Alcohol. Aubrey Fox, Tasha Lalos, Robin Jasmin, Tony Randazzo, Andrea Sobel, Emily Walter

Transcription

1 Alcohol Aubrey Fox, Tasha Lalos, Robin Jasmin, Tony Randazzo, Andrea Sobel, Emily Walter

2 History and Importance Intentionally fermented beverages have been found in the Neolithic period (~10,000 B.C.) 40 % of all college students report engaging in binge drinking ~1,825 die from alcohol related injury ~700,000 students are assaulted due to alcohol use

3 Alcoholism

4 Alcoholism A chronic and progressive disease that includes: o Problems controlling your drinking o Being preoccupied with alcohol o Continuing to use alcohol even when it causes problems o Physical dependence o Withdrawal symptoms

5 Neurochemical Systems Neurochemical systems reinforce effect of alcohol: o GABA o Serotonin o Opioid Peptide o Dopamine (DA) o Glutamate

6 Ethanol Ethanol acts as a positive enforcer o increases firing in the ventral tegmental area (VTA) o elevates extracellular DA concentrations in the nucleus accumbens (NAc) VTA and NAc both function in the reward pathway

7 Ferrer, E., M.A. Moral, and J. Bozzo. "Antiepileptic Drugs in Alcoholism: An Update." Drugs of the Future 32.5 (2007): 429. Print.

8 Positive Reinforcement A rewarding action that increases the probability of exhibiting a certain response. The positive effects on the reward system lead to alcoholism o For example, dopamine and opioid release

9 Negative Reinforcement A behavior is strengthened when stopping or avoiding a negative condition. o Ex: drinking to avoid anxiety/withdrawal symptoms A critical component during the transition to dependence. o Increases drinking to avoid withdrawal

10 Inhibition of Dopamine Release GABA normally inhibits dopamine release Alcohol (ethanol) inhibits GABA, thus increasing dopamine release DA release specifically in the Nucleus Accumbens leads directly to reward pathway

11 MOR OPRM1 is a gene that encodes MOR o MOR is an opioid receptor DA neurotransmission is modulated by MOR Heilig, Markus, David Goldman, Wade Berrettini, and Charles P. O'Brien. "Pharmacogenetic Approach to the Treatment of Alcohol Addiction." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 26 Oct

12 Why is MOR Important? A SNP on the OPRM1 gene at position 118A --> 118G has been linked to alcohol reward o encodes an asparagine (N) --> aspartate (D) substitution

13 OPRM1 and Mice 118G SNP o Mice with this SNP had a four fold increase of DA release compared to 118A mice 118A to 118G increases alcohol induced dopamine release in the nucleus accumbens

14 MOR Experiment in Human Males Heilig, Markus, David Goldman, Wade Berrettini, and Charles P. O'Brien. "Pharmacogenetic Approach to the Treatment of Alcohol Addiction." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 26 Oct

15 Naltrexone Opioid receptor antagonist A drug that aims to lessen alcohol cravings and reward outcomes. o Helps to "kick" addiction o Trade names: Revia Depade Vivitrol

16 Naltrexone Target Naltrexone targets the OPRM1 gene o Naltrexone is more beneficial in treating alcoholism in those who carry the 118 G SNP o Patients who are homozygous for 118 A SNP are not affected

17 Naltrexone and Monkeys Heilig, Markus, David Goldman, Wade Berrettini, and Charles P. O'Brien. "Pharmacogenetic Approach to the Treatment of Alcohol Addiction." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 26 Oct A 118G

18 Clinical Observation Some people improve dramatically while other addicts have no visible improvement o Found that family history and self reported cravings are important is predicting these outcomes

19 TOLERANCE Allostasis: stability through change

20 What is Tolerance? General Overview Different Types: o Behavioral Tolerance o Intrinsic Tolerance o Extrinsic Tolerance

21 Categories of Behavioral Tolerance Acute Tolerance o Fastest Effects Chronic Tolerance o Slowest Effects Rapid Tolerance o In the Middle

22 Mechanisms Post translational Modifications Interactions with Membrane Lipids Interaction with Auxiliary Proteins Spatial Organization of Membrane Proteins.

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24 BK Channel K+ channel Open longer due to alcohol Transient o Closure=acute tolerance

25 Post-translational Modification Proposed Mechanisms o Phosphorylation o Triggered by alcohol "directly" Acute Tolerance

26 Lipid Membrane Thickness o thickness= tolerance Cholesterol levels o Changing Lipid Composition membrane cholesterol levels= tolerance o Differences between 1st and subsequent consumptions. o Chronic Tolerance

27 Cholesterol

28 Cholesterol...

29 Auxiliary Proteins Subunit reorganization. Subunits which can better endure alcohol BK channel beta subunits 1 & 4 o Chronic Tolerance Takes days. However, some have shown rapid onset.

30 GABAa Enhanced function Inhibitory

31 Spatial Organization De-clusters BK channels o decreased sensitivity o Acute Tolerance

32 Genetics of Tolerance Slo gene in Fruit Flies, Worms, Mice o Slo channel expression is significant o Different effects on different levels of tolerance Acute, Rapid, and Chronic Hangover gene in Fruit Flies and Humans o Alcohol can manipulate the process of transcription of genes involved in the creation of tolerance o SNPs of Hangover genes in humans were directly correlated to alcohol dependence o In conclusion, there are many different types of genes and pathways involved in the development of alcohol tolerance

33 Putting it all together Acute, Rapid, Chronic Functional Categories o Underlying molecular borders are fuzzy Central Nervous System Adapts to Alcohol o Continual compensation from the body to different alcohol levels Stimulated simultaneously Potential Therapeutic Targets for Alcoholism o Membrane lipids, regulatory RNA molecules, channel protein subunits

34 Physical Effects of Alcohol in the Brain

35 Effects on Specific Lobes Alcohol affects the brain in a front to back manner Frontal Lobe Parietal Lobe Temporal Lobe Occipital Lobe Cerebellum Brain Stem

36 Brain Shrinkage?! Neurodegeneration with prolonged alcohol use o Chronic exposure of alcohol results in profound changes in: morphology growth survival of neurons. Alcoholics- substantial reduction in the volumes of the prefrontal cortex and cerebellum

37 Physical Brain changes Prefrontal/Orbitofrontal cortices: o deficits = faulty motivational circuits leading to alcohol seeking behavior Alcohol dependent humans have been found to have smaller amygdalae than non-dependent humans.

38 Row a) Control subject Row b) Alcoholic subject

39 Decrease in Acetylcholine Systems Slowed muscle use, lowered attention, lowered sensory perception o Pons Thalamus Cortex Diminished effects in plasticity, learning and memory

40 Increase in GABA Levels Slowed functions all throughout brain o GABA is the 'stop' neurotransmitter o Increases Dopamine

41 The Hangover The Not Fun Part

42 Hangover (not so) Fun Facts Alcohol dehydrates you Lowers your blood sugar Disturbs your sleep and circadian rhythm

43 Alcohol Dehydrates You Consumption increases urine production by inhibiting release of vasopressin in the pituitary gland o prevents kidneys from reabsorbing water Sweating, vomiting, diarrhea also common with alcohol consumption o major dehydration

44 Alcohol Lowers Your Blood Sugar Metabolism of alcohol leads to buildup of Lactic Acid (the same thing that makes your muscles sore after a workout!) o Lactic Acid inhibits Glucose production o Less Glucose = less energy for the brain = more hangover symptoms Diabetics are especially susceptible to hangovers for this reason "Cure"?: Eat while drinking to balance out the glycemic levels in your body

45 Alcohol Disturbs Your Sleep Disruption of normal circadian rhythm o Abnormal change in body temperatures o Disruption in hormone secretion that is normal in circadian rhythms Growth Hormones that help with wake cycles, bone growth and protein synthesis o Disruption of rise and fall of Cortisol levels, which are paired with metabolism and stress responses

46 Withdrawal Causes Compensation in the Body In order to balance Alcohol's sedative effects, o Decreased sensitivity of GABA receptors o Increased sensitivity of Glu receptors After removal of alcohol, body remains in 'overdrive' for some time

47 Its Not Just Alcohol That Causes Your Hangover

48 Congeners Contribute to taste, smell, appearance Evidence that alcohol with less congeners (more pure - gin/vodka) are less likely to produce hangover effects Alcohol with more congeners (like whiskey, brandy, and red wine) are more likely to produce alcohol effects

49 Methanol (CH4O) Is metabolized the same way as ethanol, but its metabolites are much more toxic: Formaldehyde and Formic Acid Brandys and Whiskeys contain much more methanol

50 Work Cited Crowley JJ, Treistman SN, Dopico AM. Cholesterol antagonizes ethanol potentiation of human brain BKCa channels reconstituted i nto phospholipid bilayers. Mol Pharmacol. 2003: 64: Ferrer, E., M.A. Moral, and J. Bozzo. "Antiepileptic Drugs in Alcoholism: An Update." Drugs of the Future 32.5 (2007): 429. Print. Heilig, Markus, David Goldman, Wade Berrettini, and Charles P. O'Brien. "Pharmacogenetic Approach to the Treatment of Alcohol Addiction." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 26 Oct Piertrzykowski, Andrzej, and Steven Treistman. "The Molecular Basis of Tolerance." University of Massachusetts, n.d. Web. 7 March Weiss, Friedbert, and Linda J. Porrino. "The Journal of Neuroscience Society for Neuroscience." Behavioral Neurobiology of Alcohol Addiction: Recent Advances and Challenges. The Journal of Neuroscience, n.d. Web. 26 Oct GABA. Digital image. Wikipedia. N.p., n.d. Web. Dopamine. Digital image. Wikipedia. N.p., n.d. Web. Serotonin. Digital image. Wikipedia. N.p., n.d. Web. Ethanol. Digital image. Wikipedia. N.p., n.d. Web. Asparagine. Digital image. Wikipedia. N.p., n.d. Web. Aspartate. Digital image. Wikipedia. N.p., n.d. Web.

51 Works Cited "Alcohol and Health." Alcohol and Health. (2012): n. page. Web. 30 Oct < Yoshimoto, K, W.J. McBride, L Lumeng, and T.K. Li. "Alcohol." Alcohol. 9.1 (1992): Web. 30 Oct Swift, Robert, and Dena Davidson. "Alcohol Health & Research World." Alcohol Health & Research World (1998): Web. 30 Oct < Boileau, Isabelle, Jean-Marc Assaad, et al. "Synapse."Synapse (2003): Web. 30 Oct Dekker, Anothony. "What are the effects of alcohol on the brain?." Scientific American. Scientific American, Web. 30 Oct <

52 Interactive Question! What are some hangover myths that you can debunk from what you've learned today about hangovers and alcohol use?