1. UW Biology of Addiction Unit V: Depressants Lecture 23: Ethanol

2. Learning Targets for Lesson 23: Ethanol appreciate that molecules do not need to bind to a receptor to have an impact on a cell understand another mechanism by which hyperpolarization occurs evaluate why ethanol addiction is so challenging to break and why one should seek medical help when trying to quit appreciate the many genetic and environmental influences that determine how we respond to ethanol understand why ethanol is a dangerous drug to take with other drugs weigh risks knowledgeably when deciding if and how to use ethanol assist friends if they choose to abuse ethanol in ways that might save lives

3. What Do You Already Know? 1.How much wine is “a drink” and how does that compare in ethanol content with a shot or a margarita? Wine= 1 Glass/5oz @ 12% v. Shot= 1.5oz @ 40% 2.What happens to the liver of a long-time ethanol abuser? Cirrhosis of the liver 3.What blood alcohol content is the maximum for driving legally in the state of Washington? BAC = 0.08 4.Which is more common – driving while drunk accidents or driving while texting accidents? Driving while texting 5.What happens to anger as an emotion in a person who uses ethanol heavily? Ethanol tends to increase anger and aggression… hello amygdala!

4. Previously Learned What is one way that a neuron can become hyperpolarized? Increase K+ conductance… as more K+ flows out of the neuron, the neuron becomes “supernegative” in charge Where are chloride ions found at higher concentration – inside or outside a neuron? Inside… thus the negative charge How do we know that genes, in part, influence ethanol abuse? Initially by twin studies and family histories

5. Forms of Alcohol 2 Ethanol is ethanol is ethanol 1 methanol 3 isopropanol 1.Methanol: (toxic) cleaning solutions, gasohol, anti- freeze, copier fluids, etc. Metabolized by ADH and ALDH Metabolites= formaldehyde (short half life) formic acid (longer and bio accumulates) Both are toxic Blindness most common symptom of poisoning 2. Ethanol (also toxic)… 3. Isopropyl alcohol (or rubbing alcohol) More potent CNS and cardiac and respiratory depressant than ethanol (2-3 x more). Metabolized into acetone which is also a depressant (so long-lasting effects).

6. Forms of Alcohol Ethanol is ethanol is ethanol Wine : 30 proof (near the top of where yeast can tolerate) Sherry : 38 proof Gin : 85 proof Rum : 94 proof (due to distillation)

7. What is Alcohol? Why do we use it? Alcohol  OLDEST SYNTHETIC CHEMICAL KNOWN Egyptians had the first documented brewery (3700BC) Not only accepted and legal, but in many circumstances – almost required Weddings, treaty signing, etc.

8. What is Alcohol? Why do we use it? Hasn’t always been legal… P rohibition 1920-1933 Linked fines and imprisonment with alcohol use and distribution Little impact on use according to statistics…

9. Why do we use alcohol? Used as a social "lubricant” Some use ethanol in greater amounts to get euphoric and a little out-of-control. highly effective "disinhibiting" drug. Used in higher amounts to sedate them - aid sleep. At yet higher doses, ethanol will bring on amnesia and other undesired effects. Too much disinhibition Lose filter  less inhibition  no negative feedback mechanism

10. Test of Content: Dosage Q: In Peru, the social lubricant (served at gatherings and festivals) is cocaine tea. In the U.S., the social lubricant is ethanol. How do these drugs compare from the perspective of brain function and symptoms? A: Cocaine is a stimulant, but ethanol is a depressant. Cocaine makes a person more aware, alert, wakeful. Ethanol makes a person sillier, sloppier, and more relaxed.

11. Ethanol Dosage

12. Ethanol Administration & Dosage Binge Drinking: The CDC defines binge drinking as use that results in blood alcohol content (BAC) to 0.08 or higher. For women, this means consuming 4 drinks within a 2-hour interval. For men, consumption of 5 drinks within 2 hours can lead to this BAC. So basically drinking to “have a buzz” is considered binge drinking LD50= BAC of 0.5 or higher is typically lethal steady consumption of 15 or more drinks (again, depending upon previous experience, health, nutritional status, and other drugs consumed). Ethanol added on to ANY depressant shrinks the therapeutic index synergistically. Binge Drinking Fact Sheet http://www.cdc.gov/alcohol/fact- sheets/binge-drinking.htm http://www.cdc.gov/alcohol/fact- sheets/binge-drinking.htm

13. Test of Content: Dosage Q: What is the relationship between "proof" and alcohol concentration (% of the volume that is alcohol and not water)? A: 100 proof is 50% alcohol. Proof is a measure of concentration that is double the percentage - maximum is 200 proof. Q: A 12-ounce beer, which is 5% alcohol, is 0.6 ounces of pure alcohol. 12 ounces x 5% = 0.6. Follow this mathematical logic to discover how many "drinks" one is having if one consumes 1.5 ounces of 160 proof tequila in a margarita. A: 1.5 ounces x 80% = 1.2 of 1.2 ounces of pure alcohol which is TWO drinks.

14. How is ethanol metabolized? ADH ALDH Half life approximately 3 – 4 hours Aldehyde Dehydrogenase Alcohol Dehydrogenase = O |OH|OH

15. Where Does Alcohol Bind? Ethanol doesn’t quite bind to ANYTHING Ethanol doesn’t quite bind to ANYTHING. Its size and chemical properties let it permeate almost every membrane of every cell. Ethanol “marinates” membranes like wine marinates meat. This causes the proteins (channels & pumps) embedded within those membranes to function abnormally Because membranes enclose all cells in the body  the impact of ethanol is extremely broad

16. inside What is Ethanol’s Affect on the Membrane? Slow ion movement and slower electrical firing of neurons GABA is impacted works through this means  indirectly by altering membranes

17. Which neurotransmitter is MOST impacted by ethanol? The neurotransmitter receptors impacted most by ethanol are the ones that bind to GABA and Glutamate GABA is an inhibitory neurotransmitter  enhances GABA binding on receptor Glutamate is excitatory  its inhibited from binding in the presence of ethanol. The impact of ethanol to a neuron via these receptors is however, the same: ethanol causes neurons to be less likely to engage in an action potential due to hyperpolarization

18. Which neurotransmitter is MOST impacted by ethanol? GABA GABA receptor now opens  allowing Cl- to move Cl - Little moves Cl - LOTS moves GABA binds poorly to its receptor in normal situations. Ethanol changes the membrane in which the GABA receptor sits which changes the receptor, making it a better fit for GABA. = enhancing the ability of GABA to bind to its receptor

19. Ethanol also causes hyperpolarization Helping GABA means inhibiting action potential  allows increase in K+ conductance Normal action potential threshold Threshold not reached

20. Test of Content Q: Contrast hyperpolarization from ethanol to previously learned hyperpolarization from opiates. A: There are two main differences: 1) Opiates bind directly to opiate receptor whereas ethanol binds to no receptor. 2) Opiates - make neuron more leaky to potassium (outward flow) whereas ethanol leads to inward flow of chloride.

21. Ethanol Addiction? YES Work through the three parts with a neighbor Reward Reward Tolerance Tolerance Dependence? Dependence? More enzyme “un-marination” of ALL body membranes Double negative, inhibit inhibitors

22. Why is Ethanol Addictive? Since ethanol influences virtually all membranes of all cells, the entire body is impacted by ethanol: The body adapts to life in an "ethanol marinated" world Withdrawal symptoms upon removal of the marinate are very difficult to tolerate and even life-threatening. Between 5% and 25% of people detoxifying from heavy ethanol consumption actually die during withdrawal! It is important to get physician help with this process. It is unwise to repeatedly detoxify and then resume drug use. Each episode of withdrawal gets progressively worse, a phenomenon called " Kindling ".

23. Why is Ethanol Addictive? Ethanol use leads to development of tolerance. As the body adjusts to the presence of the drug  more ADH and ALDH are produced so that more efficient metabolism is found among regular users. This causes increased drug clearance and reduced drug effect (resulting in the decision to use more drug). Ethanol use leads to euphoria for a number of reasons. Interference with glutamate AND GABA pathways contributes to dopamine release in the nucleus accumbens. Alcohol metabolites have the ability to stimulate opiate receptors when combined with monoamines.

24. Test of Content Q: Which phrase best explains “Kindling”? A.Early attempts to quit use of ethanol lead to greater withdrawal symptoms experienced by later attempts B.Ethanol becomes more addictive with repeated use C.Ethanol use kindles the craving to use other “hard” drugs

25. What are the benefits of ethanol? Note small doses of ethanol provide benefit J-Curve : People who consume NO ethanol have been shown to have more life- threatening health conditions than people who consume 1 – 2 drinks a day. Benefit diminishes in individuals who consume more than 3-4 drinks daily This “French Paradox” was named because despite the rich nature of a French diet, people in France suffered less from cardiovascular illness than people from cultures with more ethanol use. Lowers blood sugar, thus reduces risk of diabetes and heart disease

26. Studies on Cardiovascular Effect… too many variables Difficult to study ethanol specific cardiovascular effect TOO many variables that can influence a condition, such as cardiovascular health It can be very difficult to determine if any one life-style choice is implicated. There are typically no “single variables” in studying a complex issue. It would be challenging to control variables such as: the type of alcohol frequency of consumption other drug effects that may occur in combination with alcohol consumption stress level Genetics

27. Studies on Cardiovascular Effect… too many variables Scientists use Epidemiology to study variable complicated situations Epidemiological studies ask patients to indicate their own habits of relevance (such as ethanol consumption) and will check in with the data collectors frequently to update them on, for instance, health outcomes. From this analysis, patterns are found. Because there are so many subjects, the statistical significance of these patterns is evaluated. From these epidemiology studies, such as the Framingham “Heart” study, the “French Paradox” was validated.

28. What are the benefits of ethanol? 2 1-Lowers blood sugar, thus reduce diabetes risk and heart disease 2-Increases high-density lipoproteins (“good cholesterol”)

29. Benefits of Ethanol: How does ethanol help cardiovascular health? So why did ethanol improve cardiovascular health in moderation? Is it related to the calming (sedating) influence that ethanol has on a person? Stress elevates blood pressure: therefore stress-relievers must promote cardiovascular health. This was studied by examining the cardiovascular health of beer drinkers compared to wine drinkers compared to whiskey drinkers. Some measure of benefit is seen regardless of the ethanol form. But darker beverages, such as red wine or dark rum, were seen to be most beneficial Dark beverages have more anti-oxidants. But another ingredient was implicated because red wine was so particularly beneficial  One ingredient within red wine, named Resveretrol (rez-VAIR-a- troll), has been studied extensively, and marketed nearly as extensively.

30. What are the benefits of ethanol? 3 Resveratrol= The chemical identified in red wine (and other forms of ethanol) that produces health benefits 1.Fish 59% longer life if given resveratrol 2.Mice: Researchers Sinclair et al. fed mice a high-calorie diet, with 60% of calories coming from fat given a high calorie diet & resveratrol Results: death rate reduced by 31% and also reduced obesity-related complications associated with diabetes, heart disease and cancer. The test mice did better than a comparison group on the high-calorie diet minus resveratrol And they did almost as well as a third group of mice on a standard, lower-cal diet. Implications: More mitochondria, lower blood sugar, lower insulin, lower body temperature. Dosage = 100 glasses of wine a day….

31. Test of Content Q: Explain the “J curve” of ethanol exposure and health. A: Lowest risk of poor health is associated with LOW doses  lower than with NO doses or HIGH doses.

32. What are the side effects of ethanol use? 1 in 400 people admitted to hospital have alcohol problem Yearly college student expenditure on alcohol – 5.5 billion > all other drinks + books Moderate to heavy consumption – 4 th largest cause of death in US, third biggest health concern Found in victim, offender or both in majority of violent offenses Cost of alcohol abuse in US - $86 billion Reduced life span – 10-12 years

33. What are the side effects of ethanol use? Short-term effects of alcohol use include: distorted vision, hearing, and coordination altered perceptions and emotions impaired judgment bad breath Hangovers-– not easy to explain, relates to dehydration, buildup of biproducts (acetaldehyde), depletion of enzymes. Other studies associate hangover with buildup of acetic acid and hangover pills block ALDH!

34. What are the side effects of ethanol use? Long-term effects of heavy alcohol use include: loss of appetite vitamin deficiencies stomach ailments skin problems sexual impotence liver damage (cirrohsis -korsakoff’s) heart and central nervous system damage memory loss – poor B1 (thiamine absorption)

35. Alcohol and Brain Damage PMID: 9161613 MRI Results  loss of brain volume 62 alcoholic men – two age groups. See significant loss of gray matter, esp. frontal lobe in older group PMID: 14657449 MRI Results  lighter drinkers. No significant loss of gray BUT increase in ventricle and sulcal spaces increases significantly – suggestive of atrophy.

36. Fetal Alcohol Syndrome Fetal alcohol syndrome named by UW researcher (Dave Smith in ’73) Fetus lacks both ADH and ALDH Determined that each 12 oz beer or 4 oz wine diminishes IQ by 2 points

37. Test of Content Q: Why does a person “flush” when drinking ethanol? A.Alcohol binds to specific receptors in the hypothalamus, making one overheat B.Ethanol causes vasodilation C.Ethanol makes people seek out warmer environments D.Ethanol causes your cerebellum to react making you embarrassed E.Ethanol makes you produce more body heat Q: “Antabuse” (disulphiram) is a product that inhibits ALDH. Explain who might use antabuse and why. A: Might be used as a deterrent for some trying to quit drinking. It would do so by making a person feel particularly ill when (s)he drinks because it results in slower metabolism of aldehyde.

38. Is ethanol toxic? TI approximately 25 (toxicity) Underestimates ethanol related deaths ~40% traffic fatalities - Ethanol Stats from 1998: ethanol accounted for 33,269 exposures reported to US poison centers, of which 973 (2.9%) resulted in major toxicity and 42 (0.1%) resulted in death. isopropanol accounted for 19,301 exposures reported to US poison centers, of which 83 (0.4%) resulted in major toxicity and 3 (0.02%) resulted in death. methanol accounted for 1041 exposures reported to US poison centers, of which 24 (2.3%) resulted in major toxicity and 10 (1%) resulted in death.

39. Individual experience may vary… Nature Both genes (nature) and environment (nurture) can influence the experience had while using ethanol and the likelihood of using ethanol. The tendency to become an alcoholic are 5 x’s higher if you have a close family member who is an alcoholic

40. Individual experience may vary… Nature Enzymes=ADH & ALDH Different alleles of ADH and ALDH genes. The strongest correlation is between alleles of ALDH that make POOR quantity/quality enzyme and the PROTECTION from alcoholism that is afforded by increasing the amount of aldehyde in the blood, and the consequent ill-feeling associated with that aldehyde. D2DR People who have poor/weak dopamine reception  crave more dopamine release and need additional stimuli to trigger dopamine release This reward-deficiency syndrome can lead to abuse of drugs as well as craving for activities that induce reward pathway stimulation such as sex, gambling, and gaming. Genes There are likely to be thousands of genes that influence our alcohol consumption and it is impossible we will ever identify "THE" alcoholism gene.

41. Individual experience may vary…Nurture Factor impacting ethanol response Rationale Peer and family use A leading influence upon whether or not someone will abuse ethanol is the influences by close friends and family. Sex Males and females have different body-fat composition – different amount of “water space” to hold your ethanol Age Liver has reduced capacity to make metabolic enzymes in the very young and the very old Previous exposure Tolerance to ethanol develops, even cross tolerance to unexpected drugs such as barbiturates develops. Food eatenIf there is food in the belly, it dilutes the ethanol, slowing absorption into the blood.

42. Individual experience may vary…Nurture Other drugs used (esp. acetaminophen!) Body mass, body fat Sleep deprivation Age Setting

43. Treatment The search for alcoholism treatment options is ongoing. Antabuse is an unsavory option. The many side effects overwhelm the benefits for most alcoholics. Quitting “cold turkey” (which means just stopping without treatment or reduction in use, and which was named because [possibly] of a couple of reasons – cold turkey requires little preparation and cold-turkey quitters exhibit cold sweats) is a bad choice because of the elevated risk of death. Some newer products are being tried, including antidepressants (reducing the desire to turn to ethanol to self-medicate depression) and even psychedelic drugs (see Unit 6), which may “startle” the brain out of an addiction cycle.

44. Ethanol Addiction Drugged: High on Alcohol http://youtu.be/_dJ97Vwoup4

45. ERs for Lesson 24: Ethanol Required Reading Liska – Chapter 9: 9.1 – 9.6, and 9.8 – 9.10 and questions 1, 3, 7, 9, 10, 12, 20, 24, 29, and 31. Internet http://rethinkingdrinking.niaaa.nih.gov/WhatCountsDrink/HowMuchIsTooMuch.asp http://en.wikipedia.org/wiki/Alcohol_withdrawal_syndrome http://www.cdc.gov/alcohol/faqs.htm http://www.framinghamheartstudy.org/ Science Literature Mulligan, et al., Proc Natl Acad Sci U S A. 2006 April 18; 103(16): 6368–6373. Meta- analysis on genes influencing alcohol abuse. http://pubs.niaaa.nih.gov/publications/arh21-2/144.pdf(paper on neurotransmitters during use and withdrawal) Supplemental ANY 2010 or 2011 paper by Dr. Susan Tapert from UCSD (search on PubMed). A former UW undergraduate doing prolific and fascinating work in this area (or just read news story on her work http://www.npr.org/templates/story/story.php?storyId=122765890 ).