Alcohol

• Ethyl alcohol (=ethanol)


  Produced by yeast that consume sugar
• Alcohol

  Also sometimes produced in the body due to pathology (auto-brewery syndrome); ethanol is created in the digestive system via breakdown of carbohydrates.
• Ethanol


  • Soluble in water, but also partially lipid soluble
• Lipid solubility


  • Lipids pass directly through cell membrane (local anesthetics and steroid hormones)
  • Blood brain barrier is lipid, fat depots (THC)
• Alcohol and aldehyde dehydrogenase


  Break down ethyl alcohol into acetaldehyde (toxic) and then acetic acid in the liver and stomach
• Inactivation


  Drug clearance of ethyl alcohol (example of zero-order kinetics)
• Aldehyde dehydrogenase important for the metabolism of alcohol
• Prevalence of alleles varies across countries
• Gender Differences


  Aldehyde dehydrogenase metabolizes alcohol more effectively in men than in women
• Alcohol

  • Has actions that are both specific (i.e., on certain NT receptors) and nonspecific (e.g., on lipid membranes)
• Alcohol

  • Positive allosteric modulator of GABAA receptor
  • Binds to a different site than GABA, increases chloride flow via intracellular phosphorylation
• Overlap between alcohol and benzodiazepines/barbiturates

  All are positive allosteric modulators of the GABAA receptor but depends on the subunits that make up the channel; direction of effects reverses with chronic use; They act as sedatives; Show cross-dependence (withdrawal signs of one can be relieved by taking the other) and cross-tolerance; Can be especially dangerous when combined (likely cause of death of Jimi Hendrix)
• Alcohol

  Enhances the activity of GABAB receptors
• Baclofen

  Competitive antagonist for GABAB receptors
• Baclofen

  Reduced alcohol consumption in rats
• Effects of ethanol on NMDA receptors

  • Inhibits glutamate action in the short term
  • Causes upregulation of receptors over the long term
• Acamprosate (Campral)

  Possible treatment for alcohol use disorder, antagonist of NMDA receptor (blocks glutamate during alcohol withdrawal), also returns GABA levels to normal in alcohol- dependent rats
• Inky cap mushroom

  Contains coprine, which inhibits aldehyde dehydrogenase (so does disulfiram = Antabuse)
• Animals

  Can be bred to be alcohol-preferring (P) or non-preferring (NP) – what differs between them?
• Addictive Drugs cause increased release of dopamine into nucleus accumbens, including alcohol
• Alcohol

  Increases endogenous opioid activity, especially true for rats with a high preference for alcohol (P) vs. those with a low preference for alcohol (NP)
• Opioid receptor antagonists (e.g., naltrexone, naloxone)

  Reduce alcohol self-administration in animals
• P vs. non-P rats are more sensitive to pleasurable substances in general (e.g., sugars)
• Acute vs. chronic effects of alcohol

  Often opposite
• Tolerance

  • Metabolic, due to increase in P450 enzymes in the liver; pharmacodynamic, decrease in GABA receptor number; behavioral, where alcoholics learn to perform better at task while intoxicated
• Withdrawal

  • Can include tremors, increased heart rate, sweating, nausea, vomiting; extreme form =delirium tremens (DTs) with convulsions (increased excitatory NT activity), hallucinations, delirium
• Damage to the brain and liver
• Multiple mechanisms by which alcohol increases dopamine action in nucleus accumbens

  All involve release from inhibition
• Alcohol

  Shifts from positive to negative reinforcement with addiction
• Wernicke's encephalopathy leading to Korsakoff's syndrome

  Thiamine deficiency in Korsakoff's causes damage to the mammillary bodies of the hypothalamus (receives input from the hippocampus via the fornix) or dmThalamus, results in confabulations (lies)
• Alcohol affects many brain areas, but at different doses
• Alcohol dose effects

  • 0.05 - 0.06 - Influence on prefrontal cortex
  • 0.08 - 0.10 - Influence on cerebellum
  • 0.45 - Influence on brainstem
• Ethyl alcohol (=ethanol)


  Produced by yeast that consume sugar
• Alcohol


  Also sometimes produced in the body due to pathology (auto-brewery syndrome)
• Ethanol


  Soluble in water, but also partially lipid soluble
• Lipid solubility


  • Lipids pass directly through cell membrane (local anesthetics and steroid hormones)
  • Blood brain barrier is lipid, fat depots (THC)
• Alcohol and aldehyde dehydrogenase


  Break down ethyl alcohol into acetaldehyde (toxic) and then acetic acid in the liver and stomach
• Inactivation


  Drug clearance of ethyl alcohol (example of zero-order kinetics)
• Aldehyde dehydrogenase


  Important for the metabolism of alcohol
• Prevalence of alleles varies across countries