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Neuropharmacology > Chapter 10: Alcohol > Flashcards

Chapter 10: Alcohol Flashcards

1
Q

Alcohol Use

A

Current Use: in the past month

Binge Use:

   - M: over 5 drinks in 2 hours
   - F: over 4 drinks in 2 hours

Heavy use: over 5 binges in past 30 days

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2
Q

Ethanol is absorbed from GI tract

A
  • More alcohol + short consumption= high BAC
    - behavioral effects are described on basis of BAC, not amount ingested
  • Food (or milk) delays absorption
    - slows absorption because it delays movement into small intestine through pyloric sphincter
    - alcohol dehydrogenase has more opportunity to metabolize alcohol in stomach
  • Gender difference in absorption
    - per unit of EtOH, BAC in females will be higher than in males
    - absorption from GI: 10% from stomach and 90% from small intestine
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3
Q

Heavy alcohol use

A 
Vitamin B1 (thiamine) deficiency/ Korsakoff’s syndrome 
        Caused by damage to thalamus nuclei and brain regions involved in memory

*vasodilation occurs in brain

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4
Q

EtOH is metabolized by the […] or excreted by the […]

A

EtOH is metabolized by the liver or excreted by the lungs

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5
Q

Alcohol —->

A

Acetaldehyde

Enzyme: alcohol dehydrogenase

Byproduct: NAD+

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6
Q

Acetaldehyde —>

A

Acetic acid

Enzyme: aldehyde dehydrogenase (ALDH)

Byproduct: NAD+

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7
Q

Acetic Acid —>

A

Carbon dioxide

  • Oxidation reaction

Byproduct: water and energy

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8
Q

Alcohol flush reaction

A

Flushing
Nausea
Headache
Increased heart rate

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9
Q

EtOH —> Aldehyde metabolism

A
  • CYTP450 liver enzymes
  • CYP2E1= microsomes ethanol oxidizing system (MEOS)
  • Induction of liver enzymes: increased number of liver enzymes
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10
Q

Prolonged alcohol use —> physical dependence

A

Alcohol shows cross dependence with other drugs

  • Delirium’s Tremens (DT): sever withdrawal effects like irritability, headaches, agitation, and confusion
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11
Q

EtOH crosses […]

A

EtOH crosses cell membranes, including BBB

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12
Q

EtOH has both […] and […] actions

A

EtOH has both specific and non-specific actions

Increasing BAC:

  • Relaxation, Elevation Mood
  • Impaired judgement; relaxed inhibitions
  • Motor incoordination
  • Major mental and physical impairments
  • Death; Coma; Loss of consciousness
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13
Q

Alcohol preferring mice have gene that encodes […]

A

Alcohol preferring mice have gene that encodes mGluR2

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14
Q

Specific Alcohol Action

A

At low-moderate doses

  • influences ligand-gated channels and 2nd messenger systems
    Ex. Gs—> cAMP
  • Acts at NT binding site
  • modifies gating mechanism inside channel
  • interacts directly with channel protein
  • stimulates Gs which is linked to adenylyl cyclase
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15
Q

Non-specific alcohol actions

A

depends on alcohol’s ability to move into membranes, changing fluid character of lipids that make up membranes

  • disturbs the relationship of protein in membrane
  • interacts with polar heads of phospholipids
  • alters lipid composition
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16
Q

Acute EtOH […] neuronal excitability

A

Acute EtOH decreases neuronal excitability

Glutamate

 - EtOH inhibits iGlu receptors
         - NR1/2A or NR1/2B
         - and non-NMDA
 - Decreased Glu release
 - Has greatest effect on NMDA-R
 - Reduced Glu in hippocampus= decreased spatial memory

GABA- increased inhibition

 - EtOH increases Cl- flux through GABAa receptor
 - Subunit specificity
          - decreases loss of righting reflex in a1/B2 (mediate sedative -hypnotic effects of alcohol/ synaptic) KO mice
          - EtOH consumption in a4/d or a6/d (d= bezondiazepine insensitive) (extrasynaptic/ produce tonic inhibition) KO mice
17
Q

GABAb agonist […] prevents selection of alcohol over water

A

GABAb agonist baclofen prevents selection of alcohol over water

18
Q

Alcohol effects on NMDA-R

A
  1. Memory loss associated with intoxication
  2. Rebound hyperexcitability associated with abstinence syndrome
  3. NMDA- mediated excitotoxicity associated with alcohol-induced brain damage
  • Repeated alcohol use= increase NMDA receptors
    - Elevated Glu activity during withdrawal —> Ca2+ influx —> cell death
    - in pregnancy, impairs NMDA receptors and decrease Glu release —> decreased NMDA receptors as adult
19
Q

[…] and […] antagonize hyperpolarization and behavioral effects of alcohol

A

Picrotoxin (blocks Cl- channel) and bicuculline (competes with GABAA) antagonize hyperpolarization and behavioral effects of alcohol
* Both Cl- conductance and GABA binding to receptor are necessary for effects of alcohol to occur

Increased GABA= increased alcohol- induced behavioral effects

  • alcohol-induced behavioral effects show relationship to increase GABA- induced Cl- entry and intensity of response to alcohol
20
Q

Repeated exposure to alcohol […] GABAa- mediated Cl- flow

A

Repeated exposure to alcohol decreases GABAa- mediated Cl- flow

  • Chronic alcohol= more sensitive to seizure-inducing doses of GABA antagonist bucuculline
21
Q

Chronic Use of EtOH: Glutamate

A

Acute EtOH inhibitors NMDA receptors are decreases LTP
- “Blackouts”- disruption of memory consolidation (inhibitor of LTP)

Chronic EtOH upregulates NMDA receptors and increases Glu release

    - “Wet brain”- EtOH- Induced excitotoxic damage
    - following abstinence, increased seizure risk
22
Q

Chronic Use of EtOH: GABA

A

Acute EtOH increases GABAa receptor function
- like benzodiazepines (BDZ), related to the anxiolytic, sedative and muscle relaxing properties of EtOH

Chronic EtOH associated with down-regulation of a1, but up-regulation of a4 and a6

    - increased sensitivity to convulsants; hyperexcitability; seizures; tremors
    - BDZ’s lose potency; contributes to cross- tolerance
23
Q

Acute EtOH modulates […] and […] systems

A

Acute EtOH modulates DA and opioid systems
* Acute EtOH is positively reinforcing

Dopamine: EtOH increases firing rate of VTA neurons in the mesolimbic pathway, more DA released in N Accs

    - Rodents will self-administer EtOH directly into the VTA
    - DA antagonists reduce self-administration of EtOH, but do not block completely (reduced DOPAC and HVA)

Opioid: EtOH increases synthesis and release of enkephalins and endorphins

    - promotes DA release in the mesolimbic pathway
    - MOR antagonists (eg, naltrexone used to treat substance use disorders
24
Q

Chronic use of EtOH […] endorphins in brain

A

Chronic use of EtOH decrease endorphins in brain

25
Q

Chronic use of EtOH results in neuroadaptations

A

Dopamine

  • decreased AP firing in VTA neurons
  • decreased DA release in the N Acc
  • tolerance; lower allostatic set-point

Opioids

  • decreases opioid synthesis
  • contributes to withdrawal-induced dysphoria
26
Q

Neuroadaptations underlying changes following chronic EtOH

A

cAMP/ PKA/ pCREB

Acute EtOH

  • increased pCREB in PFC, hippocampus
  • targets of CREB include BDNF and NPY

Chronic EtOH/ withdrawal

  • decreased pCREB in PFC and decreased BDNF may cause impaired “top-down” control
  • decreased pCREB in CeA, decreased NPY (anxiolytic) and increased CRF (anxiogenic) associated with dysphoria
27
Q

Phosphorylation of pCREB may be responsible long-term changes in cell function because of […]

A

Phosphorylation of pCREB may be responsible long-term changes in cell function because of disruption of cAMP cascade

  • Rolipram (enhances cAMP cascade) can be used to treat alcohol use disorder
28
Q

Neurobiology of Addiction: Alcohol

A

(+) Reinforcing/ Reward motivated: DA/ opioids

Neuroadaptations: increased Glu, decreased GABA and pCREB

(-) Reinforcing/ Habitual:

  • less DA release: Tolerance
  • decreased NPY and increased CRF: anti-reward
  • elevated ICSS threshold
29
Q

2 types of AUD

A

Type I: begin drinking later in life, but feel guilty

Type II: thrill-seeking, antisocial, and criminal behavior

30
Q

Symptomatic Drinking

A

Reinforcing effects of alcohol when stress and tension are relieved

31
Q

Polymorphism in […] can indicate early onset of drinking

A

Polymorphism in CRF gene can indicate early onset of drinking

32
Q

Fatty Liver

A

Involved accumulation of triglycerides inside liver cell

33
Q

Alcohol-Induced Hepatits

A

Leads to liver cell death

34
Q

Alcohol- Induced Cirrhosis

A

Death of liver cells stimulates formation of scar tissue

35
Q

Fetal Alcohol Spectrum Disorders (FASD)

A

Damaging developmental effects of prenatal alcohol

*Fetal Alcohol Syndrome (FAS): more severe

36
Q

AUD Treatment

A
  1. Detoxification using chlordiazepoxide (Librium) and diazepam (Valium)
  2. Psychosocial Rehabilitation
  3. Pharmacotherapy:
    - disulfiram (Antabuse): inhibits ALDH
    - naltrexone (Regina): OP-receptor antagonist
    - Nalmefene (KOR-MOR modulator): effective in reducing lever pressing for alcohol
    - Acamprosate (Campral): NMDA partial antagonist and blocks Glu increase

Neuropharmacology (15 decks)

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