Lecture 8 - Alcohol

Alcohols 

Methyl alcohol Ethyl alcohol (usually the kind you drink) Isopropyl alcohol 

  • Class of chemicals produced by yeast cell fermentation and other processes

  • Sugar (glucose) is broken down into cellular energy (ATP) to form alcohol

  • Ethyl alcohol (ethanol, alcohol) – found in alcoholic beverages

  • Isopropyl (rubbing) alcohol – denatured, used for medical, automotive, and cleaning purposes

  • Methyl alcohol (methanol, wood alcohol) – metabolized into toxic chemicals such as formaldehyde

Absorption of alcohol

  • After oral intake, alcohol is absorbed into bloodstream via:

    • Stomach (~20%)

    • Small intestine (~80%)

  • Absorption slowed in the presence of food, increased carbonation

  • Blood alcohol concentrations (BACs) typically peak 45-60 min after injection 

  • Not a very potent drug

BAC effects on cognition and behavior

  • BACs also called blood alcohol level (BALs) or blood ethanol concentration (BECs)

  • Usually measured as a % g/100ml) or in ug/ml









Alcohol Metabolism


  • Occurs primarily in liver's first step is conversion to acetaldehyde by alcohol dehydrogenase (ADH)

  • Second step is conversion of acetaldehyde metabolized to acetic acid (acetate, also CO2, H2O, energy in form of acetyl CoA) by acetaldehyde dehydrogenase (ALDH)

  • Excessive alcohol intake oversaturates metabolic capacity of ALDH, results in acetaldehyde accumulation, causing nausea, headache, vertigo

Genetic variability of alcohol metabolism

  • Single nucleotide polymorphism (SNP or “snip”) = change in DNA nucleotide base (A,C, T, or G)

  • Can alter the function of the encoded protein, including metabolizing enzymes

  • SNPs resulting in increased acetaldehyde production:

    • Increased ADH activity

    • Decreased ALDH activity

    • Can cause aversion and limit alcohol intake

  • Such SNPs may be protetctive since homozygous carriers are 5-10 times less likely to develop alcoholism 

Alcohol clearance and excretion

  • Eliminted at a linear (not exponetial) rate

  • Thus, alchol generally not considered to have an elimanatio half-life (t ½)

  • Clearance rate varies by genetics, body mass, gender, drinking history, etc.

  • Typical elimination rates are about ~0.015% (1 drink) oer hr

  • Linearclerence rates primarily due to saturation of ADH and ALDH at low concentrations

  • ~95% of alcohol ingested metabolized by liver, metabolites excreted through kidneys 

  • ~4% excreted unchanged (aka still in alcohol form) via lungs; thus breath levels correlate strongly with BACs (will still excrete through lungs even if not taken orally)

  • ~1% excreted unchanged via skin

The GABAergic synapse 

  • GABA (primarily inhibitory neurotransmitter) synthesized from glutamate (primarily excitatory neurotransmitter) via glutamic acid decarboxylase (GAD)

  • Once released, inactivated by transport into neurons or glia via GABA transporters (GAT)

  • The primary GABA receptor type is GABA-A (GABAa) receptor, a pentameric (5 subunit) ligand-gated CI- channel, which when activated causes CI- influx and neuronal hyperpolarization 

Alcohol and other CNS depressant effects on GABAa receptors

  • Alcohol is positive allosteric modulator at GABAa receptors

  • CNS depressants frequently prescribed for anxiety & insomnia act similarily

    • Barbiturates (thiopental, pentobarbital, etc.)

    • Benzodiazepines (BZPs) - valium, xanax, flunitrazepam (Rohypnol, “roofies”), etc.

    • Non-benzodiazepine hypnotics  [presumed (but not rlly bad) to be safer b/c not in benzo classification] (“z-drugs” such as zolpiderm (ambien), zaleplon (Sonata), eszopiclone (Lunesta)

    • Benzos + alcohol work on same receptor, easy to overdose 

  • Depending on subunit composition, GABAa receptors can be either alcohol-sensitive or insensitive 

The glutamatergic synapse

  • Glutamate is synthesized from the amino acid glutamine

  • Once secreted, trasported into neurons or glia via excitatory amino acid transporters (EAATs)

  • The N-methyl-D-aspartate (NMDA) receptor, a tetrameric (4subunit) ligand-gated Na+/Ca2+ channel, is a major type of glutamate receptor and is essential for learning and memory

  • Others include AMPA and kainate receptors

Alcohol effects on NMDA receptors

Alcohol interacts with 2 diff receptors 

  • Alcohol is a negative allosteric modulator at NMDA receptors, which may be responsabile for teh amnestic effects of high doses

  • Like GABAa receptors, sensitivity, of NMDA receptors to alcohol depends on subunit configuration

Drug induced changes in receptors

  • drugs that act as receptor agonists can produce receptor desensitization and down-regulation (i.e., GABA-A receptors after chronic alcohol)

  • drugs that act as receptor antagonists can produce receptor sensitization (supersensitivity) and up-regulation (i.e., NMDA receptors after chronic alcohol)



Effects of acute and chronic alcohol on brain GABAa and NMDA signaling




Alcohol and the brain reward system

If alchol is primarily an ing=hibiaory molecule (Up gabaa redetor function down NMDA receptor function) how does it activate teh brain reward pathway?

  • Mesolimbic DA neurons are normally under teh control of GABAeric interneurons in the VTA

  • Theeese neurons which normally serve as a regulatory “braking” system to control teh activity of VTA dopamine neurons

  • GABA interneuron activity disruption “releaes teh brake” on dopamine neurons, causing tehm to become disinhibited

  • With alcohol, disruption is thought to occur by the release of -endorphin peptides (-EP), which act on inhibitory  opioid receptors (MORs) on terminals of GABA interneurons, causing DA neuronal disinhibition

Alcohol hangover (veisalgia)

  • Typiclaly occur 6+ hours after reaching peak BACs

  • Severity directly correlated to the amount and tupe of alcohol consuemd 

  • Attributed to factors taht fall into 3 general categories: direct effects of alcohol, acohol metabolites (i.e. acetaldehyde) and congeners (fermentation by-products and additives in alcoholic drinks)

  • Often mischaracterized as acute withdrawal

  • Other individual factors such as general health, genetics, and prior food/water ingested also contribute 

Auto Brewery syndrome (ABS)

  • Patients presznet with signs of alcohol intoxication but without alcohol ingestion

  • Include slurring of speech, incoordination leaidng to falls, blurring of vision, faintness, and memory loss

  • Very rare

  • Caused by presence of different yeast species in gastrointestinal tract and eating carbohydrate/sugar rich foods

  • Concentrations of blood up to 0.08% reported 



Review questions

8-1) Which of the following receptors does alcohol inhibit the function of?

a) NMDA

b) mu (μ) opioid receptor

c) GABAA

d) DAT

e) ALDH

8-2) The vast majority of alcohol ingested is absorbed into the

bloodstream from the Small___ ___Intestine___ (2 words), whereas

relatively less is absorbed from the stomach.