Lecture 8: Block 2- Alcohol

What type of receptor does alcohol primarily act on as a positive allosteric modulator?

GABAa receptors

Which receptor does alcohol NOT directly bind even though it influences its activity indirectly?

Dopamine receptors

What are the two key enzymes involved in alcohol metabolism?

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH).

What toxic intermediate is produced between ADH and ALDH?

Acetaldehyde.

How does Antabuse (disulfiram) work?

It inhibits ALDH, causing acetaldehyde buildup → flushing, nausea, vomiting.

Why do women reach higher BACs than men?

Lower stomach ADH, higher body fat, lower body water → less first-pass metabolism.W

Why do people of East Asian descent flush while drinking alcohol

ALDH2 deficiency→ acetaldehyde accumulation.

What are symptoms of early alcohol withdrawal?

Tremors, anxiety, sweating. tachycardia, isomnia.

What are symptoms of ate alcohol withdrawal (1-3 days)?

Hallucinations, seizures, delirium tremens.

What is pharmacokinetic tolerance?

The body becomes more efficient at metabolizing alcohol.

What is pharmacodynamic tolerance?

Neural receptors adapt to alcohol’s presence (e.g, downregulation of GABAa)

What animal model first captured alcohol-related disinhibition?

The neurotic cat model used in Geller-Seifter Conflict test.

What does the Geller-Seifter Conflict Test measure?

Punished responding under conflict→ anxiolytic or disinhibition drug effects.

Besides GABA, what other neurotransmitter systems does alcohol affect?

Glutamate (NMDA), DA, endogenous opioids, serotonin, glycine.

How does alcohol affect NMDA glutamate Receptors?

It inhibits them→ sedation and memory impairment.

How does alcohol affect endogenous opioid release?

It increase beta - endorphins→ contributes to reward and reinforcement.

Chronic alcohol use increases which system during withdrawal?

Glutamate (NMDA) hyperexcitability

1. What receptor(s) does alcohol directly affect? Which one does it NOT?

Directly affected:

• GABA_A (positive allosteric modulator → increases inhibition)

• NMDA glutamate receptors (inhibits them)

• Glycine receptors

• Serotonin (5-HT3) receptors

• Nicotinic acetylcholine receptors (some subtypes)

NOT directly affected:

• Dopamine receptors
  Alcohol increases dopamine indirectly via GABA disinhibition in the VTA.

Steps in alcohol metabolism & relevance to women, Asian ancestry, Antabuse

Metabolism Pathway

1. Ethanol → acetaldehyde (via Alcohol dehydrogenase, ADH)

2. Acetaldehyde → acetate (via Aldehyde dehydrogenase, ALDH)

   1. Acetate → CO₂ + H₂O

Women

• Lower gastric ADH → less first-pass metabolism

• More fat / less water → higher BAC
  Result: stronger effects at lower doses

Asian Descent:

• Many have ALDH2 deficiency (ALDH2*2 variant)

• Result: acetaldehyde buildup

  • Flushing

  • Tachycardia

  • Nausea

Antabuse

• Blocks ALDH

• Causes massive acetaldehyde accumulation

  • Produces unpleasant symptoms → used as aversion therapy

Early and late stages of withdrawal

Early Withdrawal (6–24 hours)

• Tremors

• Anxiety

• Nausea

• Insomnia

• Sweating

• Palpitations

Late Withdrawal (24–72+ hours)

• Seizures

• Hallucinations (visual, tactile—formication)

• Delirium Tremens (DTs): confusion, fever, hypertension → can be fatal

What are the two forms of tolerance?

Pharmacokinetic Tolerance

• Body metabolizes alcohol faster (↑ ADH, ↑ liver enzymes).

2. Pharmacodynamic Tolerance

• Brain changes receptor expression (↓ GABA_A sensitivity, ↑ NMDA receptors).

Other receptors besides GABA affected by alcohol

Alcohol also affects:

• Glutamate (NMDA) → inhibited

• Dopamine (indirect increase via VTA)

• Opioid receptors (endogenous β-endorphin release ↑)

• Serotonin (5-HT3)

• Glycine receptors

• Nicotinic ACh receptors