Alcohol

Question 1

What are the basics of alcohol?

Answer 1

2nd most commonly used drug, most abused
2/3 consumed, 10% addicted.
Ethanol from fermnetation by sugars and yeasts (grapes, rice, grains)
Methyl and isopropyl are toxic to ingest
Easily absorbed from GI tract and goes into tissues (brain too)
Behavioral effects on BAC (mg/100ml blood) not amount ingested cause there are different drink [ ].
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Question 2

What happens at different doses of alcohol?

Answer 2

Biphasic:
Lower doses: disinhibition, eurphoria, relaxation, impaired judgement, increased risk taking
- depresses neural activity, suppresses inhibitory GABAergic interneurons, causes a “stimulant” like effect even tho its a depressor.

Higher doses: slurred speech, impaired motor co-ordination, memory, sedation, black-out.
- suppression of cortical pyramidal neuron activity

Effects of alcohol influenced by environmental factors (alcohol occurs under placebo too!)

Question 3

how does alcohol diffuse? what effects absorption?

Answer 3

From gastro tract into blood (stomach and intestines-faster in Intestine)

• greater concentration of alcohol, more rapid, larger increase.
• contents of stomach (more food in tummy means less gets to small intestine cause sphincter is closed, since small intest does it faster there will be slower absorption. it also just takes longer to get through the cheeseburger to the stomach walls).

Question 4

How is alcohol metabolized?

Answer 4

Alcohol dehydrogenase (in liver and gastric fluid)

• more active in men 60%
• 95% metabolized by liver, the rest by lungs

Turns to acetaldehyde (makes you feel bad) then acetic acid by acetaldyhyde dehydrogenase (ALDH)
- polymorphisms exist (asian people)

• Cytochrome P450 also convert alcohol to acetaldehyde
• CYP 2E1: metabolizes ethanol, but also other drugs (Can be interactions that lead to too much competition for enzyme molecules = dangerous)

Question 5

What happens when asian people drink?

Answer 5

inactive ALDH. buildup of toxic acetaldyhyde (flushing nausea, vomiting, tachycardia, headache, dizziness, etc)

Question 6

What are the types of alcohol tolerance?

Answer 6

Acute: single exposure. Drug effects greater when levels are INCREASING but even if they are higher, if plateaued you feel sober even if you aren’t

Metabolic: incrase in CP450 liver enzymes (body gets better at metabolizing it, you have less BAL content)

Pharmacodynamic: neurons adapt via compensatory changes

Behavioral: get better at performing tasks while drunk (allows for adjustment and compensation)

Question 7

What is acute toxicity?

Answer 7

HIgh doses: unconsiousness/death (at 0.45 BAC) because of depression of respiratory centers. but this is hard to get to cause of vomiting at 0.15 and unconciousness at 0.35. but alcoholics can become tolerant to this and teenagers can drink a lot all at once (mickey chug) and cause issues
- alcohol poisining, slow and irregular breathing, cold, clammy, bluish skin

Question 8

What are the effects chronic toxicity?

Answer 8

• Liver death
• Korsakoff’s syndrome (diet related)
• Enlarged ventricles and thin gyri (glutamate exitotoxicity during withdrawal, too much withdrawal leads to this)

Question 9

What is karsakoff’s syndrome?

Answer 9

confusion, disorientation, tremors, poor coordination, ataxia

• make up stories why they can’t remember something
• severe anterograde amnesia because of medial thalamus (b1 deficiency)
• related to poor diet

Question 10

What are types of neurobiological actions alcohol has?

Answer 10

Tiny molecules that can cross BBB

nonspecific: polar heads of membrane lipids, alters compositoin, disturps relationships of proteins.
- can make them leaky, more ions flow in/out, disrupts receptor function

specific: specific sites on specific proteins resulting in specific actions
- ligand gated channels and second messenger symptoms.

Question 11

Describe alcohol and GABA transmission.

Answer 11

Alcohol acts as positive allosteric modulator on GABA A receptors. (similar to benzodiazapines)

• ionotropic receptors
• works on many subtypes
• on wired and extrasynaptic transmission.
• extrasynaptics are usually only activated at large concentrations, but these are supersensitive to alcohol! (delta, alpha 4, alpha 6 units)

Question 12

What do GABA -A antagonists

Answer 12

block inhibitory effects of alcohol and reduce its intoxicating effects.

Question 13

GABA A receptor extrasynaptic receptors: what happens to animals with delta, alpha 4, alpha 6 receptor subunits knockouts?

Answer 13

consume less alcohol. may mediate reinforcing effects

Question 14

what happens to gaba a receptors if you have repeated alcohol exposure

Answer 14

reduced GABA A receptor mediated inhibition (less Cl- flux than normal)

• pharmacodynapic tolerance and withdrawal symptoms (cortical hyperactivity, convulsions, hallucinations)

Question 15

what are the acute effects of alcohol on glutamate transmission?

Answer 15

• reduces NMDA receptor effectiveness (which is what alcohol acts on to impair learning and memory) -negative allosteric modulator
• repeated alcohol exposure up-regulates NMDA receptors to deal with reduced activation
• reduce glutamate release

IN WITHDRAWAL
leads to rebound hyperactivity (glutamate release can increase causing seizure)

Question 16

Why do we think glutamate is mediating withdrawal symptoms?

Answer 16

maximum withdrawal symptoms at the same time as maximum glutamate release?

Question 17

What happens if rebound hyperactivity happens repeatedly?

Answer 17

• excessive calcium entry
• PFC exitotoxicity
• makes it even harder to make decisions and shit

Question 18

What are alcohol’s effects on DA transmission?

Answer 18

ACUTE: increases VTA DA neuron firing, and DA release in NAc

• not too sure why
• injections of alcohol into VTA increase DA release
• rats will self administer DA into VTA , blocking DA receptors in NAc reduces alcohol self administration

CHRONIC: repeated administration sensitizes effects of alcohol on DA release (maybe why its addictive)

Withdrawal: associated with reduced DA activity: correlated with increased withdrawal behaviors and not as much responding for rewarding stimuli.

Question 19

Describe drinking rats?

Answer 19

selective breeding for alcoholic rats.

• these rats have much more responsive dopmaine systems (when they drink, more dopamine release)
• maybe why ppl get addicted?
• endogenous opiod systems more responsive
• show higher baseline levels of mu opiod receptors in NAC and Amygdala.

Question 20

What are alcohol’s effects on opiod transmission?

Answer 20

Contribute to reinforcing and pleasureable effects of alcohol.
- Acute alcohol increases endorphin and enkephalin release/production in NAc

• may contribute to alcohol induced increases in DA release
• chronic administration REDUCES opioid production, may lead to alcoholism and withdrawal

Question 21

What do opioid receptor antagonists (naltrexone) do?

Answer 21

reduce alcohol self administration (same as mu opiod receptor knockout, sometimes even show an aversion to it)
- shows that it may contribute to the addictive potential

Question 22

Describe alcohol use disorder?

Answer 22

10% have issues

• diagnosis dependant on behavioral, cognitive and physical factors
• frequency and pattern are as significant as amount of liquor (binge drinking 5 drinks in a row often is alcoholism)
• no cause identified.
• influences everyone! (family, healthcare systems)

Question 23

What are the factors that contribute to alcoholism?

Answer 23

Psychological:

• response to stress, can be reinforcing to releive (high anxiety, early life stress, family history show more cortisol)
• personality variables (novelty seekers-DA 4 receptor and system differences)

Neurobiological/

• genetic factors: close relatives 3-7x more liley to get it, lots of polymorphisms
• lower sensitivity (higher tolerance) to alcohol cause they drink more probably which leads to the brain changes.

Question 24

How is alcoholism treated?

Answer 24

• hard to recognise, for person and friends and family too.
  1) detox: withdrawal sucks but benzos can be given as replacement therapy
  2) Psychosocial: programs, AA (don’t report failures)
  3) pharmacotherapeuatic
  i) make it unpleasnt (disulfram increases acetaldyhyde), not effective)
  ii) reduce reinforcing qualities (naltrexone reduces craving, consumption and improves abstinence rates-reduces relapse best with therapy)
  iii) other factors (antagonists for NMDA or CRF receptors)