alcohol dependence Flashcards
problem of alcohol in society
Alcohol is among the top five risk factors for years lost from death or disability worldwide. It ranks first in the 15 – 49 year old age group.
It has been used for millennia, in the form of, for example, mead, beer, and wine.
Distillation increased the potency; production of gin by the Dutch is frequently credited with the start of serious alcohol abuse in Europe.
in heavy drinkers greater g/100ml would be required for tolerance
Alcohol abuse is initially driven by positive reinforcement, then
DSM 5- WHO classification
diagnositc and statisitic manual used by psychiatrists worldwide to classify illnesses
after cessation of prolonged alcohol use, the diagostic criteria is similar
initially alcohol is abuse is driven by pleasant effect (positive reinforcements), negative reinforcement (associated with unpleasant effects when you stop taking alcohol)
alcohol metabolism
alochol is broken by alcohol dehydrogenase into
acetaldehyde
which is broken by acetaldehyde dehydrogenase (genetic differences in enzyme activity or drug inhibition eg disulfaram) into acetic acid
acetic acid is oxidised into carbon dioxide and water
acetaldehyde dehyrdrogenase is a rate limiting step- individuals have a higher or lower tolderance for alcohol
blocking it can help in treatment of alcoholism, preventing breakdown of acetaldehyde to acetic acid
alcohol can be broken down by more than one pathway. If you elevate levels of substrates or other usbstrates you can produce different metabolic enzymes
eg. cytochrome p450—- such as CY P2E1
gives another route for alcohol to be broken down
non specific and specific effects of alcohol
non specific:
alters lipid composition
interacts with polar heads of phospholipids
disrupts relationship of protein in membrane
specific: acts neurotransmitter binding site modifies gating mechanism inside channel direct interaction with channel protein stimulates Gs which is linked to adenyl cyclase
describe the inhibitory effect alcohol has on glutamate transmission
Alcohol has greatest effect on NMDA receptors (ligand-gated channel made up of 4 subunits that allow Ca2+ and Na+ to enter and cause localized depolarization)
Inferred by effects on long term potentiation (LTP)
Alcohol will reduce ion flux and results in receptor upregulation
sensitivity to glutamate is compounded during withdrawal
for graph showing sucrose vs alcohol withdrawal, the glutamate output is much lower across time with sucrose
but with alcohol, the glutamate output gets higher until around 12 hours and goes down after
similarly, the withdrawal score is highest after 12 hours with a score of around 30
What neurochemical changes are caused by alcohol
Elevated glutamate during withdrawal causes excessive Ca2+ influx which contributes to cell death
Frequent withdrawal episodes may be responsible for some of the irreversible brain damage seen in alcoholism
How does alcohol have GABA potentiating effects
Inferred from the pharmacological synergism between alcohol, barbiturates and benzodiazepines
Decreased GABAA receptor subunit mRNA expression in relevant brain regions in alcohol preferring vs control strains of rats
Describe the differing effects of alcohol dependent on different subunit composition
Studies implicate importance of β and δ-subunits
Different binding sites for low/high alcohol concentrations
Extrasynaptic/presynaptic models of GABAA receptor modulation involving both GABAA receptors and receptors for other neurotransmitters
Extrasynaptic receptor activation facilitates tonic inhibition
How does alcohol act on the central nucleus of the amygdala
GABA and the neuropeptide CRF (corticotrophin releasing factor) exist as co-transmitters in many CeA neurons
This effect can be blocked in CRF1-R knock-out mice
Interesting note: these mice also show evidence for upregulation of the NR2B subunit of the glutamate NMDA receptor
What neurochemical changes are caused by alcohol
Repeated exposure to ethanol reduces the potentiation of GABAA-mediated Cl– flux
Reduced effect of positive allosteric modulators
Alterations in relative levels of receptor subunit mRNA (eg decrease in α1, increase in α4)
Chronically treated animals have decreased sensitivity to sedative, motor incoordination, acute cognitive impairment (all have GABAA receptor mediated components)
Chronically treated animals in withdrawal are sensitive to seizure activity
How does alcohol affect dopamine
The mesolimbic system plays a significant role in reinforcement and motivational mechanisms.
The terminal region, the nucleus accumbens is involved in integration of primary reinforcing cues that lead to repeated drug use and motivation for the drug
Increased dopaminergic transmission in this system occurs in response to most drugs of abuse, including alcohol
Adaptive mechanisms include downregulation of DA receptors
In ethanol withdrawal, dopamine levels steadily decrease over time
Increased responding in intra-cranial self stimulation model suggests reduced functional mesolimbic activity
What are some neurochemical changes caused by chronic use of alcohol
Chronic alcohol results in depression of mesolimbic function by various mechanisms, including receptor downregulation and DA synthesis.
In animals, withdrawal of alcohol after chronic use reduces the firing rate of mesolimbic neurons and decreases DA release in the nucleus accumbens
NB not the only reward pathway – block of the mesolimbic pathway does not extinguish reward seeking behaviour (eg alcohol self-administration)
Explain the involvement of the opioid system when you drink alcohol
Acute administration of alcohol increases endogenous opioid (endorphin and enkephalin) production and release.
Chronic administration reduces production - may contribute to the dysphoria that accompanies chronic alcohol use and withdrawal
If opioids are involved in reinforcement, receptor antagonists should reduce alcohol self-administration
μ-opioid receptor knockout mice fail to self-administer ethanol, and in some conditions show an aversion to the drug
In rat strains bred for alcohol preference, endogenous opioid systems are more responsive to the effects of alcohol.
They also have higher baseline levels of μ-opioid receptors in selected limbic areas, including the nucleus accumbens and the amygdala
