Alcohol Dependence Flashcards
Why study alc dep? (4)
Alcohol abuse represents a significant problem to 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
Effect of alcohol depends upon level of
drinker’s tolerance (5)
0.03g/100mL= euphoria, impaired attention+judgement, disinhib.
0.05g/100mL= inc. risk of accidents/injuries/violence
0.15g/100mL= COORDINATION: dyasthria. ataxia, confusion, disorientation = inc. risk of falls/fractures
0.20g/100mL = altered state of consciousness, stupor, blackouts
0.30-0.5g/100mL = inhalation of vomits, asphyx, coma + death (depression of breathing)
Alcohol dependence can result in alcohol
withdrawal syndrome upon abstinence - DSM5 + ICD10 (5)
Alcohol abuse is initially driven by
+ve reinforcement ( euphoria etc.),
then by -ve reinforcement (withdrawal symptoms)
irrespective of diagnostic tool, both criteria’s show physical + psychological effects to similar degree
(DSM5: mentions tolerant person more likely to undergo seizures too - generalised tonic-clonic seizures - CNS)
Repeated use = leads to metabolic tolerance (4)
Metabolic tolerance =
induction of CYP2E1
1) increased substrated (alc)
2) induction of CYP2E1= another route of alc breakdown to acetaldehyde (2 routes)
3) inc. tolerance because brokedn down more quickly = so higher level neede to feel efects
Metabolism of alc (4)
1) alcohol
2) Acetaldehyde (using alcohol dehydrogenase)
3) Ascetic acid (using Acetaldehyde dehydrog.)
4) CO2 + h2o + energy (oxidation)
Manipulation/differences in step 3 of Metabolism of alc (2)
genetic diff’s in Acetyl dehydrog.= higher or lower tolerance
or
using or drug inhib. (Disulfiram) - allows for increase of 2) = flushing, nausea, headcahe + inc. HR (treating alcoholism through -ve feedback)
Historical action of alc
Alcohol’s action, like that of general anaesthetics, was initially believed to be due to a non specific effect upon lipid membranes
What neurotransmitter
systems does alcohol have an effect upon?
glutamate
What CNS changes
occur in the development of
alcohol dependence?
Non-specific effects of alcohol (3)
non-specific: - cell membrane:
- alters lipid composition
- interacts w/polar heads of phospholipids
-disturbs relati. of protein in mem.
specific effects of alcohol (4)
specific - receptor mediated effects:
- acts as neurotransmitter
- allosteric -modifies gating mechanism inside channel
- direct interaction w/channel proteins
-stim. G proteins (Gs) (linked to adenylyl cyclase)
e.g.’s of receptors, channels, sites (4-8)
NMDA. GabaA
Ca2+
(Cytosol): cAMP, PKA, PKC
(Nucleus): ERK, CREB
Alcohol has an inhibitory effect on glutamate
neurotransmission (4)
glut= major exicatory neurotrans
- Alc has greatest effect on NMDA receptors (ligand-gated channel made up of 4 subunits) - removes MG2+ then allows Ca2+ and Na+ to enter = cause localized depolarization
- Inferred by effects on long term potentiation (LTP) = more you use, the stronger the connection becomes (synaptic plasticity) - impairs memory (from STM- LTM)
- Alcohol will reduce ion flux = receptor upreg. to try to compnesate for reduction
Sensitivity to glutamate compounded during
withdrawal (presynaptic effect) (3)
Increased receptors + glut release(output) is heighted during withdrawal to compensate for reduced ion flux after alc
increased time after alc = increased glut output
LT = increased sensitivity to GLUT due to inc. MDMA receptors
Neuro damage due to withdrawal (2)
Elevated glut during withdrawal = excessive Ca2+ influx (due to hyperactivity of system)= contributes to cell death (apop = strokes = damage in brain)
Frequent withdrawal episodes may be responsible for some of the irreversible brain damage seen in alcoholism
Alcohol has GABA-A
potentiating effects (3)
Gaba = inhib = inc. in GABA = cl- floods in = inc. in -ve charge = hyperpolarisation
(Inferred from the
pharmacological synergism) = effects
b/w alcohol, barbiturates (allosteric gaba) and benzodiazepines > than alc alone = not recomm. to drink when on these
Decreased GABAAr
subunit mRNA expression in relevant brain regions in alcohol
preferring vs control strains of rats = alcoholism causes changes in makeup of GABAr
Differing effects of alc dependent upon
subunit composition of GABAr (4)
- Studies implicate importance of β and δ-subunits
- Different binding sites for low/high alcohol concentrations
-Extrasynaptic/presynaptic models of GABAAr modulation involving both GABAAr and receptors for other neurotransmitters
- Extrasynaptic receptor activation facilitates tonic inhibition
Proposed action of alc in the central
nucleus of the amygdala (CeA) (4)
amygdala responsible in fear + fear responses
- GABA + neuropeptide CRF(corticotrophin releasing factor)
exist as co-transmitters in CeA neurons
= alc binds to gabaar and has ST inhib. effect
this effect can be blocked in CRF1-R knock-out mice
- these mice also show evidence for upreg. of the NR2B subunit of the glut NMDAr
Neurochemical changes caused by chronic alc usage
- Repeated exposure alc = reduces the potentiation of GABAA-mediated Cl– flux (LT)
- Red. effect of positive allosteric modulators
- Alterations in relative levels of receptor subunit mRNA (eg decrease in α1, increase in α4) = explains initial potentiation to red. of GABAA function
- Chronically treated animals have decreased
sensitivity to sedative, motor incoordination,
acute cognitive impairment (all have GABAAr mediated components) - Chronically treated animals in withdrawal are sensitive to seizure activity (chronic-tonic seizures)
Effects upon dopamine (DA) (4)
- The mesolimbic system plays a sig. role in reinforcement and motivational mechanisms
- The terminal region = the nucleus accumbens: involved in integration of primary reinforcing cues= lead to repeated drug use + motivation for the drug
- Increased dopaminergic transmission in this system occurs in response to most drugs of abuse (alcohol, coke, morphine)
- Adaptive mechanisms include downreg. of DA receptors
DAergic transmission depressed in
withdrawal - biochemical + behavioural (2)
behaviourally: withdrawal score : higher the score, higher the last time from injection in alc dependent
biochemically: dec. in DA levels by 8hrs past injection, but also the rate in which DA is released + metabolised is also slowed down
= ST : high DA (fun)
= LT : low DA (withdrawal)
Increased responding in intra-cranial self
stimulation model (3)
animal model w/ electrode implanted into brain (mesolimbic) + self stim. will occur and been seen through activ. of pathway (will see inc. response due to pleasurable effects in normal person)
model suggests = red. functional mesolimbic activity in alc withdrawal - stim. to a greater degree than control non-depen animal
= lower baseline level of activity in dependent animal (= red. DA) = higher levels of self-stim = triggering the mesolimbic pathway more than normal person would
Neurochemical changes in DA (3)
- Chronic alcohol= depression of mesolimbic function by various mechanisms, including receptor downreg. and DA synthesis.
- In animals, withdrawal of alcohol after chronic use reduces the firing rate of mesolimbic neurons and dec. 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 can still occur)
Involvement of the opioid system - mesolimbic (6)
- Acute administration of alcohol= inc. endogenous opioid (endorphin and enkephalin) production + release.
- Chronic administration = red. production - may contribute to the dysphoria that accompanies chronic alcohol use + withdrawal
- If opioids are involved in reinforcement, blocking 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 = opioid system is important in some alc reinforc.
- 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 + amygdala
In summary compare and contrast all 4 receptors in acute, chronic + behav. levels (12)
Glut:
A: r antagonist = reuc. release
C: upreg. of R = inc. release, hyperexcit. = massive ca2+ rebound
B: memory loss, brain damage
GABAA:
A: inc. GABAa induced hyperpolarisation
C: dec. in GABA function w/o change in r no.
B: sedation, tolerance, reinforc.
DA:
A: acute inc. transmission
C: red. firing rate, rele. + metab
B: withdrawl, reinforc
Opioids:
A: acute inc. in endo opioid synth + rel
C: dec. in endorphins
B; dysphoria
