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Chapter 10: Alcohol - Coggle Diagram

- - - - NMDA Receptor antagonist
      - AMPA Receptor antagonist
      - mGluR autoreceptor agonist
      - Reduces glutamate release in hippocampus --> impairs LTP
        
        alcohol-induced amnesia (blacking out)
    - - up-regulation of NMDA receptors in response to reduced glutamate activity
      - Rebound increase in glutamate release during withdrawal --> excitotoxicity (because there's more receptors) and cell death
        
        rebound hyperexcitability during withdrawal
  - - - binds to GABAa receptors and opens channel
        
        increase Cl- influx
        
        GABAa receptors that are highly sensitive to alcohol contain S subunit
        
        S subunit KO mice showed reduced preference for alcohol
    - - repeated exposure to ethanol REDUCES GABAa-mediated influx
        
        makes animals more sensitive to seizure-inducing doses of GABA antagonists (because there's a decrease in GABA function without a change in number of receptors)
  - - - rats self-admin ethanol into the VTA
        
        DA independent mechanisms of reinforcement:
        
        DA antagonists in the NAcc and 6-OHDA destruction of DA nerve terminals in NAcc REDUCE (BUT NOT ABOLISH) self-admin of ethanol
    - - withdrawal of alcohol after chronic use
        
        reduces the firing rate of mesolimbic neurons
        
        decreases DA release in the NAcc
      - Rebound depression of reinforcement mechanisms during withdrawal
        
        elevation of threshold for ICSS
        
        reinforcement is now less rewarding (reward system is damaged during withdrawal)
  - - - alcohol-induced opioid release may produce reinforcement by MODULATING DA
        
        endorphin inhibits GABA neuron
        
        frees DA neuron from inhibition
        
        allows it to release DA into the NAcc
    - - opioid receptor ANTAGONISTS reduce alcohol self-administration
        
        i.e. naloxone and naltrexone
    - - higher baseline levels of mu-opioid receptors in NAcc and amygdala
- - - - .04% BAC to produce MEASURABLE behavioral effect
      - 0%: normal
        
        .05%: personality changes, relief from anxiety, social lubricant, disinhibition
        
        .08%: significant disinhibition, impaired judgement, impaired cognition, impaired motor function
        
        .15%: marked ataxia (staggering, slurred speech), major motor impairment, impaired reaction time, blackouts
        
        .30%: increased sedation/hypnosis, approaching general anesthesia, approaching coma
        
        .40%: lethal dose for half of people
    - - absorption from a single dose will continue for 3-4 hours
  - - - carbonated alcohols are absorbed quicker
  - - - Acetalaldehyde (VERY TOXIC) is acted on by acetaldehyde deydrogenase -->
        
        acetic acid is oxidized -->
        
        carbon dioxide
    - - ADH also in stomach: higher in males
      - Asian flush
        
        about 10% of Asians are homozygous for inactive form of ALDH gene
        
        40% are heterozygous
        
        marker for low risk of alcoholism
        
        ADH breaks down alcohol --> acetaldehyde, but inactive ALDH gene means that there's very high levels of acetaldehyde in the body (very bad side effects)
    - - CYP450 family member (CYP2E1; aka MEOS)
        
        only is active after a person has consumed LARGE amounts of alcohol
        
        can be induced
        
        repeated exposure --> CYP2E1 enzymes can more than double expression levels within two weeks)
      - Catalase
        
        metabolizes only a small fraction of alcohol
- - - - critical for brain glucose metabolism
      - low levels cause cell death
      - ethanol interferes with THIAMINE UPTAKE in the GI tract
      - animals fed thiamine deficient diets/given antagonists have similar brain lesions and deficits in learning and memory
      - Wernicke-Korsakoff syndrome
        
        example of vitamin B1-induced brain damage --> neurodegenerative
        
        confusion and disorientation, tremors, poor coordination, ataxia
        
        first stage: confusion/disorientation
        
        later stages: patient remembers the remote past (past that is more than a few days ago), nothing else
        
        bilateral cell loss in the medial thalamus and mammilary bodies
        
        Thiamine treatment can STOP the degeneration, but CANNOT reverse it
    - - ventricle enlargement
      - frontal lobe cell loss --> personality changes
      - hippocampal and MTL cell loss --> memory dysfunction
      - cerebellar cell loss --> ataxia
    - - dilation of peripheral blood vessels (more blood flow to skin) --> flushing and feeling warm
        
        in actuality, body is losing heat
      - vasodilation in the brain --> improves cognitive function in older adults
  - - - death of liver cells --> scar formation
      - blood vessels carrying oxygen are cut off
- - - - drug effects are greater while the blood level of alcohol is increasing and smaller while the blood level is falling
    - - increase in CYP450 liver enzymes that metabolize alcohol
    - - neurons adapt to the continued presence of alcohol by making compensatory changes in cell function
    - - practicing behaviors while under the influence of alcohol allows adjustment and compensation
  - - - symptoms: tremor, anxiety, high blood pressure, rapid heart rate, sweating, rapid breathing, nausea, vomiting
        
        Delirium tremens (DTs) - rare: convulsions, hallucinations, disorientation, panic attacks, unstable blood pressure
    - - relief from withdrawal: negative reinforcement
        
        leads to continuous loop of repeated abstinence and relapse
- - - - Disulfiram: inhibits ALDH
        
        drinking even 1oz of alcohol --> flushing, pounding heart, nausea, vomiting
      - Naltrexone: mu-opioid receptor antagonist
        
        reduces "high" associated with alcohol
        
        alcohol loses its rewarding effects, becomes less reinforcing
        
        improves absistence rate
        
        taken PO
        
        longer acting, better for long-term dependence
        
        Naloxone: rapid onset, short acting, not available PO
      - Acamprosate: partial NMDA receptor antagonist
        
        blocks glutamate release during withdrawal
        
        restores basal GABA levels in dependent rats
        
        reduces some of the brain's hyperexcitability associated with withdrawal