. >> questions or comments? we'd like you to use the micro microphone, because there are several /huhundred people whoare watching, and they can't use -- hear the question, but they can hear the answer.

they send me e-mails. okay. >> okay. hi. i read some -- about some studies and anecdotal evidence of people going on psyche/tkdelic drugs and then suddenly in instantly breaking an alcoholic

have you researched this at all? >> i haven't personally researched it. it's a very, very old story. i mean, lsd in the 60's by al albert hoffman, who developed it at stanford university for human studies. that was a brief shining moment

when meth /apl /tpamphetaminewas introduced produced and psychetherapeutic process. and there is probably some truth to the fact that psyche /tkdelic drugs can, in individuals who tolerate them, short test /the psychotherapeutic process. but unfortunately the /stefbgts and the problems associated with

using psyche /tkdelic drugs have left most of us in science off to the side of that. psyche therapy can be very use useful for individuals who want treatment for mental disorders, but the short cut using psyche dellics can work, but it can go really hay wire and i can give

more details if you want. about psychotherapeutic process going hay wire. so it's a dangerous kind of a approach. >> i was wondering what's actually happening at the level of the cell in terms of when you have alcohol?

is it membrane destabilization or direct inter/aobaction with a receptor? what is happening? because it has a draft effect from multiple receptors, et cetera, so i was wondering if you knew anything about that. >> the answer is no.

and as remarkable as that may sound, we are in the process of putting together an rsa for funding announcement to look at ten million more alcohol. over /the years there has beenan argument that alcohol works at doses that would be the e equivalent of one drink, that's

around 10 mill /*imiller ongather receptors, glut /a*amatereceptors, with glycoene receptors. i know that there is an /ebextra extrasignificaynaptic receptorwhere one group at least has argued argued the doses between 10 and 20 are activating it. alcohol is hanging out in the

water pocket and influencehirydro hydro/tp*ephilic components. that way there's a deeper /tkoerp -- a year ago in " "nature" on that subject by the group from texas who did it with also the institute -- so very little is known about how actually alcohol works at the

molecular level. it doesn't just jiggle membranes but it does seem to hang out in certain pockets that are water pockets in the membranes that maybe are moderateing certain receptors and we want /to know what they are. a very good question.

>> hi. so i want to ask what is the reason of the --inaudib[inaudible] >> the what? >> the reason of the gap? >> the gap? >> the australian boy? yeah. why is that?

>> oh, why did he die? i think that's pretty easy. it shuts off your res/prpiratory drive in the brain stem. i mean there is probably at those kind of doses you are talking about membrane changes that would -- and i don't know.

i mean, there would be castlcium changes. at those doses you are shutting off newurons. >> the nerves shut off? >> and the brain stem would be res /prpiratory. >> thank you. >> and pro proposal is a perfect

example. it's a gabareleasing drug and everybody knows about it because of /phaoeubgs. so that -- michael jackson. and by the way, if you combine the two, two plus two equals five. so you are more likely to die.

>> a quick question. long term and kind of excessive use as /kpol -- alcohol, as you /skpwhraeurpbgsd sort of de decreases your reward path wway and anti-/skpwraeurd get all these negative effects. how does that -- why do you still have addiction then?

it seems like you would no longer biologically be dependent on it. >> in those kind of what i call terminal alcoholics, basically the only way they can get through the day /or can even manage is to drink. and so this is what we call

negative reinforcement. so at some point -- what's the word i'm searching for? but it's a gut feeling -- no pun find -- intended -- that if you don't have a drink, you are going in so much pain and misery that /ta*ur going to die. so they drink now to avoid pain,

not for the pleasure. the pleasure is gone. and even a heroin addict who is on enormous doses of heroin, it's far beyond what would kill you -- i'm assuming sure -- you're not a heroin addict -- laught[laughter] -- are stillget some pleasure from the injection, but

it's much less than the first time and it's mainly to /relieve the pain of not taking the op opiate and it's the same with >> i don't want /to take up all of bin's time. >> i was just wondering how can you explain the success of alcohol on?{}mus and so many

people having complete reversal of their alcoholism? technically i /tkpwguess they're always alcoholics but they're able to completely abstain from some of them, the rest of the lot -- is -- >> that's a really good question and there is not a

whole lot /of science about -- around it. but i will speculate, which i will do. i would argue thatinter/aobaction is a very, very powerful rin reinforceer, very powerful reward. we are human beings and primates

and we interact with other prime primates and when you're an -- in alcoholics anonymous, you are getting bond with people and being reinforced for that behavior, which is a big boost. and there are other parts, too, of alcoholics anonymous, but that's one of the positive rin

reinforcing parts. one of the other parts is that they have a lot /of emphasis on getting rid of the guilt that's associated with alcoholism. and so guilt is driving your di dinor fin system. it's a newtra stressor guilty -- /kpweult and you have to go make

amends to everyone you've offend offended and that's part of the so there is a whole bunch of sources of reinforcement and i would argue that that slowly and reducing your stress system by removing the guilt and facility facilitating your reward system by the social inter/aobaction.

so you're rebuilding your represent tile brain in the right direction. that's the way i would put it. >> and i think targeted behavioral therapy utilize similar things. you're using your own bang -- brain to recover.

>> thank you very much. i think we'll save the rest for after -- in/eu[indiscernible]. it is my great pleasure to give a lecture with my boss george koob. he just did nicely on how this affects -- alcohol affects the today i will mainly discuss how

drinking affects the liver, which is another major problem caused by the alcohol drinking. everyone has one and the reason we have one -- if you take good care of yourself, your liver probably /phrebl look like this, very nice, red, soft and tender. what if you drink a large amount

of alcohol alcohol? so the first response of the liver to alcohol drinking is ac accumulation. your liver becomes fatty, pale color and accumulating in the liver. the study of liver -- if you stop drinking, the liver can

recover to the normal liver. luckily in /aea majority of 6 /0to 7 70% of heavy drinkers, probably maintain the patty liver fire long, long time. so they have fatty liver for life. but unfortunately, there is about 30 to 40% of them develop

inflammation in the liver. they in/tpefiltrate manyin/tphrapl inflammatory cells in the liver. so we call alcoholics hepatitis hepatitisis. most of the earliest stages of alcoholics also reversible if you stop drinking, the liver can recover.

but some alcoholics have help hepatitis even when with you stop drinking still progresses to a more severe form of liver injury, such as sir /ocirrhosis. the sir /ocirrhosis usually, we believe, is reversible. -- is ir/refreversible. it cannot revert back to the

some patients are -- with early sir /ocirrhosis can be reversedback to normal. if you have liver sir/ocirrhosis, a chance of liver cancer is very high. even 1 to 3% of liver sir/ocirrhosis, you can develop cancer every year.

the reason the liver histology and the normal level -- in /aafat fatty liver you can see there is many accumulate in the cells. in alcoholics you have he hepatitis, you also have in in/tpefiltration of manyin/tphrapflamstry -- in/tphraflammatory immunecells in in the sir /ocirrhosis livercells was

lost by fibrougtic tissue. in most of those chronic liver disease, most of the patients will not have symptoms. were even if you have liver sir osis, you don't have any symptoms. you /hraolook like a normalperson. but in some patients they can

develop acute alcoholic help hepatitis. there is a significant clinical syndrome. the typical one is jaundice omeg /hr*eu and the liver enzyme on al t ratio is more than two. and there is a clinical syndrome the short term mortality for

those alcoholic help /stao*euts very high. usually 30 to 50% of them go fought hospital. 30% of them after 30 days or 60 days. so the next question i want to ask is how is ethanol metabolite in the liver?

the liver is a majoringan to met metabolite alcohol. the metabolite by alcohol -- so ethanol can be met/pwhraoeabolized by 51 51. but adh alcohol homoogoese is a major enzyme. it gets into the mitochondrion and is met /pwhraoeabolized intothe ase

asetate. so this is the mitochondrion. it can quickly be released from the mitochondrion into the circumstanlation to further met bolize by the muscle or hard tissue into the water. everyone maybe has a different ability to met /pwhraoebolizeethanol or

this is because the enzyme poly polymorphism. one of the most -- of poll morph morphism is acute polymorphism. the position 504 is a glut/a*amate and those are normal enzyme activities, which can quickly met /pwhraoebolize into the a/kr-fplcetate. but in 50% of american asians,

one is is a glutam aate 504 isre re/phraeplaced bid immunoassays. they only have 6% normal activity. they reduce the enzyme activity reduced by 94%. just also 5 to 8% -- actually, two, copies is to/re/phraeuplace the list oomes in the homozygouswith

no activity. basically those people cannot met /pwhraoebolize -- sotherefore in those, you get very high level, which cannot met /pwhraoebolizein the a acetate. it can cause flushing, then cause methyl dillation. clearly i am one /of them.

so when i drink alcohol, i get flushed. actually, many alcoholics is in the -- in the u.s. -- do not fit with east asian. because i only drink a half a bottle of beer. my alcoholic consumption is very low.

so we should we should design different for different mutation mutations. so as /i mentioned, this alcoholic level disease with this patient has been ex/tepbs extensively -- in countries. liver disease in patients with the deficiency have not been

studied carefully, which may be /spraeub different from a patient with ald 2 and one with this fephenotype. so the question i want to ask are there individuals who have alcohol flushing reaction more susceptible to alcoholic liver inflammation?

like myself, i chink alcohol and flushing and more susceptible to alcohol liver injury. to answer this question, we used this in deficient mice or knock knockout mice. the deficient mice with alcohol and there was flush /prurpbs in those mice as well.

the result show clearly that the first met /pwhraoebolize bolizeof eth ethanol is -- most people believe this causes a problem. but surprisingly in those mice, the fatty liver, the liver en enzyme is lower compared to the wild type mice. and liver fifi/pwrobrosis and in

inflammation is much higher in those knockout mice compared to the wild type mice. so we have evidence of this he will /sraeugs in inflammation is trying to /repair the liver and lower level enzyme. so what does this mean for the patient which is a human?

for the people who have deficiency, when you drink alcohol, you are flushing, you probably have very high level of he wielevation. whereas if you go to the doctor to have a checkup, ultrasound look at your liver and it livers you don't have a fatty liver,

your liver enzyme in your blood is okay, is normal. but when you have liver problem, you have liver fi/pwrobrosis orin inflammation, which can progress to more severe sir /ocirrhosis. even when you have a normal liver enzyme, you still have to be cautious.

you may have liver fi/pwrobrosisin inflammation. personally we don't don't have biomarkers for diagnosis in the early fi/pwrobrosis orinflammation. so the second question i want to discuss, how does ethanol cause liver injury? ethanol is a kind of carbohigh

carbohydrate /stkwraoeufplt we need so many carbohigh demonstrates, why we are drink drinking this -- this causes such a broad strum -- spectrum of liver disease injury for the fatty liver. ethanol and met /pwhraoeuts do not -- they do not -- they

cannot sin /tynthesize thefoughto foughtostats. ethanol leads to a fatty liver metabolism associated with stress and promote fatosin/tthey sis. when you are drinking alcohol in your liver, it cannot degrade it and it causes accumulation in

for the alcoholics, they have hepatitis inflammation. how alcohol /tkro*eupbging cause it has been shown alcohol drink drinking increases bacteria over overgrowth in your gut. and permeability increase and all this can lead to more bacterial products such as endo

endotoxins, into the liver. and production of stress and cause in/tpefiltration ofinflammat another one is sir /ocirrhosis. sir /ocirrhosis is a progressionof disease in which you have liver tissue. it's replace placed by the car those are mainly produced by a

cell in the liver. those alcoholic cells met bolize and is stimulated by activation. and also activates cellular cells and causes fi/pwrobrosis. so again, this ethanol drinking cause a broad spectrum of alcohol level injuries.^ another question that is mentioned.

some heavy drinker has a fatty liver for /aa long time. why heavy drinker progress progress to the more severe form of liver injury? well, because it's an acquired factor that has been identified. many of them have not been confirmed, and i do not have

time to discuss all of them today. i will just discuss two on drink drinking pattern and another one is obesity. a drinking pattern, while it is in in a human, chronically and slowly drink. some people like binge drinking

and getting drunk all the time. they are happy. in alcoholic hepatitis patient, most of the patients actually have a history of chronic long term drinking, plus excessive drinking. basically chronic drinking in those alcoholic help /thao*eupts

patients. then if you look at the an /phapbl models and study injury, the animal models -- the most widely used model over /the last 40 years is /the mice with a liquid diet containing ethanol for 4 to 6 weeks. because the mice done like drink

drinking alcohol. then we have to put the ethanol in /aa liquid diet so that heeats and drink together. the model is very uneasy to perform. so the problem probability cause causes mild fatty liverory. does not cause a significant

amount of liver injury. i /tkpwguess this drinking is probably similar similar to humans drinking like this, slowly drinking and never getting drunk. because alcoholics have -- patients have chronic drinking and classifications of binge

drink. we developed this new model that we call chronic feeding plus binge. we feed the mice with a liquid diet containing ethanol for up to 12 weeks or 8 weeks. basically the mice eats, drinks and every day 24 hours.

and at the end a single binge and those of ethanol binge, which really causes significant liver injury, like alcoholic alcoholic hepatitis. the datta is a normal liver. . the liver from the mice. chronically fed alcohol for 8 weeks.

histology -- this is a liver from the mice with chronic alcohol feeding for 8 weeks. then when we give them sing-sing le dose binge, the liver clearly is more pale than this one. when you look at the liver hist histology, accumulation. as psyche, with single binge you

can make /the suspect liverworse and worse. the liver enzymes. the markup for liver damage. if you look at the ethanol for eight weeks, the liver enzyme in the blood he wielevates. so in /this chronic eight weeks binge market -- markedly he will

elevates compared to this chronic cells. so this suggests the chronic binge drinking is really bad for the liver, can cause severe liver injury. so the next i want to compare alcohol and obese /kpwraoeuts,, you two major problems in /this

country. so how does alcohol -- the inter inter/aobaction of alcoholaffect the liver? well, the obesityity associated with liver disease have very similar patterns progression as alcoholic liver disease. obesity develops a fatty liver

and develop inflammation in the so we call non-alcoholic help which can process -- progress to sir /ocirrhosis and livercancer. but the alcoholic and non- non-alcoholic fat aty diseases are two separate disease. the an /ttag nosis /pwreubld in the american liver society.

then also for the -- the non- non-alcoholic fatty liver disease published how /to diagnose this disease? those are two separate diseases. you can see here most people are obese or overweight drink. fat and alcohol always together the question asked is how obese

obesity and alcohol contribute contribute to the path /ogenesis of /aa fatty liver disease? how much from alcohol or how much from the fat? the main clinical with several hepatologist and developed alcoholic disease and non- non-alcoholic fatty disease in

index. this is a website. in /this website actually you can enter the value like as t and art and weight and height and gender and gives you a score. then based on the score, it can tell you this fatty liver liver disease, how much from alcohol

drinking and how much from the fat. so it's very useful model to distinguish alcoholic liver disease and fatty liver non- non-alcoholic disease. one of the most typical difference is /the as t and al t ratio in the /tph-rbt alcoholic

liver disease and non-alcoholic fatty liver disease. in the alcoholic liver disease the ratio liberia is more than two. in the non-alcoholic study -- fatty liver disease the ratio is less than one. these -- this also occurs in

mice. if you feed the mice with alcohol, this ratio is more than but if you feed the mice with high fat, this mice is obese, less than one ratio. this ratio between one and two, probably makes alcohol drinking and obesity of fat.

so the reason why the alcohol drinking is a higher level of as asd is /the as g is a mitochondrion enzyme. we know alcohol is a poison for the mitochondrion, which can cause the mitochondrion injuries injuries, which affects the asd more than the al t.

that's the reason why the alcohol is higher than art. -- al t. well, how does alcohol affect the non-alcoholic fatty liver disease? there is many publications already documented excessive alcoholic drinking.

so this is a mechanism. here i show you one study from a group that feed -- fed the mice with a high fat diet do at and alcohol together. if you feed high fat alone, the he wielevation of liver enzymeslarge largely he will /skwraeufplts but if you put them together,

it's much higher compared to low alone. so alcohol drinking basically in induces the liver injury in inflammation and fi/pwrobrosis. of course, there are mechanisms that contribute to this sinogest sinogestic aaffect. most of them are not excessive

most of them are moderated alcohol drinking. how'd that affect fatty liver there is also ethanol. we have bacteria that can produce a lot /of alcohol. most believe every day our gut breakthrough -- bacteria can

produce two bottles of bile. we do have en/tkopbdogenous -- howdoes that affect the study of liver there are several publications suggesting the moderate alcohol drinking is beneficial for non- disease. in contrast there is a paper published that suggests those in

low concentrations in alcohol actually promote alcoholic fatty because they believe in those, the gut producing bacteria is s he wielevated so they increaseblood alcohol concentration into the liver, stimulate the liver, in inflammation, causes non- non-alcoholic fatty i liver

so there is a conflict in mod moderate alcohol drinking. we probably need more study to clarify or confirm this. then the question what should we recommend to our patients with disease regarding alcohol use? there is an article published that actually recommended until

further data fray rigorous percespective on studies become available, non-alcoholic fatty disease people should avoid alcohol of any time or any amount. finally, a couple minutes to discuss for alcoholic /kpho*lg stop drinking probably is /the

most effect /kwreuive therapy.if you stop drinking, you can avoid fat fatty liver and reverse but for sir /ocirrhosis, thereis no fda-approved drugs /stkwrufplgt many alcoholic sir /ocirrhosisand liver cancer is very similar to the others such as hepatitis and sir /ocirrhosis.

the only form of treatment is for alcoholic hepatitis. this alcoholic hepatitis has a very high short term mortality. 30% to 50% of them enter the hospital. but because of the inflammation, it is believed is a key factor league to the liver failure.

most people focus -- control the just leave them on a steroid pathogen used for the treatment of alcoholic hepatitis over/-the last 40 years. it was first used for the alcoholic hepatitis in the 1971. even today we use the same prot protocol between the alcoholic

/tao*eupts. the data is very controversial. most of the data suggests im im/proprove the short termsurvival rate. for the long term there are no beneficial effects for the that's the reason support large contortia to conduct trans

translational research on the therapeutic target for alcoholic hopefully, we'll have some new studies available in the new future -- near future. in one group we identified a new drug. so we believe it's very promising. from the mayo clinic an article

propose the combination of therapy. basically alcoholic hepatitis in inflammation is a key factor league to the liver injury. but usually the liver injury the liver can regenerate. the problem with alcoholic help hepatitis, the liver cannot re

regenerate for some reason. impair the liver regeneration. they also have many complication complications. in the past we used a steroid to control the inflammation but does not control this problem. so we think we can use -- which can promote the liver re

re/kwrepbgs and prevent against pense damage. interligamentry can control many complications from hepatitis -- alcoholic liver hepatitis. here is a key point. this is probably the only sicyto cytokine that is produced by the immune cell but this does not

target immune cell. the -- they mainly target ep ep/thaoithelial cells, livercells or fib roblasts. we demonstrated this. almost ten years ago, induce liver stem cells, induce liver stem cell proliferation and in induce expression of anti-

antibacterial genes. so collaborated -- and finished the phase one clinical trial. so we are discussing now phase one b and phase two for alcoholic hepatitis hopefully early next year or end of this so finally i want to conclude and challenge for alcoholic

liver disease in the future. again stop drinking probably is the most effect /kwreuivetherapy for george just mention mentioned how /to stop drinking. overcoming addiction. and also the drinking is bad for your liver. if you want to drink slowly,

don't get drunk. another question every time a heavy drinker probably develops a fatty liver. it's not clear why the -- some get the most severe form of injury and others do not. and the and generic susceptibility of alcoholic

liver disease is not clear. the deficiency affects alcoholic liver disease and probably is the most studied. the pathogenesis of alcoholic liver disease is probably very /kphraebgs -- complex. maybe it develops from patient to patient and remains largely

unknown. biomarkers or diagnosis of early alcoholic liver disease is very important in looking for those markers. there is no approved drugs for the treatment of alcoholic liver disease so /tpfar. hopefully, this contortia on our

study identifies some new drugs in the near future. although we developed a model, this model still presents earlier stage of alcoholic there is no model really on alcoholic liver in the mice. we're still looking for the new model for alcoholic liver

oi'll stop here. so /tphourbg your attention. thank you for your attention. >> i'd like to ask why is it that people who are heterozygous or dehy drogen aase, instead o 50%, do they have one healthy and one 504 mutations? why only 6% instead of 50? >> this is a good question.

because the form of -- four proteins form together. one was mutateed and activity was reduced by the 90%. does that answer your question? >> hello. i was just wondering about the scientific variation as well. many people remember this in

medical school about the ac m have another -- it doesn't seem to stop them from drinking. i've been in japan, and many people enjoyed drinks, alcohol is it only the 6% that don't have any problems? the 40 to 50 -- >> no.

50 to 40% for the homozygous mutation. we thought there is no activity. those people have a 6% activity, they still can drink. i guess if you practiced to drink more, you probably can drink mow. >> you practice?

laught[laughter]. >> great talk. what is your take on those medications such as hepa vion? it's a vitamin d complex, b 1, b 6, b it 1? some people take that before drinking because it protects liver before and after drinking.

do you have any opinion on that? >> there is several clinical trials using this for alcoholic hepatitis that says it's more beneficial. clinical clinical trial is for severe alcoholic liver disease. and most /oufs -- most of us who don't have liver problems, i

think eat some vitamin has some effect. >> the alcohol intake -- >> so what percentage goes to the liver versus brain? alcohol clinic -- alcohol drink drinking control the gaps that go to the liver first. so the problem is many of them

met /pwhraoeuts and then goes /tkpwoetz brain. so how much goes /pwoepz to the liver? in the distribution, the brain very easy form because in the r rfa you showed the whole part of the brain. and then some part of the brain

is act activated to the higher level. is it related to the cons concentration of the alcohol? >> alcohol likes the water components of the body. but the distribution to the brain is pretty uniform. where -- it's still an unknown

question to some extent. that's a low dose. at a high dose, you will be pro fuseing all the brain fairly quickly. but which pieces get activated first, we would have to speculate that there are some components of that basal gang

/kpwhreuia that is activated first because that's why you feel the in/tobtoxication. there is a frontal cortex component because /kpwraeurlz on you dis/euinhibit it as well. there need to be /aa diagram and ken probably saw. this used to be this old die

/kpwrapl that alcohol went through a wave through /kwryour brain and started in your cortex and then moved down. there may be some truth to the fact that the frontal cortex probably gets hit first. >> inaudib[inaudible]. in the -- the alcohol mainly met

bolizes -- many do express alcohol on metabolite enzyme. i think there has not been been a really careful study. we do have these conditional we can knock out to the enzyme in a different fephenotype, then wecan study how does it met -- met metabolism in the brain affect

behavior? >> recently more and more people realize that obesity is not from eating too much fat. it's in fact, too much fructoose and induces chronic -- very similar to alcohol. how much is similar in terms of that higher intake or -- of

fruct oose and alcohol? >> so how much fruct oose? fruct oose, i think produces 5 grams of calories per gram and alcohol produces much higher calories than fruct oose. and the metabolism is very different because alcohol met metabolism causes stress.

and causes problems. for the fruct oose, i don't know whether fruct oose can cause problem. usually fruct oose plus high-fat diet together -- just may cause liver problem. fruct oose by itself may notcause major liver problem.

this is what i think. >> i wonder if i could ask you a question. you presented this model. is it applicable to a variety of circumstances from drugs to alcohol? would that also include things like obesity itself, compulsive

eating? is there a similar pattern from the newurofizphysio/hropbllogicpoint of view? and if this is a common pattern, is there evidence for spec fis fisity in the circuitry for any of these agonists? >> i think /thaopbz.

>> yep. a number of other people have argued this from afephenotypical phenotypicalic picture pirk that there are elements of compulsive eating that re/sefrsembleelements of compulsive drug /h--takingbehaviors behaviors. so we assume that the same

circuits are involved. but for the most part it's still largely an assumption. there is some work being done on internet addiction and compuls compulsive gambling and basogang glia do light up in some of the studies and there are d 2 recept receptor decreases in some of

the studies. but it's pretty initiate and planned at the early stages. do drugs enter the cycle at different places? absolutely. if you are doing heroin or op opiates, you are going to be entering largely through the

different summer and the there are similarities but there are differences. for one, with opiates, the pain of withdrawal is excruciateing. the pain of alcohol, it's the physical pain, sometimes as well as emotional pain with opiates. and the same with psychostimulus

psychostimulus. they're going to be entering largely through the release of dopamine. and there are some nyctotines influencing the dopamine system. there are different ways -- different waves in the cycle. people for years said they

didn't have dependence conference liability, but we now know that they are being abused and they don't really make you high very much. but they probably are entering through the anxioety withdrawal negative affect stage because once start taking large amounts

of ben zoates, one /of them -- it's really hard to get off of zanax. xanax. >> i don't know. that's for bin. >> methon ol? mixinging alcohol. anyone can answer?