[Script Info]
Title: 
[Events]
Format: Layer, Start, End, Style, Name, MarginL, MarginR, MarginV, Effect, Text
Dialogue: 0,0:00:06.04,0:00:12.28,Default,,0000,0000,0000,,The first substance of abuse\Nthat I'll be talking about is alcohol,
Dialogue: 0,0:00:12.28,0:00:17.40,Default,,0000,0000,0000,,so two things -- or one thing\Nthat you should remember --
Dialogue: 0,0:00:17.40,0:00:20.70,Default,,0000,0000,0000,,Well, one of many things you\Nshould remember, the first thing
Dialogue: 0,0:00:20.70,0:00:25.36,Default,,0000,0000,0000,,you should remember is\Nsedative and CNS depressant.
Dialogue: 0,0:00:25.36,0:00:29.90,Default,,0000,0000,0000,,What that means is, alcohol\Nwill cause drowsiness,
Dialogue: 0,0:00:29.90,0:00:33.28,Default,,0000,0000,0000,,it'll make you go to sleep\Nat a high dose,
Dialogue: 0,0:00:33.28,0:00:39.03,Default,,0000,0000,0000,,and it's an over-suppression,\Nor depressant, of your nervous system.
Dialogue: 0,0:00:39.03,0:00:46.53,Default,,0000,0000,0000,,So, it basically has an over-inhibitory --\Ninhibitory influence
Dialogue: 0,0:00:46.53,0:00:48.82,Default,,0000,0000,0000,,on your nervous system.
Dialogue: 0,0:00:48.82,0:00:51.20,Default,,0000,0000,0000,,So, let's dive into it.
Dialogue: 0,0:00:51.20,0:00:55.14,Default,,0000,0000,0000,,So, first, I have to tell you that\Nthere are different forms of alcohol.
Dialogue: 0,0:00:55.14,0:01:02.79,Default,,0000,0000,0000,,So, the one that we drink\Nis active alcohol, also known as ethanol.
Dialogue: 0,0:01:02.79,0:01:07.07,Default,,0000,0000,0000,,But there's also -- I mean, there are\Nmany different types, but let's just
Dialogue: 0,0:01:07.07,0:01:09.10,Default,,0000,0000,0000,,talk about these three.
Dialogue: 0,0:01:09.10,0:01:13.01,Default,,0000,0000,0000,,The other one is methyl alcohol,\Nwe also call that methanol.
Dialogue: 0,0:01:13.01,0:01:20.12,Default,,0000,0000,0000,,This is extremely toxic, so\Nyou don't want to drink this ever,
Dialogue: 0,0:01:20.12,0:01:23.53,Default,,0000,0000,0000,,and that can actually --\NThat can cause death.
Dialogue: 0,0:01:23.53,0:01:29.22,Default,,0000,0000,0000,,So, one of the metabolites of this\Nis formaldehyde, and we never drink
Dialogue: 0,0:01:29.22,0:01:30.67,Default,,0000,0000,0000,,formaldehyde.
Dialogue: 0,0:01:30.67,0:01:37.56,Default,,0000,0000,0000,,So, there was actually an article\Nand recall -- Not necessarily a recall,
Dialogue: 0,0:01:37.56,0:01:41.45,Default,,0000,0000,0000,,but warning about some of\Nthe hand sanitizers that are
Dialogue: 0,0:01:41.45,0:01:46.37,Default,,0000,0000,0000,,being distributed right now, and because\Nof the shortage, there might be some
Dialogue: 0,0:01:46.37,0:01:52.28,Default,,0000,0000,0000,,hand sanitizers that are not made\Nin the best way, and they are finding
Dialogue: 0,0:01:52.28,0:01:58.67,Default,,0000,0000,0000,,some methanol in these hand sanitizers,\Nso definitely need to be careful.
Dialogue: 0,0:01:58.67,0:02:02.32,Default,,0000,0000,0000,,And then the other type of alcohol\Nis isopropyl alcohol;
Dialogue: 0,0:02:02.32,0:02:06.44,Default,,0000,0000,0000,,we typically know them\Nas rubbing alcohol. Okay.
Dialogue: 0,0:02:06.44,0:02:12.32,Default,,0000,0000,0000,,Couple of things to talk about.\NAlcohol, other than caffeine,
Dialogue: 0,0:02:12.32,0:02:18.51,Default,,0000,0000,0000,,alcohol is the most commonly used\Npsychoactive drugs, and also,
Dialogue: 0,0:02:18.51,0:02:24.05,Default,,0000,0000,0000,,in America, and it is most abused drug\Nas well.
Dialogue: 0,0:02:24.05,0:02:28.87,Default,,0000,0000,0000,,We may not talk about this, or we may not\Nhear about this as much as
Dialogue: 0,0:02:28.87,0:02:34.45,Default,,0000,0000,0000,,some other drugs, because these are\Nlegally available, but it is most used
Dialogue: 0,0:02:34.45,0:02:37.38,Default,,0000,0000,0000,,and most abused, other than caffeine.
Dialogue: 0,0:02:37.38,0:02:44.92,Default,,0000,0000,0000,,Now, ethanol is produced the fermentation\Nof sugars by yeasts, so if you --
Dialogue: 0,0:02:44.92,0:02:50.83,Default,,0000,0000,0000,,You know, you can make wine out of grapes,\Nsake out of rice, beer from grains.
Dialogue: 0,0:02:50.83,0:02:59.55,Default,,0000,0000,0000,,The first time that we start seeing\Nserious alcohol abuse issues is
Dialogue: 0,0:02:59.55,0:03:04.95,Default,,0000,0000,0000,,around the time when gin was produced,\Nso that's when people learned to make,
Dialogue: 0,0:03:04.95,0:03:11.94,Default,,0000,0000,0000,,to distill the alcohol, so basically they\Ncan make much higher concentration
Dialogue: 0,0:03:11.94,0:03:18.91,Default,,0000,0000,0000,,of alcoholic beverages, and that's when we\Nstarted seeing the rise of alcohol abuse.
Dialogue: 0,0:03:19.24,0:03:24.30,Default,,0000,0000,0000,,Even though alcohol has high calorie,\Nit doesn't provide any nutrients,
Dialogue: 0,0:03:24.30,0:03:30.22,Default,,0000,0000,0000,,so it's not really good form of, you know,\Nsupplementing your diet.
Dialogue: 0,0:03:30.70,0:03:36.49,Default,,0000,0000,0000,,Okay, so, let's briefly talk about\Nthe behavioral effects of alcohol,
Dialogue: 0,0:03:36.49,0:03:41.58,Default,,0000,0000,0000,,and the behavioral output is actually\Nquite dose-dependent.
Dialogue: 0,0:03:41.58,0:03:48.86,Default,,0000,0000,0000,,So, first of all, as low as .04%\Nof alcohol concentration in your blood
Dialogue: 0,0:03:48.86,0:03:53.36,Default,,0000,0000,0000,,will start influencing your\Nbehavior output.
Dialogue: 0,0:03:53.36,0:03:57.65,Default,,0000,0000,0000,,So, you can sort of see in this chart\Nthat it goes all the way up
Dialogue: 0,0:03:57.65,0:04:05.37,Default,,0000,0000,0000,,to lethal dose, so that's LD 50,\Nright, lethal dose for 50% of the people.
Dialogue: 0,0:04:05.37,0:04:11.31,Default,,0000,0000,0000,,It generally starts out with relieving\Nyour anxiety, which then goes into
Dialogue: 0,0:04:11.31,0:04:17.56,Default,,0000,0000,0000,,disinhibition, so you guys can easily\Nthink of examples of your friends
Dialogue: 0,0:04:17.56,0:04:22.22,Default,,0000,0000,0000,,or yourself, where you become\Nthe life of the party, right?
Dialogue: 0,0:04:22.22,0:04:28.50,Default,,0000,0000,0000,,Because with a little bit of alcohol,\Nyou become a lot more talkative,
Dialogue: 0,0:04:28.50,0:04:33.91,Default,,0000,0000,0000,,so that's the state that you are in,\Nbut then if you continue to consume
Dialogue: 0,0:04:33.91,0:04:39.07,Default,,0000,0000,0000,,alcohol, you get to the point where you\Nbecome sleepy and then you fall asleep,
Dialogue: 0,0:04:39.07,0:04:44.92,Default,,0000,0000,0000,,but if you go past that point, then you\Nare starting to get to the point of where
Dialogue: 0,0:04:44.92,0:04:49.53,Default,,0000,0000,0000,,you fall into a coma, and then with\Nreally high dose, you can actually die
Dialogue: 0,0:04:49.53,0:04:51.33,Default,,0000,0000,0000,,from alcohol in the system.
Dialogue: 0,0:04:52.17,0:04:58.97,Default,,0000,0000,0000,,Okay, so in the next slide, let's talk\Nabout how alcohol gets into our system.
Dialogue: 0,0:04:58.97,0:05:06.21,Default,,0000,0000,0000,,It is a passive diffusion, that means\Nit just moves from wherever the alcohol
Dialogue: 0,0:05:06.21,0:05:12.17,Default,,0000,0000,0000,,is highly concentrated to wherever\Nthe alcohol is not highly concentrated.
Dialogue: 0,0:05:12.17,0:05:18.19,Default,,0000,0000,0000,,So, typically, we drink alcohol, so\Nthat means it goes into our GI tract,
Dialogue: 0,0:05:18.19,0:05:20.42,Default,,0000,0000,0000,,that's where it's highly concentrated
Dialogue: 0,0:05:20.42,0:05:24.84,Default,,0000,0000,0000,,So, it will diffuse into or seep into\Nyour blood system.
Dialogue: 0,0:05:24.84,0:05:26.97,Default,,0000,0000,0000,,So, that's how the alcohol moves.
Dialogue: 0,0:05:26.97,0:05:30.68,Default,,0000,0000,0000,,So, if you have a lot of alcohol in\Nyour GI tract, then it will get into
Dialogue: 0,0:05:30.68,0:05:38.38,Default,,0000,0000,0000,,your blood system, or more of it\Nwill go into your blood system
Dialogue: 0,0:05:38.38,0:05:43.48,Default,,0000,0000,0000,,than if you don't have as much, and\Nthat's what the Graph A is showing you.
Dialogue: 0,0:05:43.48,0:05:49.41,Default,,0000,0000,0000,,So, there are different volumes\Nof ethanol that has gone into the system,
Dialogue: 0,0:05:49.41,0:05:58.53,Default,,0000,0000,0000,,and you see that -- orally -- and then\Nyou see this different blood-ethanol
Dialogue: 0,0:05:58.53,0:06:04.44,Default,,0000,0000,0000,,concentration based on the volume\Nthat was ingested, and because
Dialogue: 0,0:06:04.44,0:06:10.05,Default,,0000,0000,0000,,it gets -- we drink alcohol and it goes\Nthrough this diffusion process,
Dialogue: 0,0:06:10.05,0:06:15.04,Default,,0000,0000,0000,,if you have something in your stomach,\Nit will sort of interfere with
Dialogue: 0,0:06:15.04,0:06:19.43,Default,,0000,0000,0000,,this diffusion process, and it will\Ndilute out the concentration,
Dialogue: 0,0:06:19.43,0:06:25.93,Default,,0000,0000,0000,,so -- And you guys, you know,\Nthose of you who drink alcohol
Dialogue: 0,0:06:25.93,0:06:30.22,Default,,0000,0000,0000,,probably know this, that if you\Ndrink something on an empty stomach,
Dialogue: 0,0:06:30.22,0:06:37.76,Default,,0000,0000,0000,,it affects your functioning much greater\Nthan if you had a meal, so that's what
Dialogue: 0,0:06:37.76,0:06:40.24,Default,,0000,0000,0000,,the graph below is showing you.
Dialogue: 0,0:06:41.56,0:06:46.73,Default,,0000,0000,0000,,Okay, so, in the next slide, let's talk\Nabout alcohol metabolism.
Dialogue: 0,0:06:46.73,0:06:52.94,Default,,0000,0000,0000,,Ninety-five percent of your alcohol\Nis going to metabolize by the liver,
Dialogue: 0,0:06:52.94,0:06:57.94,Default,,0000,0000,0000,,and that's partly why if you abuse\Nalcohol, you eventually end up with
Dialogue: 0,0:06:57.94,0:07:05.10,Default,,0000,0000,0000,,serious liver issues, because, you know,\Nit's doing a lot of work to break down
Dialogue: 0,0:07:05.10,0:07:07.42,Default,,0000,0000,0000,,and get rid of this alcohol.
Dialogue: 0,0:07:07.42,0:07:14.02,Default,,0000,0000,0000,,So, and then, about 5% gets taken out\Nby your lungs, and that's how
Dialogue: 0,0:07:14.02,0:07:19.31,Default,,0000,0000,0000,,the breathalyzer works, because you can\Ndetect presence of alcohol through
Dialogue: 0,0:07:19.31,0:07:21.31,Default,,0000,0000,0000,,just your breathing.
Dialogue: 0,0:07:22.55,0:07:27.84,Default,,0000,0000,0000,,Now, I usually don't spend a lot of time\Ntalking about the metabolic process
Dialogue: 0,0:07:27.84,0:07:31.87,Default,,0000,0000,0000,,of different substances, but\NI'm going to have to talk about
Dialogue: 0,0:07:31.87,0:07:34.01,Default,,0000,0000,0000,,alcohol metabolic process.
Dialogue: 0,0:07:34.83,0:07:39.37,Default,,0000,0000,0000,,So, alcohol goes through two steps\Nto finally get to the point
Dialogue: 0,0:07:39.37,0:07:45.79,Default,,0000,0000,0000,,of inactive form, which is a form that\Nno longer affects our body, and that
Dialogue: 0,0:07:45.79,0:07:49.76,Default,,0000,0000,0000,,will be acidic acid, but there is\Nan intermediate step.
Dialogue: 0,0:07:49.76,0:07:56.48,Default,,0000,0000,0000,,Alcohol gets converted to acetaldehyde,\Nand then acetaldehyde will get converted
Dialogue: 0,0:07:56.48,0:08:00.39,Default,,0000,0000,0000,,to acidic acid, and\Nwhy do I care about this?
Dialogue: 0,0:08:00.39,0:08:06.61,Default,,0000,0000,0000,,Because acetaldehyde is actually\Nquite toxic for our body, so it is
Dialogue: 0,0:08:06.61,0:08:12.59,Default,,0000,0000,0000,,beneficial for us to basically\Nget rid of or break down acetaldehyde
Dialogue: 0,0:08:12.59,0:08:15.89,Default,,0000,0000,0000,,right away when alcohol\Ngets converted to it,
Dialogue: 0,0:08:15.89,0:08:23.35,Default,,0000,0000,0000,,but there is a genetic difference\Nin human population where the enzyme
Dialogue: 0,0:08:23.35,0:08:28.45,Default,,0000,0000,0000,,that breaks down acetaldehyde,\Nso acetaldehyde dehydrogenase,
Dialogue: 0,0:08:28.45,0:08:35.63,Default,,0000,0000,0000,,doesn't always work properly, and\Nhigher percentage of East Asians have
Dialogue: 0,0:08:35.63,0:08:43.45,Default,,0000,0000,0000,,this variation in this genetic makeup,\Nand that's why you might see --
Dialogue: 0,0:08:43.45,0:08:48.20,Default,,0000,0000,0000,,Some of your friends might turn\Nbright red as they drink something,
Dialogue: 0,0:08:48.20,0:08:54.22,Default,,0000,0000,0000,,and they might have much severe reaction\Nor severe hangover the next day
Dialogue: 0,0:08:54.22,0:09:01.07,Default,,0000,0000,0000,,if they drink it, and that's because\Nall this flushing, nausea, headache,
Dialogue: 0,0:09:01.07,0:09:09.71,Default,,0000,0000,0000,,and what we typically say "the hangover,"\Nor reaction to alcohol, is really due to
Dialogue: 0,0:09:09.71,0:09:14.41,Default,,0000,0000,0000,,a reaction to the presence\Nof acetaldehyde, so if you don't
Dialogue: 0,0:09:14.41,0:09:20.08,Default,,0000,0000,0000,,break down this readily, then you are\Nbasically having a buildup of acetaldehyde
Dialogue: 0,0:09:20.08,0:09:21.06,Default,,0000,0000,0000,,in your system.
Dialogue: 0,0:09:21.28,0:09:26.18,Default,,0000,0000,0000,,So, let's look at the next slide,\Nand basically this is just showing you
Dialogue: 0,0:09:26.18,0:09:33.99,Default,,0000,0000,0000,,that you can have two set of this genes\Nthat work fine, then you should be able
Dialogue: 0,0:09:33.99,0:09:38.07,Default,,0000,0000,0000,,to break down your acetaldehyde\Nwithout a problem, but you could
Dialogue: 0,0:09:38.07,0:09:43.61,Default,,0000,0000,0000,,also have just one gene that is\Nworking properly and the other one
Dialogue: 0,0:09:43.61,0:09:47.72,Default,,0000,0000,0000,,in inactive form, then you'll get\Nsome flushing, but you might
Dialogue: 0,0:09:47.72,0:09:53.19,Default,,0000,0000,0000,,be able to tolerate alcohol okay,\Nand then you have subset of people
Dialogue: 0,0:09:53.19,0:09:58.68,Default,,0000,0000,0000,,who just totally have inactive form\Nof acetaldehyde dehydrogenase,
Dialogue: 0,0:09:58.68,0:10:04.31,Default,,0000,0000,0000,,then they are basically not able\Nto break down acetaldehyde further,
Dialogue: 0,0:10:04.31,0:10:08.69,Default,,0000,0000,0000,,and they will have severe reaction\Nto drinking alcohol.
Dialogue: 0,0:10:08.69,0:10:16.29,Default,,0000,0000,0000,,So, by utilizing or capitalizing\Non this mechanism, there is actually
Dialogue: 0,0:10:16.29,0:10:24.76,Default,,0000,0000,0000,,a drug treatment that taps into this, and\Nit's disulfiram, brand name is antabuse,
Dialogue: 0,0:10:24.76,0:10:32.59,Default,,0000,0000,0000,,and basically it artificially inhibits\Nthe acetaldehyde dehydrogenase activity.
Dialogue: 0,0:10:32.59,0:10:41.02,Default,,0000,0000,0000,,So, basically what it's doing is\Nit's inhibiting the enzyme to break down
Dialogue: 0,0:10:41.02,0:10:47.97,Default,,0000,0000,0000,,acetaldehyde. So, if you drink alcohol,\Nyou basically become extremely sick,
Dialogue: 0,0:10:47.97,0:10:54.04,Default,,0000,0000,0000,,and this is one treatment option for\Npeople who are addicted to alcohol, right?
Dialogue: 0,0:10:54.04,0:11:02.10,Default,,0000,0000,0000,,So, by basically literally making them\Nphysically sick when they drink alcohol,
Dialogue: 0,0:11:02.10,0:11:05.38,Default,,0000,0000,0000,,it is a deterrent for them\Nto abuse alcohol.
Dialogue: 0,0:11:05.38,0:11:10.40,Default,,0000,0000,0000,,Okay, let's talk about tolerance.
Dialogue: 0,0:11:10.40,0:11:16.10,Default,,0000,0000,0000,,You develop tolerance to alcohol through\Nevery mechanism that is known to us.
Dialogue: 0,0:11:16.10,0:11:20.60,Default,,0000,0000,0000,,So, when we were talking about\NIntro to Pharmacology, I told you about
Dialogue: 0,0:11:20.60,0:11:28.13,Default,,0000,0000,0000,,three mechanisms that can be responsible\Nfor tolerance development.
Dialogue: 0,0:11:28.13,0:11:33.69,Default,,0000,0000,0000,,So, number one is metabolic tolerance;\Nthe moment you take a certain drug,
Dialogue: 0,0:11:33.69,0:11:37.98,Default,,0000,0000,0000,,your body becomes really efficient\Nat getting rid of it, so that happens
Dialogue: 0,0:11:37.98,0:11:39.55,Default,,0000,0000,0000,,with alcohol.
Dialogue: 0,0:11:39.55,0:11:42.35,Default,,0000,0000,0000,,The other one is\Npharmacodynamic tolerance,
Dialogue: 0,0:11:42.35,0:11:45.73,Default,,0000,0000,0000,,or functional tolerance, basically,\Nthis is a tolerance that happens
Dialogue: 0,0:11:45.73,0:11:52.96,Default,,0000,0000,0000,,because of the action that happens\Nat the receptor side or the synaptic area,
Dialogue: 0,0:11:52.96,0:11:55.69,Default,,0000,0000,0000,,so it's at the molecular level.
Dialogue: 0,0:11:55.69,0:12:00.28,Default,,0000,0000,0000,,The other one is behavioral tolerance;\Nin fact, I used the drop
Dialogue: 0,0:12:00.28,0:12:06.62,Default,,0000,0000,0000,,in body temperature in response\Nto alcohol as an example to explain
Dialogue: 0,0:12:06.62,0:12:09.15,Default,,0000,0000,0000,,what behavioral tolerance is.
Dialogue: 0,0:12:09.15,0:12:16.38,Default,,0000,0000,0000,,Now, in addition to those three,\Nthere are two other tolerance phenomena
Dialogue: 0,0:12:16.38,0:12:18.39,Default,,0000,0000,0000,,that I need to talk about.
Dialogue: 0,0:12:18.39,0:12:22.21,Default,,0000,0000,0000,,One is acute tolerance, and this\Npretty much really only happens
Dialogue: 0,0:12:22.21,0:12:29.75,Default,,0000,0000,0000,,with alcohol, I think, and this happens\Nwithin the course of a single ingestion,
Dialogue: 0,0:12:29.75,0:12:34.16,Default,,0000,0000,0000,,or one episode of alcohol ingestion.\NAnd then what happens is,
Dialogue: 0,0:12:34.16,0:12:43.66,Default,,0000,0000,0000,,you develop tolerance, you sort of\Ndevelop -- You feel less affected
Dialogue: 0,0:12:43.66,0:12:48.61,Default,,0000,0000,0000,,by the alcohol as time goes on,\Nand that is completely independent
Dialogue: 0,0:12:48.61,0:12:53.26,Default,,0000,0000,0000,,of how much alcohol you have\Nin your blood system.
Dialogue: 0,0:12:53.26,0:12:59.60,Default,,0000,0000,0000,,So, look at the graph on the right.\NWhat that is showing you on the y-axis
Dialogue: 0,0:12:59.60,0:13:03.93,Default,,0000,0000,0000,,is blood-ethanol concentration,\Nso how much ethanol is still circulating
Dialogue: 0,0:13:03.93,0:13:07.79,Default,,0000,0000,0000,,through your body, and then\Nit shows ABCs,
Dialogue: 0,0:13:07.79,0:13:14.22,Default,,0000,0000,0000,,so it basically shows you three\Nconsecutive consumption of alcohol,
Dialogue: 0,0:13:14.22,0:13:21.91,Default,,0000,0000,0000,,and then as the subjects are sitting there\Nover six hour period, the researchers
Dialogue: 0,0:13:21.91,0:13:26.61,Default,,0000,0000,0000,,are asking them periodically,\N"Do you feel intoxicated?"
Dialogue: 0,0:13:26.61,0:13:30.16,Default,,0000,0000,0000,,And so, when they say,\N"I feel intoxicated,"
Dialogue: 0,0:13:30.16,0:13:34.44,Default,,0000,0000,0000,,they made a note, right?\NSo that's the time point between
Dialogue: 0,0:13:34.44,0:13:39.31,Default,,0000,0000,0000,,hour one and two, and then you just\Nkeep on asking them, "How do you feel?
Dialogue: 0,0:13:39.31,0:13:42.96,Default,,0000,0000,0000,,Do you feel intoxicated or\Ndo you feel sober enough?"
Dialogue: 0,0:13:42.96,0:13:47.91,Default,,0000,0000,0000,,and then they make a note.\NSo, when they said, "I feel sober,"
Dialogue: 0,0:13:47.91,0:13:52.46,Default,,0000,0000,0000,,they made a note, and that's\Nin hour six.
Dialogue: 0,0:13:52.46,0:13:59.26,Default,,0000,0000,0000,,So, from this subjective feeling,\Nthey are saying, "I feel intoxicated,"
Dialogue: 0,0:13:59.26,0:14:03.91,Default,,0000,0000,0000,,about 1.5 hours into this experiment,\Nand then at sixth hour,
Dialogue: 0,0:14:03.91,0:14:08.34,Default,,0000,0000,0000,,they feel totally fine,\N"I can go home, I can drive," right?
Dialogue: 0,0:14:08.34,0:14:13.55,Default,,0000,0000,0000,,But look at\Nthe blood-alcohol concentration.
Dialogue: 0,0:14:13.55,0:14:19.45,Default,,0000,0000,0000,,It is actually higher at sixth hour\Nwhen the subjects are saying
Dialogue: 0,0:14:19.45,0:14:26.92,Default,,0000,0000,0000,,they feel sober, and this an example\Nof how you can develop acute tolerance,
Dialogue: 0,0:14:26.92,0:14:33.90,Default,,0000,0000,0000,,so within a single sitting, basically,\Nindependent of what's happening
Dialogue: 0,0:14:33.90,0:14:41.88,Default,,0000,0000,0000,,at the physiological level, you develop\Ntolerance and you feel fine.
Dialogue: 0,0:14:41.88,0:14:46.51,Default,,0000,0000,0000,,Now, cross-tolerance is --\NSo, cross-tolerance will pop up
Dialogue: 0,0:14:46.51,0:14:51.23,Default,,0000,0000,0000,,in other substances to, and basically,\Nwhat that means is you actually
Dialogue: 0,0:14:51.23,0:14:57.65,Default,,0000,0000,0000,,develop tolerance to another drug\Nas a result of developing tolerance
Dialogue: 0,0:14:57.65,0:15:01.48,Default,,0000,0000,0000,,to the drug that you're\Ncurrently exposed to
Dialogue: 0,0:15:01.48,0:15:09.12,Default,,0000,0000,0000,,and it usually happens within or among\Ndrugs that share same mechanisms or
Dialogue: 0,0:15:09.12,0:15:16.47,Default,,0000,0000,0000,,they are under same category of drugs,\Nso if you develop tolerance to alcohol,
Dialogue: 0,0:15:16.47,0:15:22.20,Default,,0000,0000,0000,,the chances of you already having\Nsome tolerance to other sedatives
Dialogue: 0,0:15:22.20,0:15:26.73,Default,,0000,0000,0000,,or other CNS depressants\Nis pretty high, so things like
Dialogue: 0,0:15:26.73,0:15:31.55,Default,,0000,0000,0000,,benzodiazepines or barbiturates\Nthat all share same mechanisms,
Dialogue: 0,0:15:31.55,0:15:38.24,Default,,0000,0000,0000,,you will have already developed\Nsome tolerance, so the significance
Dialogue: 0,0:15:38.24,0:15:46.75,Default,,0000,0000,0000,,of this, or the practical outcome of this\Nis that, let's say, you have developed
Dialogue: 0,0:15:46.75,0:15:51.73,Default,,0000,0000,0000,,significant tolerance to alcohol,\Nand now you have to be prescribed
Dialogue: 0,0:15:51.73,0:15:56.04,Default,,0000,0000,0000,,some kind of medication this is\Nbenzodiazepine-based,
Dialogue: 0,0:15:56.04,0:16:04.72,Default,,0000,0000,0000,,you will likely have to adjust your dose\Nand probably increase the dose much higher
Dialogue: 0,0:16:04.72,0:16:11.14,Default,,0000,0000,0000,,than somebody who may not have developed\Nsignificant tolerance to alcohol.
Dialogue: 0,0:16:11.14,0:16:17.63,Default,,0000,0000,0000,,Okay, and then there is also\Nthis relationship between tolerance
Dialogue: 0,0:16:17.63,0:16:26.36,Default,,0000,0000,0000,,and withdrawal, so our body's always\Ntrying to maintain a homeostatic range,
Dialogue: 0,0:16:26.36,0:16:30.86,Default,,0000,0000,0000,,and if something happens to our body,\Nlet's say if there's sort of
Dialogue: 0,0:16:30.86,0:16:40.13,Default,,0000,0000,0000,,external event, external force that is\Nchanging how our body is currently in,
Dialogue: 0,0:16:40.13,0:16:50.15,Default,,0000,0000,0000,,the rest of the physiological mechanisms\Nwill try to compensate, and it will try
Dialogue: 0,0:16:50.15,0:16:52.96,Default,,0000,0000,0000,,to basically bring our body back\Nto the way it should be, so
Dialogue: 0,0:16:52.96,0:16:57.90,Default,,0000,0000,0000,,it's sort of counteracting whatever\Nexternal force is being exerted
Dialogue: 0,0:16:57.90,0:16:59.50,Default,,0000,0000,0000,,onto the body.
Dialogue: 0,0:16:59.50,0:17:01.56,Default,,0000,0000,0000,,So, let me walk you through this.
Dialogue: 0,0:17:01.56,0:17:05.26,Default,,0000,0000,0000,,So, we'll go through\Nin the sprial arrow way.
Dialogue: 0,0:17:05.26,0:17:09.63,Default,,0000,0000,0000,,So, we start with the initial state\Nwhere everything's well-balanced,
Dialogue: 0,0:17:09.63,0:17:14.50,Default,,0000,0000,0000,,and then we take alcohol,\Nwe ingest some alcohol.
Dialogue: 0,0:17:14.50,0:17:19.66,Default,,0000,0000,0000,,I told you it's a CNS depressant, so\Nyou see sort of this scale going down,
Dialogue: 0,0:17:19.66,0:17:28.66,Default,,0000,0000,0000,,simply just representing some\Nstate of over-CNS depression,
Dialogue: 0,0:17:28.66,0:17:36.31,Default,,0000,0000,0000,,so our body is going to try to compensate\Nthis by basically giving a little more
Dialogue: 0,0:17:36.31,0:17:42.17,Default,,0000,0000,0000,,excitation, putting up a little more\Nexcitability from your nervous system,
Dialogue: 0,0:17:42.17,0:17:46.29,Default,,0000,0000,0000,,so you go back to sort of this\Nhomeostatic range,
Dialogue: 0,0:17:46.29,0:17:50.15,Default,,0000,0000,0000,,and that is indicated here as\Na tolerant state.
Dialogue: 0,0:17:50.15,0:17:55.88,Default,,0000,0000,0000,,Now, at that point, if you take\Nthe drug out of your system,
Dialogue: 0,0:17:55.88,0:18:01.75,Default,,0000,0000,0000,,or if the alcohol leaves your system,\Nwhat you will end up is,
Dialogue: 0,0:18:01.75,0:18:06.92,Default,,0000,0000,0000,,you have this over-excited nervous system\Nthat was trying to compensate
Dialogue: 0,0:18:06.92,0:18:12.43,Default,,0000,0000,0000,,for the presence of alcohol, so now\Nthe scale tips the other way, so that
Dialogue: 0,0:18:12.43,0:18:20.76,Default,,0000,0000,0000,,the excitation, or over-excitation,\Nof your nervous system is the state
Dialogue: 0,0:18:20.76,0:18:24.11,Default,,0000,0000,0000,,that you are in.
Dialogue: 0,0:18:24.11,0:18:27.64,Default,,0000,0000,0000,,That's one of the reasons\Nwhy you have hangover.
Dialogue: 0,0:18:27.64,0:18:32.88,Default,,0000,0000,0000,,If you've consumed significant amount\Nof alcohol the night before --
Dialogue: 0,0:18:32.88,0:18:37.67,Default,,0000,0000,0000,,some of you have had this experience\Nthe next day --
Dialogue: 0,0:18:37.67,0:18:44.56,Default,,0000,0000,0000,,you feel pretty lousy, right, and it takes\Na while for you to feel, come back
Dialogue: 0,0:18:44.56,0:18:48.68,Default,,0000,0000,0000,,to normal state, and so that takes\Na little while, but eventually,
Dialogue: 0,0:18:48.68,0:18:50.93,Default,,0000,0000,0000,,we'll come back to normal state.
Dialogue: 0,0:18:50.93,0:18:58.80,Default,,0000,0000,0000,,Now, that happens even at, even when\Nyou're not addicted to something.
Dialogue: 0,0:18:58.80,0:19:02.70,Default,,0000,0000,0000,,So, I know this graph is kind of\Ntalking about it in terms of
Dialogue: 0,0:19:02.70,0:19:08.87,Default,,0000,0000,0000,,if you are dependent on certain drugs,\Nbut even if you are not dependent
Dialogue: 0,0:19:08.87,0:19:13.52,Default,,0000,0000,0000,,on something, this type of balancing\Nand counteracting whatever
Dialogue: 0,0:19:13.52,0:19:18.01,Default,,0000,0000,0000,,is in our body happens, but you can\Nimagine this happening in
Dialogue: 0,0:19:18.01,0:19:21.100,Default,,0000,0000,0000,,more severe cases when you are\Ndependent on it, right,
Dialogue: 0,0:19:21.100,0:19:28.37,Default,,0000,0000,0000,,and that your body is not actually\Nable to overcome this over-excitation
Dialogue: 0,0:19:28.37,0:19:34.97,Default,,0000,0000,0000,,without the presence of alcohol,\Nso then you get this really severe
Dialogue: 0,0:19:34.97,0:19:41.37,Default,,0000,0000,0000,,withdrawal symptoms, and the only way\Nfor you to really come back
Dialogue: 0,0:19:41.37,0:19:46.89,Default,,0000,0000,0000,,to normal state at that point is\Nto consume alcohol again,
Dialogue: 0,0:19:46.89,0:19:52.89,Default,,0000,0000,0000,,which then will bring the balance\Nback into the homeostatic range.
Dialogue: 0,0:19:52.89,0:20:01.36,Default,,0000,0000,0000,,Okay, so, in the next slide,\NI don't really need you to remember
Dialogue: 0,0:20:01.36,0:20:07.30,Default,,0000,0000,0000,,any of this, i think, but this is just\Nto highlight what happens when you're
Dialogue: 0,0:20:07.30,0:20:13.49,Default,,0000,0000,0000,,going through this withdrawal state\Nafter chronic alcohol abuse.
Dialogue: 0,0:20:13.49,0:20:18.71,Default,,0000,0000,0000,,So, if you're trying to go cold-turkey,\Nand you --
Dialogue: 0,0:20:18.71,0:20:24.26,Default,,0000,0000,0000,,So, this particular study was done\Nwith people who have been consuming
Dialogue: 0,0:20:24.26,0:20:30.40,Default,,0000,0000,0000,,10 to 15 drinks per day over 10 days,\Nso it's actually a significant amount
Dialogue: 0,0:20:30.40,0:20:31.42,Default,,0000,0000,0000,,of drinking.
Dialogue: 0,0:20:31.42,0:20:39.01,Default,,0000,0000,0000,,I actually figured out that a bottle\Nof wine contains about 5 drinks,
Dialogue: 0,0:20:39.01,0:20:42.46,Default,,0000,0000,0000,,so that would be like drinking\N2 to 3 bottles of wine everyday
Dialogue: 0,0:20:42.46,0:20:45.46,Default,,0000,0000,0000,,for 10 days, so that's a lot of drinking.
Dialogue: 0,0:20:45.46,0:20:52.19,Default,,0000,0000,0000,,And then they've monitored people\Nas they come out of this state,
Dialogue: 0,0:20:52.19,0:20:57.83,Default,,0000,0000,0000,,so at the end of 10 days, this is\Nwhat they were observing as people
Dialogue: 0,0:20:57.83,0:20:59.95,Default,,0000,0000,0000,,are going through withdrawal state.
Dialogue: 0,0:21:00.58,0:21:05.61,Default,,0000,0000,0000,,We start with just being anxious,\Nagitated, and then you start having
Dialogue: 0,0:21:05.61,0:21:10.20,Default,,0000,0000,0000,,some sleeping issues, but then\Nyou also start having actual
Dialogue: 0,0:21:10.20,0:21:16.88,Default,,0000,0000,0000,,motor issues, so there might be tremor,\Nand then it starts to affect
Dialogue: 0,0:21:16.88,0:21:22.64,Default,,0000,0000,0000,,your cognition, so you could be\Ndisoriented, sometimes you actually have
Dialogue: 0,0:21:22.64,0:21:30.88,Default,,0000,0000,0000,,seizure episodes, you have convulsion,\Nand then the really final stage,
Dialogue: 0,0:21:30.88,0:21:37.19,Default,,0000,0000,0000,,here it is noted as delirium tremens,\Nand the reason that I have a bunch of
Dialogue: 0,0:21:37.19,0:21:42.83,Default,,0000,0000,0000,,pink elephant on the left is because\Na long time ago, somebody who was
Dialogue: 0,0:21:42.83,0:21:47.47,Default,,0000,0000,0000,,going through this withdrawal state\Nwas writing down all the things
Dialogue: 0,0:21:47.47,0:21:51.73,Default,,0000,0000,0000,,that were happening to him,\Nand he was hallucinating pink elephant
Dialogue: 0,0:21:51.73,0:21:55.96,Default,,0000,0000,0000,,in the room, so there's really\Nnothing cute about pink elephant.
Dialogue: 0,0:21:55.96,0:22:02.65,Default,,0000,0000,0000,,It kind of symbolizes this\Nsevere withdrawal from alcohol.
Dialogue: 0,0:22:02.65,0:22:10.41,Default,,0000,0000,0000,,And if not done properly, you can actually\Ndie from some of these convulsions
Dialogue: 0,0:22:10.41,0:22:12.14,Default,,0000,0000,0000,,and some side effects.
Dialogue: 0,0:22:12.14,0:22:19.61,Default,,0000,0000,0000,,With chronic alcohol abuse, you can also\Nactually have brain damage.
Dialogue: 0,0:22:19.61,0:22:25.83,Default,,0000,0000,0000,,So, in this slide, you will see\Non coronal sections of
Dialogue: 0,0:22:25.83,0:22:30.90,Default,,0000,0000,0000,,actual brain imaging, so the picture\Non the left is taken from somebody
Dialogue: 0,0:22:30.90,0:22:35.88,Default,,0000,0000,0000,,who has been abusing alcohol\Nfor a long time,
Dialogue: 0,0:22:35.88,0:22:39.44,Default,,0000,0000,0000,,and the right is a control brain, right,\Nand then the pictures below
Dialogue: 0,0:22:39.44,0:22:49.65,Default,,0000,0000,0000,,are basically 3D image of these\Nactual human, actual imaging,
Dialogue: 0,0:22:49.65,0:22:54.57,Default,,0000,0000,0000,,and they've costructed what the cortex\Nbasically looks like, and you see
Dialogue: 0,0:22:54.57,0:23:02.07,Default,,0000,0000,0000,,a lot of atrophy, or basically reduction\Nin brain mass in this person
Dialogue: 0,0:23:02.07,0:23:05.12,Default,,0000,0000,0000,,who's been abusing alcohol\Nfor a long time.
Dialogue: 0,0:23:05.12,0:23:07.32,Default,,0000,0000,0000,,So that can actually happen.
Dialogue: 0,0:23:07.32,0:23:11.41,Default,,0000,0000,0000,,And it can happen because of\Nvarious factors:
Dialogue: 0,0:23:11.41,0:23:14.92,Default,,0000,0000,0000,,the alccohol itself, \Nthe elevated acetaldehyde
Dialogue: 0,0:23:14.92,0:23:22.46,Default,,0000,0000,0000,,that I said was highly toxic,\Nalso liver -- I'm not talking about
Dialogue: 0,0:23:22.46,0:23:26.59,Default,,0000,0000,0000,,liver issues here, but the liver\Nis getting hit really hard,
Dialogue: 0,0:23:26.59,0:23:33.67,Default,,0000,0000,0000,,and oftentimes people who abuse alcohol\Nalso really don't eat properly,
Dialogue: 0,0:23:33.67,0:23:42.21,Default,,0000,0000,0000,,so that's another huge factor, in fact,\Nthere is actually a brain disease
Dialogue: 0,0:23:42.21,0:23:47.81,Default,,0000,0000,0000,,called Korsakoff syndrome, and\Nthe actual cause of Korsakoff syndrome
Dialogue: 0,0:23:47.81,0:23:55.02,Default,,0000,0000,0000,,is deficiency of thiamine, vitamin B_1,\Nbut at least in United States,
Dialogue: 0,0:23:55.02,0:24:01.08,Default,,0000,0000,0000,,the main cause of Korsakoff syndrome\Nis alcohol abuse, and that's partly
Dialogue: 0,0:24:01.08,0:24:06.56,Default,,0000,0000,0000,,because for some reason, alcohol\Nactually prevents the,
Dialogue: 0,0:24:06.56,0:24:13.77,Default,,0000,0000,0000,,or at least impairs the body\Nto fully use thiamine as a nutrient,
Dialogue: 0,0:24:13.77,0:24:18.28,Default,,0000,0000,0000,,but also because people don't\Neat properly, so they have an
Dialogue: 0,0:24:18.28,0:24:25.99,Default,,0000,0000,0000,,over-inadequate nutrition, and if you\Nhave very low thiamine, it can actually
Dialogue: 0,0:24:25.99,0:24:31.61,Default,,0000,0000,0000,,start affecting your nervous system\Nand various other things,
Dialogue: 0,0:24:31.61,0:24:38.98,Default,,0000,0000,0000,,and it can actually show up as a,\Ninitially, some confusion, disorientation,
Dialogue: 0,0:24:38.98,0:24:44.63,Default,,0000,0000,0000,,but eventually it will progress\Nto memory loss and cognitive deficit.
Dialogue: 0,0:24:44.63,0:24:53.07,Default,,0000,0000,0000,,Okay, there's also fetal alcohol syndrome,\Nand that's when the pregnant woman
Dialogue: 0,0:24:53.07,0:24:58.32,Default,,0000,0000,0000,,is exposed to high levels of alcohol,\Nand that's because the alcohol
Dialogue: 0,0:24:58.32,0:25:07.16,Default,,0000,0000,0000,,can cross placenta really readily,\Nand this actually, especially if
Dialogue: 0,0:25:07.16,0:25:13.10,Default,,0000,0000,0000,,the pregnant woman is exposed\Nto alcohol at early stage of pregnancy,
Dialogue: 0,0:25:13.10,0:25:18.46,Default,,0000,0000,0000,,so somewhere between four and nine weeks\Nof pregnancy, that's when it affects
Dialogue: 0,0:25:18.46,0:25:22.57,Default,,0000,0000,0000,,the fetus the most.
Dialogue: 0,0:25:22.57,0:25:28.33,Default,,0000,0000,0000,,And the problem with this is,\Nor the really sad thing about this
Dialogue: 0,0:25:28.33,0:25:32.62,Default,,0000,0000,0000,,is that most women do not know\Nthat they are pregnant during that time,
Dialogue: 0,0:25:32.62,0:25:38.65,Default,,0000,0000,0000,,so if you have someone who already\Nabuses alcohol quite a bit or
Dialogue: 0,0:25:38.65,0:25:44.03,Default,,0000,0000,0000,,who drinks alcohol quite a bit,\Nby the time they realize that they
Dialogue: 0,0:25:44.03,0:25:50.27,Default,,0000,0000,0000,,are pregnant, it might be already too late\Nin terms of how much alcohol has affected
Dialogue: 0,0:25:50.27,0:25:59.82,Default,,0000,0000,0000,,the fetus, and there are all these other\Nsymptoms including: low birth rate,
Dialogue: 0,0:25:59.82,0:26:05.94,Default,,0000,0000,0000,,physical abnormalities, and also\Nincluding the brain function.
Dialogue: 0,0:26:05.94,0:26:11.89,Default,,0000,0000,0000,,So, and then, one of the unique things\Nis that it also affects the formation
Dialogue: 0,0:26:11.89,0:26:18.80,Default,,0000,0000,0000,,of their face or cranial facial formation,\Nso let's look at the next picture.
Dialogue: 0,0:26:18.80,0:26:29.46,Default,,0000,0000,0000,,So, that's sort of a -- the top left\Npicture is a typical, I guess,
Dialogue: 0,0:26:29.46,0:26:36.99,Default,,0000,0000,0000,,formation that you see in a child\Nwho has fetal alcohol syndrome,
Dialogue: 0,0:26:36.99,0:26:42.99,Default,,0000,0000,0000,,and the picture below is actually\Na animal model that tries
Dialogue: 0,0:26:42.99,0:26:48.13,Default,,0000,0000,0000,,to copy or mimic this\Nfetal alcohol syndrome
Dialogue: 0,0:26:48.13,0:26:54.12,Default,,0000,0000,0000,,so that we can study what is going on\Nin the nervous system, and the animals
Dialogue: 0,0:26:54.12,0:27:04.04,Default,,0000,0000,0000,,also show similar facial formation\Nas human, and then one thing
Dialogue: 0,0:27:04.04,0:27:07.61,Default,,0000,0000,0000,,I just want to point out,\Nat least in this model,
Dialogue: 0,0:27:07.61,0:27:12.76,Default,,0000,0000,0000,,you see that there's a complete\Nelimination of olfactory bulb
Dialogue: 0,0:27:12.76,0:27:17.18,Default,,0000,0000,0000,,which is shown by the arrow,\Nand then the overall cortex
Dialogue: 0,0:27:17.18,0:27:20.21,Default,,0000,0000,0000,,seems to be a little smaller too.
Dialogue: 0,0:27:20.21,0:27:26.14,Default,,0000,0000,0000,,On the right side, we have some\Nbrain scans of individual kids,
Dialogue: 0,0:27:26.14,0:27:31.34,Default,,0000,0000,0000,,the number represents the age,\Nand M or F represents
Dialogue: 0,0:27:31.34,0:27:36.88,Default,,0000,0000,0000,,male or female; the very top row\Nis a kid who doesn't have
Dialogue: 0,0:27:36.88,0:27:41.02,Default,,0000,0000,0000,,fetal alcohol syndrome, so that's\Nwhat it's supposed to look like,
Dialogue: 0,0:27:41.02,0:27:46.04,Default,,0000,0000,0000,,and then the three subjects\Nhave varying degree
Dialogue: 0,0:27:46.04,0:27:48.24,Default,,0000,0000,0000,,of fetal alcohol syndrome.
Dialogue: 0,0:27:48.24,0:27:52.19,Default,,0000,0000,0000,,And one thing that I just\Nwant you to take away from this
Dialogue: 0,0:27:52.19,0:27:57.44,Default,,0000,0000,0000,,is that we can't really say,\NIf you have fetal alcohol syndrome,
Dialogue: 0,0:27:57.44,0:28:00.76,Default,,0000,0000,0000,,"these are the brain structures\Nthat are affected, and this is
Dialogue: 0,0:28:00.76,0:28:05.68,Default,,0000,0000,0000,,how the outcome is going to be."\NThere seems to a lot of variations
Dialogue: 0,0:28:05.68,0:28:08.86,Default,,0000,0000,0000,,and kids are affected differently.
Dialogue: 0,0:28:08.86,0:28:13.71,Default,,0000,0000,0000,,The one example being, if you look at\Nthe brain with red arrow, there is
Dialogue: 0,0:28:13.71,0:28:19.29,Default,,0000,0000,0000,,sort of an abnormal formation\Nof corpus callosum;
Dialogue: 0,0:28:19.29,0:28:24.05,Default,,0000,0000,0000,,corpus callosum is the white fiber that\Nconnects the left and right hemispheres,
Dialogue: 0,0:28:24.05,0:28:34.60,Default,,0000,0000,0000,,and it looks like a C that's been rotated\N90 degree highlighted with white color,
Dialogue: 0,0:28:34.60,0:28:38.44,Default,,0000,0000,0000,,but if you look at the brain\Nall the way at the bottom,
Dialogue: 0,0:28:38.44,0:28:44.39,Default,,0000,0000,0000,,pointed by the yellow arrow,\Nyou see shrinkage of cerebellum,
Dialogue: 0,0:28:44.39,0:28:52.64,Default,,0000,0000,0000,,so again, effect of alcohol on fetus\Nseems to vary quite a bit.
Dialogue: 0,0:28:52.64,0:28:59.20,Default,,0000,0000,0000,,Okay, there is also some\Nbeneficial effect of alcohol.
Dialogue: 0,0:28:59.20,0:29:04.13,Default,,0000,0000,0000,,It generally seems to apply\Nto older people,
Dialogue: 0,0:29:04.13,0:29:09.80,Default,,0000,0000,0000,,and one of the reason that\Nit might be beneficial
Dialogue: 0,0:29:09.80,0:29:14.92,Default,,0000,0000,0000,,is that it can work as vasodilation,\Nor dilator.
Dialogue: 0,0:29:14.92,0:29:20.56,Default,,0000,0000,0000,,So, basically, the idea is that it allows\Nthe blood to flow a little better,
Dialogue: 0,0:29:20.56,0:29:25.19,Default,,0000,0000,0000,,and that can actually help some\Ncognitive function or even
Dialogue: 0,0:29:25.19,0:29:31.73,Default,,0000,0000,0000,,vascular function in some older adults,\Nbut we're talking very moderate amount
Dialogue: 0,0:29:31.73,0:29:34.64,Default,,0000,0000,0000,,of alcohol drinking.
Dialogue: 0,0:29:36.42,0:29:39.62,Default,,0000,0000,0000,,Okay, I think that's all I want to say\Non this slide.
Dialogue: 0,0:29:39.62,0:29:44.63,Default,,0000,0000,0000,,So, ah, okay, so, if you need\Nto take a break, now is
Dialogue: 0,0:29:44.63,0:29:47.92,Default,,0000,0000,0000,,a good time to take a break,\Nbecause now we are going to dive
Dialogue: 0,0:29:47.92,0:29:53.95,Default,,0000,0000,0000,,into the neurochemical effects\Nof alcohol, and I'm going to talk about
Dialogue: 0,0:29:53.95,0:29:59.18,Default,,0000,0000,0000,,various neurotransmitters that\Nthe alcohol influences.
Dialogue: 0,0:29:59.18,0:30:06.02,Default,,0000,0000,0000,,Okay, so, alcohol influences\Na lot of neurotransmitters,
Dialogue: 0,0:30:06.02,0:30:09.14,Default,,0000,0000,0000,,or neurotransmitter systems.
Dialogue: 0,0:30:09.14,0:30:15.48,Default,,0000,0000,0000,,This particular picture separates\Nwhat's considered to be non-specific
Dialogue: 0,0:30:15.48,0:30:19.13,Default,,0000,0000,0000,,alcohol effect and\Nspecific alcohol effect.
Dialogue: 0,0:30:19.13,0:30:24.42,Default,,0000,0000,0000,,The nonspecific alcohol effects are\Nbasically how the alcohol can disrupt
Dialogue: 0,0:30:24.42,0:30:28.49,Default,,0000,0000,0000,,your cell membranes, including\Nblood-brain barriers,
Dialogue: 0,0:30:28.49,0:30:33.49,Default,,0000,0000,0000,,and because the alcohol can diffuse\Nthrough these cell membranes,
Dialogue: 0,0:30:33.49,0:30:40.28,Default,,0000,0000,0000,,sometimes repeated exposure or\Nheavy exposure to heavy concentration
Dialogue: 0,0:30:40.28,0:30:44.61,Default,,0000,0000,0000,,of alcohol can mess up with\Nthe structural integrity
Dialogue: 0,0:30:44.61,0:30:49.41,Default,,0000,0000,0000,,of the membrane, but I'm really\Nnot going to talk about that.
Dialogue: 0,0:30:49.41,0:30:52.64,Default,,0000,0000,0000,,I'm going to talk about\Nwhat's consider specific effects,
Dialogue: 0,0:30:52.64,0:30:57.56,Default,,0000,0000,0000,,meaning how the alcohol targets\Ndifferent receptors and different
Dialogue: 0,0:30:57.56,0:31:00.35,Default,,0000,0000,0000,,neurotransmission.
Dialogue: 0,0:31:00.35,0:31:06.17,Default,,0000,0000,0000,,The alcohol works as glutamate antagonist;\Nif you are exposed to it for
Dialogue: 0,0:31:06.17,0:31:11.18,Default,,0000,0000,0000,,the first time or if you're not\Nreally abusing it.
Dialogue: 0,0:31:11.18,0:31:16.56,Default,,0000,0000,0000,,So, it will block especially\NNMDA receptors, so we talked
Dialogue: 0,0:31:16.56,0:31:22.93,Default,,0000,0000,0000,,about NMDA receptors being different\Nfrom the other ionotropic receptors,
Dialogue: 0,0:31:22.93,0:31:26.83,Default,,0000,0000,0000,,such as AMPA and Kainate,\Nso it primarily works
Dialogue: 0,0:31:26.83,0:31:34.01,Default,,0000,0000,0000,,as an NMDA antagonist, but\Nif you are repeatedly exposed to alcohol,
Dialogue: 0,0:31:34.01,0:31:39.64,Default,,0000,0000,0000,,basically, if you abuse alcohol,\Nthere's going to be some up-regulation
Dialogue: 0,0:31:39.64,0:31:44.18,Default,,0000,0000,0000,,of NMDA receptors, and I think\NI've told you this at some point,
Dialogue: 0,0:31:44.18,0:31:45.81,Default,,0000,0000,0000,,that's what our body does.
Dialogue: 0,0:31:45.81,0:31:50.44,Default,,0000,0000,0000,,Let's say, if you are bombarding\Nthe synaptic area with
Dialogue: 0,0:31:50.44,0:31:55.65,Default,,0000,0000,0000,,some sort of agonists, the receptors\Nare going to try to down-regulate,
Dialogue: 0,0:31:55.65,0:32:01.53,Default,,0000,0000,0000,,basically not respond to the agonist\Nas much, and the opposite happens too.
Dialogue: 0,0:32:01.53,0:32:07.46,Default,,0000,0000,0000,,If you bombard the synaptic area with\Nsome kind of antagonist, then
Dialogue: 0,0:32:07.46,0:32:12.96,Default,,0000,0000,0000,,the receptor is going to try to maximize\Nwhatever's around, so that it can respond.
Dialogue: 0,0:32:12.96,0:32:18.80,Default,,0000,0000,0000,,So, basically, that's what you're seeing.\NBecause alcohol inhibits an NMDA receptor,
Dialogue: 0,0:32:18.80,0:32:24.54,Default,,0000,0000,0000,,if you do that continuously\Nor over a regular time,
Dialogue: 0,0:32:24.54,0:32:29.76,Default,,0000,0000,0000,,what the NMDA receptors are going to do\Nis up-regulate now.
Dialogue: 0,0:32:29.76,0:32:35.85,Default,,0000,0000,0000,,That's okay if you have alcohol\Nin the system, you are still maintaining
Dialogue: 0,0:32:35.85,0:32:38.35,Default,,0000,0000,0000,,some homeostatic state.
Dialogue: 0,0:32:38.35,0:32:42.17,Default,,0000,0000,0000,,But imagine what happens if\Nyou try to go cold-turkey, right?
Dialogue: 0,0:32:42.17,0:32:47.16,Default,,0000,0000,0000,,So you have been abusing alcohol,\Nwhich means you pretty much
Dialogue: 0,0:32:47.16,0:32:52.88,Default,,0000,0000,0000,,have alcohol on board almost\Nall the time, now if you try
Dialogue: 0,0:32:52.88,0:32:57.12,Default,,0000,0000,0000,,to stop drinking, all of the sudden,\Nyou have all this up-regulated
Dialogue: 0,0:32:57.12,0:33:03.02,Default,,0000,0000,0000,,NMDA receptors, and what is it\Ngoing to do, even just regular functioning
Dialogue: 0,0:33:03.02,0:33:08.51,Default,,0000,0000,0000,,whenever there's some glutamate released\Nis going to respond to glutamate
Dialogue: 0,0:33:08.51,0:33:14.30,Default,,0000,0000,0000,,a lot better and more efficiently\Nthan they need to in a regular system.
Dialogue: 0,0:33:14.30,0:33:19.27,Default,,0000,0000,0000,,And that's how you could end up with\Nhyper-excitability of your nervous system,
Dialogue: 0,0:33:19.27,0:33:24.88,Default,,0000,0000,0000,,your brain, which then can cause seizures,\Nbecause you have too much excitation
Dialogue: 0,0:33:24.88,0:33:30.25,Default,,0000,0000,0000,,going on, and the unique thing\Nabout NMDA receptors is that
Dialogue: 0,0:33:30.25,0:33:35.81,Default,,0000,0000,0000,,it can let it calcium ions\Nas well as sodium ions, right,
Dialogue: 0,0:33:35.81,0:33:41.92,Default,,0000,0000,0000,,and I told you very early on that\Nas much as calcium is important
Dialogue: 0,0:33:41.92,0:33:47.23,Default,,0000,0000,0000,,for our regular cell-signaling,\Ntoo much of it is very, very toxic
Dialogue: 0,0:33:47.23,0:33:52.02,Default,,0000,0000,0000,,for our cells, so if you have\Na lot of calcium coming into the cells,
Dialogue: 0,0:33:52.02,0:33:54.70,Default,,0000,0000,0000,,you can also cause cell death.
Dialogue: 0,0:33:54.70,0:33:59.93,Default,,0000,0000,0000,,That can also be responsible\Nsome of the brain damage that you see
Dialogue: 0,0:33:59.93,0:34:02.55,Default,,0000,0000,0000,,in people who abuse alcohol.
Dialogue: 0,0:34:02.55,0:34:09.02,Default,,0000,0000,0000,,Okay, this is an example of\Nbasically what I just said,
Dialogue: 0,0:34:09.02,0:34:13.05,Default,,0000,0000,0000,,so it's an evidence, so you will\Nbelieve me or you know
Dialogue: 0,0:34:13.05,0:34:18.16,Default,,0000,0000,0000,,I'm not just making this up,\Nso this is -- They measured
Dialogue: 0,0:34:18.16,0:34:22.67,Default,,0000,0000,0000,,over dopamine output\Nor dopamine level or release
Dialogue: 0,0:34:22.67,0:34:25.88,Default,,0000,0000,0000,,in the striatum in animals\Nthat are going through,
Dialogue: 0,0:34:25.88,0:34:27.83,Default,,0000,0000,0000,,currently going through withdrawal.
Dialogue: 0,0:34:27.83,0:34:33.29,Default,,0000,0000,0000,,So, these rats have been exposed\Nto a lot of alcohol, to the point
Dialogue: 0,0:34:33.29,0:34:39.99,Default,,0000,0000,0000,,where now their body is dependent on it,\Nand then they stop receiving alcohol.
Dialogue: 0,0:34:39.99,0:34:45.12,Default,,0000,0000,0000,,So, let's look at the graph\Non the top left with the line graphs,
Dialogue: 0,0:34:45.12,0:34:50.65,Default,,0000,0000,0000,,and that is showing you\Nover glutamate release, or output.
Dialogue: 0,0:34:50.65,0:34:56.87,Default,,0000,0000,0000,,And basically, there are some\Nother groups, but what you want
Dialogue: 0,0:34:56.87,0:35:01.80,Default,,0000,0000,0000,,to note is the graph that is,\Nthe line graph that's going high,
Dialogue: 0,0:35:01.80,0:35:05.79,Default,,0000,0000,0000,,basically, that's the glutamate level\Nthat you get from animals
Dialogue: 0,0:35:05.79,0:35:09.66,Default,,0000,0000,0000,,that are going through\Nthe withdrawal right now.
Dialogue: 0,0:35:09.66,0:35:15.88,Default,,0000,0000,0000,,And then the bottom bar graph is showing\Nyou over withdrawal severity,
Dialogue: 0,0:35:15.88,0:35:22.32,Default,,0000,0000,0000,,so the experimenters, there are\Nvarious behavior measures
Dialogue: 0,0:35:22.32,0:35:28.43,Default,,0000,0000,0000,,that you can do to see how severe\Nthe withdrawal is for the animals,
Dialogue: 0,0:35:28.43,0:35:34.34,Default,,0000,0000,0000,,and basically, you are looking at\Ntime dependent withdrawal being,
Dialogue: 0,0:35:34.34,0:35:39.20,Default,,0000,0000,0000,,and that basically lines up with\Nthe level of glutamate you see,
Dialogue: 0,0:35:39.20,0:35:46.06,Default,,0000,0000,0000,,so around 12 hour time, from the time\Nof stopped receiving alcohol,
Dialogue: 0,0:35:46.06,0:35:51.16,Default,,0000,0000,0000,,you get most severe withdrawal output,\Nand that's also when you see
Dialogue: 0,0:35:51.16,0:35:57.35,Default,,0000,0000,0000,,very high level of glutamate increase\Nin the striatum.
Dialogue: 0,0:35:57.35,0:36:01.92,Default,,0000,0000,0000,,And then finally, the graph in the middle\Nis just showing you the correlation,
Dialogue: 0,0:36:01.92,0:36:07.16,Default,,0000,0000,0000,,so the y-axis is showing you\Nover withdrawal score
Dialogue: 0,0:36:07.16,0:36:11.43,Default,,0000,0000,0000,,and the x-axis are showing you\Nover glutamate output,
Dialogue: 0,0:36:11.43,0:36:16.80,Default,,0000,0000,0000,,and so these are individual data point,\Nso if the animal didn't show a lot of
Dialogue: 0,0:36:16.80,0:36:23.22,Default,,0000,0000,0000,,withdrawal score, you also see that they\Ndidn't have a lot of glutamate output.
Dialogue: 0,0:36:23.22,0:36:28.44,Default,,0000,0000,0000,,The animals that showed really severe\Nwithdrawal symptoms also had
Dialogue: 0,0:36:28.44,0:36:33.68,Default,,0000,0000,0000,,very high levels of glutamate output,\Nso this is one piece of evidence
Dialogue: 0,0:36:33.68,0:36:38.04,Default,,0000,0000,0000,,that supports that this increase\Nin glutamate output might
Dialogue: 0,0:36:38.04,0:36:41.88,Default,,0000,0000,0000,,be responsible for some of\Nthe withdrawal symptoms
Dialogue: 0,0:36:41.88,0:36:44.33,Default,,0000,0000,0000,,that people experience.
Dialogue: 0,0:36:44.33,0:36:47.58,Default,,0000,0000,0000,,So, let's finally talk about GABA.
Dialogue: 0,0:36:49.32,0:36:54.33,Default,,0000,0000,0000,,Just like how alcohol influences\Nglutamate, sort of at the initial state
Dialogue: 0,0:36:54.33,0:36:59.40,Default,,0000,0000,0000,,versus over repeated use,\Nsomething similar happens to GABA.
Dialogue: 0,0:36:59.40,0:37:08.74,Default,,0000,0000,0000,,First, alcohol is a non-competitive \NGABA agonists, so the presence of alcohol
Dialogue: 0,0:37:08.74,0:37:14.64,Default,,0000,0000,0000,,will increase the function of GABA,\Nand that's why it is CNS depressant,
Dialogue: 0,0:37:14.64,0:37:20.49,Default,,0000,0000,0000,,because GABA is the major inhibitory\Nneurotransmitter, so when you engage
Dialogue: 0,0:37:20.49,0:37:26.85,Default,,0000,0000,0000,,in GABA system, you basically let\Nchloride ions go in, which causes
Dialogue: 0,0:37:26.85,0:37:31.94,Default,,0000,0000,0000,,hypopolarization, right, and that's how\Nyou end up with inhibitory output.
Dialogue: 0,0:37:31.94,0:37:39.24,Default,,0000,0000,0000,,So, basically, what alcohol does\Nis it enhances the flow of chloride ion
Dialogue: 0,0:37:39.24,0:37:42.87,Default,,0000,0000,0000,,into the post-synaptic cell,\Nso you are helping the GABA
Dialogue: 0,0:37:42.87,0:37:49.65,Default,,0000,0000,0000,,do its job better, but again, if you are\Nexposed to alcohol over and over,
Dialogue: 0,0:37:49.65,0:37:54.80,Default,,0000,0000,0000,,or if the alcohol is in the system\Nover and over, what will happen is
Dialogue: 0,0:37:54.80,0:38:03.90,Default,,0000,0000,0000,,the GABA is going to try to down-regulate\Nits function, so you go from having
Dialogue: 0,0:38:03.90,0:38:10.100,Default,,0000,0000,0000,,this enhanced GABA function over\Nthe influx of chloride to basically
Dialogue: 0,0:38:10.100,0:38:18.38,Default,,0000,0000,0000,,reducing the chloride inflow further from\Neven the baseline, so you reduce
Dialogue: 0,0:38:18.38,0:38:20.50,Default,,0000,0000,0000,,the GABA function.
Dialogue: 0,0:38:20.50,0:38:25.32,Default,,0000,0000,0000,,And think about what will happen\Nif you have an over-reduction
Dialogue: 0,0:38:25.32,0:38:33.22,Default,,0000,0000,0000,,in inhibitory mechanism, you are basically\Nallowing your nervous system's
Dialogue: 0,0:38:33.22,0:38:37.61,Default,,0000,0000,0000,,excitatory output to go without\Nproper check, right?
Dialogue: 0,0:38:37.61,0:38:41.08,Default,,0000,0000,0000,,When we are talking about\Nglutamate and GABA,
Dialogue: 0,0:38:41.08,0:38:45.10,Default,,0000,0000,0000,,I said you need to have sort of \Nthis ying and yang of excitation
Dialogue: 0,0:38:45.10,0:38:47.37,Default,,0000,0000,0000,,and inhibition being in check.
Dialogue: 0,0:38:47.37,0:38:53.10,Default,,0000,0000,0000,,Now, with repeated exposure\Nto alcohol, you basically have
Dialogue: 0,0:38:53.10,0:38:57.36,Default,,0000,0000,0000,,malfunctioning inhibitory mechanism.
Dialogue: 0,0:38:57.36,0:39:01.24,Default,,0000,0000,0000,,And then in the previous slide when\NI was talking about glutamate
Dialogue: 0,0:39:01.24,0:39:07.31,Default,,0000,0000,0000,,I said, independent of this GABA\Nfunction alcohol can also basically
Dialogue: 0,0:39:07.31,0:39:11.26,Default,,0000,0000,0000,,increase glutamate activity \Nso you have sort of this
Dialogue: 0,0:39:11.26,0:39:15.60,Default,,0000,0000,0000,,two really bad situation\Noccurring at the same time.
Dialogue: 0,0:39:15.60,0:39:19.19,Default,,0000,0000,0000,,You are enhancing this excitation\Nof the nervous system
Dialogue: 0,0:39:19.19,0:39:23.64,Default,,0000,0000,0000,,while you are inhibiting \Nthe inhibition system.
Dialogue: 0,0:39:23.64,0:39:30.01,Default,,0000,0000,0000,,Your brain is very vulnerable to\Ngoing into this excitatory drive
Dialogue: 0,0:39:30.01,0:39:33.55,Default,,0000,0000,0000,,and that's partly why you can\Nget seizures when you're going
Dialogue: 0,0:39:33.55,0:39:36.86,Default,,0000,0000,0000,,through severe withdrawal stage.
Dialogue: 0,0:39:39.13,0:39:42.97,Default,,0000,0000,0000,,The other neurotransmitter system\Nthat is involved is dopamine.
Dialogue: 0,0:39:42.97,0:39:49.18,Default,,0000,0000,0000,,Dopamine is going to show up\Nover and over in other substances.
Dialogue: 0,0:39:49.18,0:39:56.66,Default,,0000,0000,0000,,Partly why, this will not be a substance\Nof abuse if dopamine is not involved.
Dialogue: 0,0:39:56.66,0:40:02.48,Default,,0000,0000,0000,,Why? Because in order for you to \Nhave this positive reinforcing effect,
Dialogue: 0,0:40:02.48,0:40:08.85,Default,,0000,0000,0000,,this euphoria effect from this drug,\Nwhich then encourages you to take
Dialogue: 0,0:40:08.85,0:40:13.40,Default,,0000,0000,0000,,the drug again, you need to\Nhave dopamine involved.
Dialogue: 0,0:40:13.40,0:40:15.92,Default,,0000,0000,0000,,And that's one of the first thing\Nthat we figure out,
Dialogue: 0,0:40:15.92,0:40:19.36,Default,,0000,0000,0000,,whether the drug has\Npositive reinforcing effect, right?
Dialogue: 0,0:40:19.36,0:40:21.43,Default,,0000,0000,0000,,Do animals self-administer?
Dialogue: 0,0:40:21.43,0:40:27.17,Default,,0000,0000,0000,,We know that dopamine is very important \Nfor the self-administration part.
Dialogue: 0,0:40:27.17,0:40:34.10,Default,,0000,0000,0000,,Any drug that is consider \Nsort of abusive drug,
Dialogue: 0,0:40:34.10,0:40:37.12,Default,,0000,0000,0000,,you will see some involvement of dopamine.
Dialogue: 0,0:40:37.12,0:40:41.27,Default,,0000,0000,0000,,Whether it works directly on\Nthe dopamine receptors,
Dialogue: 0,0:40:41.27,0:40:46.72,Default,,0000,0000,0000,,or not, there's sort of this indirect\Nway of influencing them too.
Dialogue: 0,0:40:46.72,0:40:51.74,Default,,0000,0000,0000,,So you basically get enhanced\Ndopamine activity
Dialogue: 0,0:40:51.74,0:40:54.97,Default,,0000,0000,0000,,in presence of these drugs,\Nespecially at the beginning
Dialogue: 0,0:40:54.97,0:40:56.92,Default,,0000,0000,0000,,when you're first being exposed to it.
Dialogue: 0,0:40:56.92,0:41:00.12,Default,,0000,0000,0000,,And these graphs are basically\Nshowing you this.
Dialogue: 0,0:41:00.12,0:41:05.10,Default,,0000,0000,0000,,The one on the left, the line graphs,\Nare just two different types of rats,
Dialogue: 0,0:41:05.10,0:41:12.56,Default,,0000,0000,0000,,the "Wistar Rats" is type of rat strain\Nand "P Rats" here is actually,
Dialogue: 0,0:41:12.56,0:41:17.19,Default,,0000,0000,0000,,rats that are derived from what\Nwe call "selective breeding".
Dialogue: 0,0:41:17.19,0:41:21.61,Default,,0000,0000,0000,,So they happened to find some\Nindividual rats that seemed to
Dialogue: 0,0:41:21.61,0:41:25.65,Default,,0000,0000,0000,,drink a lot more alcohol than\Ntheir counterparts.
Dialogue: 0,0:41:25.65,0:41:31.63,Default,,0000,0000,0000,,If you'd only select those rats, and\Nbreed them over multiple generations,
Dialogue: 0,0:41:31.63,0:41:36.01,Default,,0000,0000,0000,,you basically end up with a bunch\Nof rats that prefer alcohol
Dialogue: 0,0:41:36.01,0:41:38.32,Default,,0000,0000,0000,,and that's what "P" stands for.
Dialogue: 0,0:41:38.32,0:41:43.73,Default,,0000,0000,0000,,Anyway these rats show very \Nhigh increase of dopamine.
Dialogue: 0,0:41:43.73,0:41:48.90,Default,,0000,0000,0000,,The one on the right, the bar graph,\Nthe middle and the one on the right
Dialogue: 0,0:41:48.90,0:41:52.92,Default,,0000,0000,0000,,are animals who've received\Ndopamine antagonist into
Dialogue: 0,0:41:52.92,0:41:56.55,Default,,0000,0000,0000,,their nucleus accumbens so this\Nis a case where the dopamine
Dialogue: 0,0:41:56.55,0:42:00.60,Default,,0000,0000,0000,,is not working properly in\Nthe mesolimbic pathway.
Dialogue: 0,0:42:00.60,0:42:04.21,Default,,0000,0000,0000,,And then they're looking at\Nthe over-response to ethanol.
Dialogue: 0,0:42:04.21,0:42:09.53,Default,,0000,0000,0000,,As you can see, they do not\Nrespond to ethanol as much as
Dialogue: 0,0:42:09.53,0:42:13.29,Default,,0000,0000,0000,,a control group that has\Nintact mesolimbic pathways.
Dialogue: 0,0:42:13.29,0:42:16.86,Default,,0000,0000,0000,,So just highlighting the importance \Nof dopamine here.
Dialogue: 0,0:42:19.15,0:42:22.87,Default,,0000,0000,0000,,I think the next one is opioids, yes.
Dialogue: 0,0:42:24.44,0:42:29.78,Default,,0000,0000,0000,,The next lecture is entirely on\Nopioids, things like morphine,
Dialogue: 0,0:42:29.78,0:42:32.07,Default,,0000,0000,0000,,heroin, and fentanyl.
Dialogue: 0,0:42:32.07,0:42:35.06,Default,,0000,0000,0000,,Why am I talking about opioids here?
Dialogue: 0,0:42:35.06,0:42:41.64,Default,,0000,0000,0000,,It turns out there is actually tight\Nrelationship between alcohol and--
Dialogue: 0,0:42:41.64,0:42:47.28,Default,,0000,0000,0000,,let me rephrase it, alcohol can also\Ninfluence opioid system,
Dialogue: 0,0:42:47.28,0:42:51.68,Default,,0000,0000,0000,,and you can also manipulate \Nopioid system to regulate
Dialogue: 0,0:42:51.68,0:42:57.35,Default,,0000,0000,0000,,overall alcohol consumption behavior.
Dialogue: 0,0:42:57.35,0:43:01.75,Default,,0000,0000,0000,,Kind of like glutamate and GABA,\Nif you are exposed to alcohol
Dialogue: 0,0:43:01.75,0:43:07.06,Default,,0000,0000,0000,,for the first time or not \Nin a repeated fashion,
Dialogue: 0,0:43:07.06,0:43:15.90,Default,,0000,0000,0000,,you increase the opioid activity\Nand one of the outputs is
Dialogue: 0,0:43:15.90,0:43:17.43,Default,,0000,0000,0000,,increase in endorphins.
Dialogue: 0,0:43:17.43,0:43:21.59,Default,,0000,0000,0000,,So endorphin is an endogenous \Nopiate substance.
Dialogue: 0,0:43:21.59,0:43:25.29,Default,,0000,0000,0000,,You guys have probably heard\Nof endorphin,
Dialogue: 0,0:43:25.29,0:43:31.92,Default,,0000,0000,0000,,some marathon runners will say\Nwhen they run, they think they
Dialogue: 0,0:43:31.92,0:43:37.26,Default,,0000,0000,0000,,release endorphin which then\Nsort of blunts some of the
Dialogue: 0,0:43:37.26,0:43:41.42,Default,,0000,0000,0000,,muscle pains or some of the pains \Nthey might get, or some will say
Dialogue: 0,0:43:41.42,0:43:44.86,Default,,0000,0000,0000,,this is responsible for some of \Nthe highs they get, sometimes
Dialogue: 0,0:43:44.86,0:43:47.39,Default,,0000,0000,0000,,they call it "runner's high".
Dialogue: 0,0:43:47.39,0:43:51.40,Default,,0000,0000,0000,,Anyway this is something that\Nour body naturally makes,
Dialogue: 0,0:43:51.40,0:43:57.14,Default,,0000,0000,0000,,and opioid system is heavily\Ninvolved in blocking pain
Dialogue: 0,0:43:57.14,0:44:02.84,Default,,0000,0000,0000,,or regulating pain so endorphin is\Nkind of like the natural pain-killer
Dialogue: 0,0:44:02.84,0:44:05.99,Default,,0000,0000,0000,,our body's capable of making.
Dialogue: 0,0:44:05.99,0:44:11.41,Default,,0000,0000,0000,,When you're exposed to alcohol,\Nyour endorphin goes up,
Dialogue: 0,0:44:11.41,0:44:15.87,Default,,0000,0000,0000,,also contributing to sort of this high\Nor euphoric effect that you get
Dialogue: 0,0:44:15.87,0:44:18.13,Default,,0000,0000,0000,,from taking alcohol.
Dialogue: 0,0:44:18.13,0:44:24.36,Default,,0000,0000,0000,,Again, if you are exposed to alcohol\Nchronically and you abuse them,
Dialogue: 0,0:44:24.36,0:44:30.39,Default,,0000,0000,0000,,it seems that the opioid system\Ngenerally-- or the activity goes down,
Dialogue: 0,0:44:30.39,0:44:34.83,Default,,0000,0000,0000,,including reduction in\Nendorphin production.
Dialogue: 0,0:44:34.83,0:44:38.19,Default,,0000,0000,0000,,Now the graph is showing you \Nsomething slightly different,
Dialogue: 0,0:44:38.19,0:44:43.60,Default,,0000,0000,0000,,they are using Naltrexone, \Nwhich is an opioid antagonist,
Dialogue: 0,0:44:43.60,0:44:48.43,Default,,0000,0000,0000,,and to see it's effect on\Nalcohol self-administration.
Dialogue: 0,0:44:48.43,0:44:54.30,Default,,0000,0000,0000,,In the previous study I showed you how\Nyou can inject dopamine antagonist,
Dialogue: 0,0:44:54.30,0:45:00.38,Default,,0000,0000,0000,,and that also reduces response to alcohol.
Dialogue: 0,0:45:00.38,0:45:07.05,Default,,0000,0000,0000,,In this case they were injecting\Nopioid antagonist, and again,
Dialogue: 0,0:45:07.05,0:45:11.66,Default,,0000,0000,0000,,there seems to be some reduction\Nin self-administration,
Dialogue: 0,0:45:11.66,0:45:16.85,Default,,0000,0000,0000,,and you see a dose-dependent\Nresponse, meaning if you received
Dialogue: 0,0:45:16.85,0:45:23.77,Default,,0000,0000,0000,,the highest dose in this study, your self-\Nadministration behavior was the lowest.
Dialogue: 0,0:45:26.87,0:45:31.94,Default,,0000,0000,0000,,Finally, one other substance or \Nneuromechanism that I want
Dialogue: 0,0:45:31.94,0:45:38.98,Default,,0000,0000,0000,,to talk about with alcohol is CRF,\Ncorticotrophin releasing factor.
Dialogue: 0,0:45:38.98,0:45:44.66,Default,,0000,0000,0000,,This is kind of like a hormone\Nthat is involved in our body
Dialogue: 0,0:45:44.66,0:45:49.29,Default,,0000,0000,0000,,responding to stress but it is \Nalso used centrally,
Dialogue: 0,0:45:49.29,0:45:51.72,Default,,0000,0000,0000,,meaning used by your brain.
Dialogue: 0,0:45:51.72,0:45:57.14,Default,,0000,0000,0000,,And our brain is capable of\Nproducing CRF, as well,
Dialogue: 0,0:45:57.14,0:46:03.77,Default,,0000,0000,0000,,and it is especially used by the amygdala,\NI know I wrote down a very detailed
Dialogue: 0,0:46:03.77,0:46:08.95,Default,,0000,0000,0000,,brain name, so the central amygdala/\Nbed nucleus of the stria terminalis,
Dialogue: 0,0:46:08.95,0:46:12.97,Default,,0000,0000,0000,,we are just going to remember them\Nas the amygdala, and then I talked
Dialogue: 0,0:46:12.97,0:46:18.93,Default,,0000,0000,0000,,about in the previous lecture how\Nthere is this sort of change in
Dialogue: 0,0:46:18.93,0:46:23.31,Default,,0000,0000,0000,,neurostructure that goes or--\Nneuromechanisms that go from
Dialogue: 0,0:46:23.31,0:46:30.23,Default,,0000,0000,0000,,relying on the mesolimbic pathway\Nto the amygdala pathway kicking in
Dialogue: 0,0:46:30.23,0:46:35.51,Default,,0000,0000,0000,,as you go from non-dependent use\Nof drug to dependent use of drug.
Dialogue: 0,0:46:35.51,0:46:42.29,Default,,0000,0000,0000,,And we know the CRF goes up\Nas you go from taking alcohol
Dialogue: 0,0:46:42.29,0:46:47.55,Default,,0000,0000,0000,,occasionally to when you start\Nabusing alcohol.
Dialogue: 0,0:46:49.41,0:46:53.56,Default,,0000,0000,0000,,We know that CRF plays an \Nimportant role in sort of
Dialogue: 0,0:46:53.56,0:46:55.73,Default,,0000,0000,0000,,this alcohol-addictive behavior.
Dialogue: 0,0:46:59.25,0:47:05.79,Default,,0000,0000,0000,,Here is just another study that\Nhighlights what I just said,
Dialogue: 0,0:47:05.79,0:47:11.54,Default,,0000,0000,0000,,they are now looking at the \Nlevel of CRF in the amygdala,
Dialogue: 0,0:47:11.54,0:47:18.06,Default,,0000,0000,0000,,and the graph on the left is showing\Na comparison, what happens to
Dialogue: 0,0:47:18.06,0:47:22.50,Default,,0000,0000,0000,,the CRF when the animal is going\Nthrough some sort of stress event.
Dialogue: 0,0:47:22.50,0:47:25.31,Default,,0000,0000,0000,,Because that's what CRF \Nis really known for.
Dialogue: 0,0:47:25.31,0:47:31.88,Default,,0000,0000,0000,,In this case the animals are basically\Nrestrained, for about 20 minutes,
Dialogue: 0,0:47:31.88,0:47:36.73,Default,,0000,0000,0000,,they don't like to be restrained\Nso it's a mild stressor,
Dialogue: 0,0:47:36.73,0:47:40.35,Default,,0000,0000,0000,,and you see the level of CRF\Ngoing up, right?
Dialogue: 0,0:47:40.35,0:47:45.57,Default,,0000,0000,0000,,And then the one in the middle,\Nis the increase of CRF
Dialogue: 0,0:47:45.57,0:47:49.73,Default,,0000,0000,0000,,as the animals go through\Nwithdrawal stage.
Dialogue: 0,0:47:49.73,0:47:56.48,Default,,0000,0000,0000,,So another set of animals will\Nhave been exposed to ethanol
Dialogue: 0,0:47:56.48,0:48:00.47,Default,,0000,0000,0000,,over and over so now they are\Nsort of physically dependent
Dialogue: 0,0:48:00.47,0:48:04.28,Default,,0000,0000,0000,,on ethanol, and then they\Nstop receiving ethanol.
Dialogue: 0,0:48:04.28,0:48:10.05,Default,,0000,0000,0000,,And then what you are seeing\Nhere is this gradual rise of CRF,
Dialogue: 0,0:48:10.05,0:48:16.96,Default,,0000,0000,0000,,and so we think that increased level\Nof CRF also contributes to some of the
Dialogue: 0,0:48:16.96,0:48:21.17,Default,,0000,0000,0000,,adverse effects or adverse symptoms\Nyou get when you are going through
Dialogue: 0,0:48:21.17,0:48:22.91,Default,,0000,0000,0000,,a withdrawal stage.
Dialogue: 0,0:48:27.78,0:48:31.53,Default,,0000,0000,0000,,Let's talk about alcohol use disorder\Nand some of the treatments,
Dialogue: 0,0:48:31.53,0:48:36.55,Default,,0000,0000,0000,,some of the contributing factors\Nand the treatments that go with it.
Dialogue: 0,0:48:36.55,0:48:40.64,Default,,0000,0000,0000,,In order to diagnose somebody \Nwith alcohol use disorder,
Dialogue: 0,0:48:40.64,0:48:45.42,Default,,0000,0000,0000,,a lot of things need to be\Ntaken into consideration,
Dialogue: 0,0:48:45.42,0:48:48.22,Default,,0000,0000,0000,,like the frequency and pattern of use,
Dialogue: 0,0:48:48.22,0:48:54.56,Default,,0000,0000,0000,,binge drinking itself is doesn't--\Nif you are engaged in binge drinking,
Dialogue: 0,0:48:54.56,0:48:58.98,Default,,0000,0000,0000,,it doesn't necessarily mean that\Nyou have alcohol use disorder,
Dialogue: 0,0:48:58.98,0:49:03.84,Default,,0000,0000,0000,,but binge drinking itself is also a\Nproblem especially young people
Dialogue: 0,0:49:03.84,0:49:06.02,Default,,0000,0000,0000,,like your age group.
Dialogue: 0,0:49:06.02,0:49:11.62,Default,,0000,0000,0000,,There are a bunch of diagnoses that need\Nto happen to diagnose this disorder.
Dialogue: 0,0:49:11.62,0:49:13.95,Default,,0000,0000,0000,,But that part I'm not really\Ngoing to talk about.
Dialogue: 0,0:49:13.95,0:49:21.33,Default,,0000,0000,0000,,Let's talk about some of the contributing\Nfactors that go into alcohol use disorder.
Dialogue: 0,0:49:21.33,0:49:29.40,Default,,0000,0000,0000,,In the next slide, we call this--\Nit's the three-factor model,
Dialogue: 0,0:49:29.40,0:49:34.46,Default,,0000,0000,0000,,and I've talked about some of these\Nfactors sort of in the broad term
Dialogue: 0,0:49:34.46,0:49:38.07,Default,,0000,0000,0000,,when we are talking about \Ndifferent factors contributing
Dialogue: 0,0:49:38.07,0:49:42.23,Default,,0000,0000,0000,,to addictive behavior, right?\NThere's the psychological factors,
Dialogue: 0,0:49:42.23,0:49:46.40,Default,,0000,0000,0000,,and there's sociocultural factors,\Nand biological factors.
Dialogue: 0,0:49:46.40,0:49:51.24,Default,,0000,0000,0000,,Let's first talk about psychological \Nfactors in the next slide.
Dialogue: 0,0:49:51.24,0:49:58.90,Default,,0000,0000,0000,,One of the things that is heavily\Nlinked to people who abuse alcohol
Dialogue: 0,0:49:58.90,0:50:03.16,Default,,0000,0000,0000,,is sort of over anxiety level.
Dialogue: 0,0:50:03.16,0:50:08.88,Default,,0000,0000,0000,,We think that one of the things \Nthat alcohol alleviates is
Dialogue: 0,0:50:08.88,0:50:11.29,Default,,0000,0000,0000,,sort of your stress levels.
Dialogue: 0,0:50:11.29,0:50:15.98,Default,,0000,0000,0000,,When you're facing with a lot\Nof stressors in your life,
Dialogue: 0,0:50:15.98,0:50:21.83,Default,,0000,0000,0000,,alcohol can have reinforcing effects\Nand then you can sort of--
Dialogue: 0,0:50:21.83,0:50:25.76,Default,,0000,0000,0000,,make you feel a little relieved\Nfrom the stress and the tension.
Dialogue: 0,0:50:25.76,0:50:31.83,Default,,0000,0000,0000,,There is a high level of lifetime anxiety\Namong people who abuse alcohol,
Dialogue: 0,0:50:31.83,0:50:39.64,Default,,0000,0000,0000,,also if you take people who abuse\Nalcohol there's a significant number
Dialogue: 0,0:50:39.64,0:50:48.01,Default,,0000,0000,0000,,of people who dealt with a major stressor\Nin their early life, to put it the other
Dialogue: 0,0:50:48.01,0:50:56.16,Default,,0000,0000,0000,,way around the major stressor in early \Nlife is a risk factor for developing
Dialogue: 0,0:50:56.16,0:50:59.38,Default,,0000,0000,0000,,alcohol abuse disorder later in life.
Dialogue: 0,0:51:00.88,0:51:05.50,Default,,0000,0000,0000,,In the next slide let's talk about\Nsome of the neurobiological factors.
Dialogue: 0,0:51:05.50,0:51:12.47,Default,,0000,0000,0000,,One thing that this particular \Nstudy it's suggesting, is
Dialogue: 0,0:51:12.47,0:51:19.12,Default,,0000,0000,0000,,if you react to alcohol not as much\Nas some other people,
Dialogue: 0,0:51:19.12,0:51:23.68,Default,,0000,0000,0000,,maybe your chance of developing\Nalcohol use disorder is greater,
Dialogue: 0,0:51:23.68,0:51:26.43,Default,,0000,0000,0000,,so low sensitivity to alcohol.
Dialogue: 0,0:51:26.43,0:51:32.35,Default,,0000,0000,0000,,But that really only is within\Nthe people who have parents
Dialogue: 0,0:51:32.35,0:51:35.38,Default,,0000,0000,0000,,who already have alcohol use disorder.
Dialogue: 0,0:51:35.38,0:51:41.29,Default,,0000,0000,0000,,In this particular study they've only\Ntaken sons of parents who have AUD,
Dialogue: 0,0:51:41.29,0:51:45.42,Default,,0000,0000,0000,,alcohol use disorder, \Nand then they've just
Dialogue: 0,0:51:45.42,0:51:49.61,Default,,0000,0000,0000,,looked at their reaction to alcohol,\Nso their subjective high,
Dialogue: 0,0:51:49.61,0:51:53.24,Default,,0000,0000,0000,,which is the top graph, and\Ntheir sort of motor reaction,
Dialogue: 0,0:51:53.24,0:51:57.52,Default,,0000,0000,0000,,motor response to alcohol,\Nso in this one a sway score.
Dialogue: 0,0:52:00.80,0:52:08.84,Default,,0000,0000,0000,,They've looked at people who\Nlater developed alcohol abuse--
Dialogue: 0,0:52:08.84,0:52:13.07,Default,,0000,0000,0000,,later who abused alcohol \Nversus who didn't,
Dialogue: 0,0:52:13.07,0:52:18.22,Default,,0000,0000,0000,,they see a difference in their\Nbaseline response to alcohol.
Dialogue: 0,0:52:18.22,0:52:25.41,Default,,0000,0000,0000,,That might be some neurobiological\Ncontributing factor.
Dialogue: 0,0:52:25.41,0:52:29.64,Default,,0000,0000,0000,,In the next slide I think I talk\Nabout some genetic components.
Dialogue: 0,0:52:29.64,0:52:34.01,Default,,0000,0000,0000,,Yes there's some heritability,\Nif you have parents who have
Dialogue: 0,0:52:34.01,0:52:40.57,Default,,0000,0000,0000,,abused alcohol the advice is that\Nyou try not to be exposed to alcohol
Dialogue: 0,0:52:40.57,0:52:45.13,Default,,0000,0000,0000,,because your chance of developing\Nthe same disorder is pretty high.
Dialogue: 0,0:52:45.13,0:52:51.12,Default,,0000,0000,0000,,The concordance rate among identical twins\Nis higher than fraternal twins,
Dialogue: 0,0:52:51.12,0:52:56.16,Default,,0000,0000,0000,,so fraternal twins are the twins who don't\Nreally share the same genetic make-up
Dialogue: 0,0:52:56.16,0:52:58.47,Default,,0000,0000,0000,,whereas the identical twins do.
Dialogue: 0,0:52:58.47,0:53:04.11,Default,,0000,0000,0000,,The concordance rate basically means\Nif your twin has a particular disorder,
Dialogue: 0,0:53:04.11,0:53:07.35,Default,,0000,0000,0000,,what is your chance of having\Nthe same disorder?
Dialogue: 0,0:53:07.35,0:53:14.92,Default,,0000,0000,0000,,It is much higher among identical twins\Nin terms of the alcohol use disorder.
Dialogue: 0,0:53:14.92,0:53:21.16,Default,,0000,0000,0000,,And then there are this bunch of genes\Nthat show that might be linked to
Dialogue: 0,0:53:21.16,0:53:25.83,Default,,0000,0000,0000,,alcoholism but like I said \Nin the previous lecture,
Dialogue: 0,0:53:25.83,0:53:32.21,Default,,0000,0000,0000,,we can't really pinpoint a particular\Ngene or even a set of particular genes
Dialogue: 0,0:53:32.21,0:53:38.78,Default,,0000,0000,0000,,and say "Hey, if you have variations\Nin these genes then we know
Dialogue: 0,0:53:38.78,0:53:43.05,Default,,0000,0000,0000,,what your chances of developing\Nalcoholism is."
Dialogue: 0,0:53:43.05,0:53:44.78,Default,,0000,0000,0000,,So we are not quite there.
Dialogue: 0,0:53:44.78,0:53:50.78,Default,,0000,0000,0000,,And oftentimes, and also we've\Ntalked about epigenetic mechanisms,
Dialogue: 0,0:53:50.78,0:53:56.22,Default,,0000,0000,0000,,so even if you have some of \Nthese genes, if you're in a--
Dialogue: 0,0:53:56.22,0:54:02.13,Default,,0000,0000,0000,,if you can control your environment\Nwhere those genes are not fully expressed,
Dialogue: 0,0:54:02.13,0:54:05.60,Default,,0000,0000,0000,,then your chances of developing\Nthe particular disorder might
Dialogue: 0,0:54:05.60,0:54:08.33,Default,,0000,0000,0000,,also go down significantly.
Dialogue: 0,0:54:08.33,0:54:10.100,Default,,0000,0000,0000,,Okay, so let's talk about treatments.
Dialogue: 0,0:54:10.100,0:54:14.23,Default,,0000,0000,0000,,This is the last slide of the lecture.
Dialogue: 0,0:54:14.23,0:54:21.11,Default,,0000,0000,0000,,First, you have to go cold turkey,\Nor you have to basically detox,
Dialogue: 0,0:54:21.11,0:54:24.13,Default,,0000,0000,0000,,you have to go through a\Ndetoxification process,
Dialogue: 0,0:54:24.13,0:54:28.10,Default,,0000,0000,0000,,before you can receive some \Nsort of long-term treatment.
Dialogue: 0,0:54:28.10,0:54:39.48,Default,,0000,0000,0000,,And as you saw earlier, the withdrawal\Nstage, from alcohol abuse can be quite
Dialogue: 0,0:54:39.48,0:54:46.29,Default,,0000,0000,0000,,bad, and you actually go through\Nreally severe physical reaction
Dialogue: 0,0:54:46.29,0:54:49.12,Default,,0000,0000,0000,,as you try to detox from alcohol.
Dialogue: 0,0:54:49.12,0:54:56.20,Default,,0000,0000,0000,,One drug that can be useful during that \Nprocess so that you don't have all this
Dialogue: 0,0:54:56.20,0:55:01.77,Default,,0000,0000,0000,,really severe bad symptoms,\Nto the point where it can be
Dialogue: 0,0:55:01.77,0:55:07.76,Default,,0000,0000,0000,,actually a danger to your health,\Nis the use of benzodiazepine drug.
Dialogue: 0,0:55:07.76,0:55:13.34,Default,,0000,0000,0000,,So things like diazepam, \Nwe also know them as Valium,
Dialogue: 0,0:55:13.34,0:55:17.84,Default,,0000,0000,0000,,because they are targeting \Nthe same GABA mechanism,
Dialogue: 0,0:55:17.84,0:55:23.77,Default,,0000,0000,0000,,so alcohol, benzodiazepine are both\Nnon-competitive GABA agonists.
Dialogue: 0,0:55:23.77,0:55:30.29,Default,,0000,0000,0000,,Basically instead of having alcohol,\Nyou are basically having benzodiazepine
Dialogue: 0,0:55:30.29,0:55:36.79,Default,,0000,0000,0000,,still influencing the GABA system so\Nthat you can gradually reduce this
Dialogue: 0,0:55:36.79,0:55:41.50,Default,,0000,0000,0000,,without having the alcohol being\Nin the system so that's one thing
Dialogue: 0,0:55:41.50,0:55:44.45,Default,,0000,0000,0000,,that is used during detoxification stage.
Dialogue: 0,0:55:44.45,0:55:49.19,Default,,0000,0000,0000,,And then once you've gone through\Nthe withdrawal stage successfully,
Dialogue: 0,0:55:49.19,0:55:52.81,Default,,0000,0000,0000,,you kind of need to be on some\Nsort of long-term treatment plan.
Dialogue: 0,0:55:52.81,0:55:59.69,Default,,0000,0000,0000,,There is definitely cognitive\Ntreatment that can be done,
Dialogue: 0,0:55:59.69,0:56:05.39,Default,,0000,0000,0000,,and behavior therapy that can be done,\Nbut in terms of drug treatment,
Dialogue: 0,0:56:05.39,0:56:09.20,Default,,0000,0000,0000,,there are two things that \Nare currently used most,
Dialogue: 0,0:56:09.20,0:56:13.52,Default,,0000,0000,0000,,one is Disulfiram, I talked about this\Nearlier when we were talking about
Dialogue: 0,0:56:13.52,0:56:18.49,Default,,0000,0000,0000,,the metabolic process, so this is\Nthe inhibitor of the enzyme
Dialogue: 0,0:56:18.49,0:56:24.82,Default,,0000,0000,0000,,the acetaldehyde dehydrogenase\Nthat is supposed to break down
Dialogue: 0,0:56:24.82,0:56:30.85,Default,,0000,0000,0000,,acid aldehyde so it physically makes\Nyou sick when you drink alcohol
Dialogue: 0,0:56:30.85,0:56:32.92,Default,,0000,0000,0000,,if you have this drug on board.
Dialogue: 0,0:56:32.92,0:56:36.92,Default,,0000,0000,0000,,The other one is Naltrexone, \Nso I talked about this when
Dialogue: 0,0:56:36.92,0:56:42.88,Default,,0000,0000,0000,,we were talking about opioids'\Ninvolvement in alcohol processing,
Dialogue: 0,0:56:42.88,0:56:50.88,Default,,0000,0000,0000,,because of the alcohol's influence on\Nopioid, if you give them opioid antagonist
Dialogue: 0,0:56:50.88,0:56:56.55,Default,,0000,0000,0000,,it seems to reduce their craving for\Nalcohol, so the graph down here
Dialogue: 0,0:56:56.55,0:57:03.03,Default,,0000,0000,0000,,is showing you, this survival rate\Nin a way, so the percentage of
Dialogue: 0,0:57:03.03,0:57:07.27,Default,,0000,0000,0000,,people who are not relapsing,\Nso who are still staying on-course,
Dialogue: 0,0:57:07.27,0:57:10.05,Default,,0000,0000,0000,,so the higher number the better, right?
Dialogue: 0,0:57:10.05,0:57:16.58,Default,,0000,0000,0000,,The group that is receiving Naltrexone,\Nwith behavior therapy are staying
Dialogue: 0,0:57:16.58,0:57:24.49,Default,,0000,0000,0000,,at the end of 12 weeks of therapy about\N70% of the people are not relapsing
Dialogue: 0,0:57:24.49,0:57:29.86,Default,,0000,0000,0000,,whereas the group in the blue line\Nare going through behavior therapy,
Dialogue: 0,0:57:29.86,0:57:35.20,Default,,0000,0000,0000,,cognitive therapy without Naltrexone,\Nand at the end of 12 weeks only about
Dialogue: 0,0:57:35.20,0:57:37.100,Default,,0000,0000,0000,,30% of people have not relapsed.
Dialogue: 0,0:57:37.100,0:57:42.15,Default,,0000,0000,0000,,So there's a significant difference\Nwith the use of Naltrexone.
Dialogue: 0,0:57:43.65,0:57:47.41,Default,,0000,0000,0000,,Okay so that is all I have \Nto say about alcohol,
Dialogue: 0,0:57:47.41,0:57:51.54,Default,,0000,0000,0000,,in the next lecture we'll \Ntalk about opioids.