Alcohol - University of Colorado Boulder

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

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

Alcoholism

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

• Neurochemical systems reinforce effect
of alcohol:
o GABA
Neurochemical Systems
o Opioid Peptide
o Dopamine (DA)
www.wikipedia.org/
o Serotonin
o Glutamate

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
www.wikipedia.org/

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

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

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

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

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. 2012.

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
www.wikipedia.org/

• 118G SNP
OPRM1 and Mice
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

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. 2012.

• 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
Naltrexone
www.wikipedia.org/

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

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. 2012.
118A
118G

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

TOLERANCE
Allostasis: stability through change
http://pubs.niaaa.nih.gov/publications/arh314/298-309.htm

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

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

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

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

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

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

Cholesterol

Cholesterol...

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.

GABAa
• Enhanced function
• Inhibitory

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

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

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

Physical Effects of
Alcohol in the Brain

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

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

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.
http://pubs.niaaa.nih.gov/publications/arh313/185-195.htm

Row a) Control subject
Row b) Alcoholic subject
http://drugtoxicology.wikispaces.com/Nervous+System+Damage

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

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

The Hangover
The Not Fun Part

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

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

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

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

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

Its Not Just Alcohol
That Causes Your
Hangover

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

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

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: 365-372.
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.
2012. http://www.ncbi.nlm.nih.gov/pubmed/22011682.
Piertrzykowski, Andrzej, and Steven Treistman. "The Molecular Basis of Tolerance." University of Massachusetts, n.d. Web. 7
March 2008. http://pubs.niaaa.nih.gov/publications/arh314/298-309.htm
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. 2012. http://
www.jneurosci.org/content/22/9/3332.full.
GABA. Digital image. Wikipedia. N.p., n.d. Web. http://en.wikipedia.org/wiki/GABA.
Dopamine. Digital image. Wikipedia. N.p., n.d. Web. http://en.wikipedia.org/wiki/Dopamine.
Serotonin. Digital image. Wikipedia. N.p., n.d. Web. http://en.wikipedia.org/wiki/Serotonin.
Ethanol. Digital image. Wikipedia. N.p., n.d. Web. http://en.wikipedia.org/wiki/Ethanol.
Asparagine. Digital image. Wikipedia. N.p., n.d. Web. http://en.wikipedia.org/wiki/Asparagine.
Aspartate. Digital image. Wikipedia. N.p., n.d. Web. http://en.wikipedia.org/wiki/Aspartate.

•
"Alcohol
• Yoshimoto,
•
Swift,
• Boileau,
Dekker,
Works Cited
and Health." Alcohol and Health. (2012): n. page. Web. 30 Oct. 2012. .
K, W.J. McBride, L Lumeng, and T.K. Li. "Alcohol." Alcohol. 9.1 (1992): 17-22. Web. 30 Oct. 2012.
Robert, and Dena Davidson. "Alcohol Health & Research World." Alcohol Health & Research World. 22.1
(1998): 54-60. Web. 30 Oct. 2012. .
Isabelle, Jean-Marc Assaad, et al. "Synapse."Synapse. 49.4 (2003): 226-231. Web. 30 Oct. 2012.
Anothony. "What are the effects of alcohol on the brain? ." Scientific American. Scientific American, 26
1999. Web. 30 Oct 2012. .

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