Chapter 10: Alcohol Flashcards
Alcohol Use
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
Ethanol is absorbed from GI tract
- 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
Heavy alcohol use
Vitamin B1 (thiamine) deficiency/ Korsakoff’s syndrome
Caused by damage to thalamus nuclei and brain regions involved in memory
*vasodilation occurs in brain
EtOH is metabolized by the […] or excreted by the […]
EtOH is metabolized by the liver or excreted by the lungs
Alcohol —->
Acetaldehyde
Enzyme: alcohol dehydrogenase
Byproduct: NAD+
Acetaldehyde —>
Acetic acid
Enzyme: aldehyde dehydrogenase (ALDH)
Byproduct: NAD+
Acetic Acid —>
Carbon dioxide
- Oxidation reaction
Byproduct: water and energy
Alcohol flush reaction
Flushing
Nausea
Headache
Increased heart rate
EtOH —> Aldehyde metabolism
- CYTP450 liver enzymes
- CYP2E1= microsomes ethanol oxidizing system (MEOS)
- Induction of liver enzymes: increased number of liver enzymes
Prolonged alcohol use —> physical dependence
Alcohol shows cross dependence with other drugs
- Delirium’s Tremens (DT): sever withdrawal effects like irritability, headaches, agitation, and confusion
EtOH crosses […]
EtOH crosses cell membranes, including BBB
EtOH has both […] and […] actions
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
Alcohol preferring mice have gene that encodes […]
Alcohol preferring mice have gene that encodes mGluR2
Specific Alcohol Action
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
Non-specific alcohol actions
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
Acute EtOH […] neuronal excitability
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
GABAb agonist […] prevents selection of alcohol over water
GABAb agonist baclofen prevents selection of alcohol over water
Alcohol effects on NMDA-R
- Memory loss associated with intoxication
- Rebound hyperexcitability associated with abstinence syndrome
- 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
[…] and […] antagonize hyperpolarization and behavioral effects of alcohol
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
Repeated exposure to alcohol […] GABAa- mediated Cl- flow
Repeated exposure to alcohol decreases GABAa- mediated Cl- flow
- Chronic alcohol= more sensitive to seizure-inducing doses of GABA antagonist bucuculline
Chronic Use of EtOH: Glutamate
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
Chronic Use of EtOH: GABA
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
Acute EtOH modulates […] and […] systems
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
Chronic use of EtOH […] endorphins in brain
Chronic use of EtOH decrease endorphins in brain
Chronic use of EtOH results in neuroadaptations
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
Neuroadaptations underlying changes following chronic EtOH
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
Phosphorylation of pCREB may be responsible long-term changes in cell function because of […]
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
Neurobiology of Addiction: Alcohol
(+) 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
2 types of AUD
Type I: begin drinking later in life, but feel guilty
Type II: thrill-seeking, antisocial, and criminal behavior
Symptomatic Drinking
Reinforcing effects of alcohol when stress and tension are relieved
Polymorphism in […] can indicate early onset of drinking
Polymorphism in CRF gene can indicate early onset of drinking
Fatty Liver
Involved accumulation of triglycerides inside liver cell
Alcohol-Induced Hepatits
Leads to liver cell death
Alcohol- Induced Cirrhosis
Death of liver cells stimulates formation of scar tissue
Fetal Alcohol Spectrum Disorders (FASD)
Damaging developmental effects of prenatal alcohol
*Fetal Alcohol Syndrome (FAS): more severe
AUD Treatment
- Detoxification using chlordiazepoxide (Librium) and diazepam (Valium)
- Psychosocial Rehabilitation
- 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
