Alcohol

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• 2 bill people world wide consume alcohol

• more than half of US resdents consume alcoholic bev

• All alcoholic bev contain ethyl alcholol

  • absorbed into blood thro stomach lining and instestines'

  • takes effect in blood stream and CNS

• Alcohol has depresant actions on the CNS

  • increases seditive effect of anti histamines

• Dose response for alcholol

  • In nontolerant individuals, Low levels (10 to 50 mg%) are anxiolytic and predoce a feeling of weel being and increased socialbity

  • As levels increase (150-200 mg%) produce

  • exceeds 300mg% throw up and blackout

  • 400-500mg% fatal

• Alcholol use disorder

  • clinical pic

    • reg consumption and reliance affects cognition, social life, and work behaviors

    • individual patterns of use vary

  • Destroys families relationships and carreers

    • Alcohol plays a role in suicicdes, homicides, sexual and phisical assults as well as car accdents

    • Long term exessive drinking

  • Tolerance

    • the leathal does 50% (LD50) in nontolarant humans is aprox 400-500Mg%

    • Blood levels exceding these levels are often repoted for drunk driving

    • capacity to metabolize alcholol and in cellular adaptions

• College binge drinking

  • 38% of students binge drink once a month, 1/3rd binge 6 times or more monthly

    • lingering impact on mood mem and heart/brain functioning

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• Where does alcohol exert its effect

  • Increases VTA domaine firing rates

    • animals will self adminster alcholol to posterior VTA (but not anterior)

  • Long term exposure chnaged the excitabity of the dopamine neurons in the absance of alcholol

  • Increased doapmine in nucleus accumbens

  • increaded dopamine durring anticaption of drinking

  • increased glutamate signaling in straitum and limbic (amygdala) regions leads to stonger learned responses

    • NMDA receptors are senstive to alcholol -LTP!

  • Widespread interactions

    • no one receptor that alcohol binds to

    • ion channels

  • Ion channels involved in alcholol

    • Lingand gated

      • Ach

      • GABA

      • Glycine

      • 5HT3

      • Glutamate

      • Purinergic

    • Voltage gated

      • potasium K+

      • Calcium Ca+2

• The impact on dopamine neurons

  • NMDA receptors help inhibit VTA dopamine

    • alchol disinhibits VTA

    • NMDA antagonists can mimic alcohol (rat discrimination test)

  • Votoage gatted ptasioum channels reduce excitabity of VTA dopmaine neurons (alcohol removes that regulation)

• Phosophorylation of GABA receptors may be important

• Serotonin and acetylcholine

  • Reduced serintionin levels (5-HT) in problamitic drinkers

    • SSRIs do not help

    • In part the prob is likely recpeptor subtype (5-HT) specific

  • Alcholol increases currents thro 5-HT3 receptors and antagonists like Zofran reduces drinking (espcialy early in the addiction)

  • Nicotinic acteyocloine receptors are effected by alcholol

  • Chantix- partial agonist at the a4B2 nicotinic recpetor- used for smoking cessation also appears to reduce alcohol seeking in rats

• P2x

  • ATP activates these channles

  • BLAH

• Structure of the subunits going into receptors matters

  • Change amino acids in protein subunits (e.g. GABBA) and it changes alcohol response.

• Opioids (already in body)

  • alcohol inreases the reaslease of endogenous opioids

    • this is part of pleasure feeling

  • Opioid antagonists (naloxone and naltrexone) reduce alcohol intake in people

• Chronic exposure

  • NMDA channles up regulate over time- more channels get stuck in membane- because the are chronically inhibited

  • This can cause seizures durring withdrawl

    • Delirium tremens (the shakes)

    • 3 days into withdrawl and lasts for 2-3 days

    • can result in death

  • Long term changes

    • Anygdala is overactive when seaking cuesn associated with drinking

    • craving is pronounced even in abstanince

    • even after withdrawl we see increased reposniveness to associated cues