ECON 546 Lecture Notes - Lecture 23: Endophenotype, Immunogenicity, Disulfiram
27 Jun 2018
School
Department
Course
Professor
Lecture 23: Addiction and Alcoholism II Wednesday, April 6, 2018
Dr. Kathryn Gill
- Literature can be confusing because different studies are measuring different
phenotypes
oWant to know if a phenotype is related to the intake of a substance for many
studies, the phenotypes being measured are not related to the amount
consumed
oIgnore most of the literature because of the phenotypes measured
- Dosing is also irrelevant
oBlood alcohol concentrations being achieved in model animals would be lethal in
a human
o5g/kg
- 0.8 mg is the legal limit for humans
oLed to multiple cycles of intoxication and withdrawal
Forced Ethanol Administration Study
- Acute intoxication dosage: equivalent to a bolus of 5 drinks for a human
oClose to lethal dose
- For chronic intermittent ethanol treatment, this is the hypothesized model
oBinding of positive modulators to GABARs = overstimulation
- Within 1 hour, internalization of delta-containing GABA
- Within a few hours, internalization of synaptic GABARs
- Major increase in surface alpha2beta1gamma1 and alpha4betagamma2
- Issue: alcohol is not self-administered but forced brain response is different
oAlso adds to mice being very stressed interaction effects between alcohol and
the stress negates forced administration of saline control mice
Background
- Maternal separation during infancy causes long-lasting modulation of neurons in the
limbic system acts as a stressor
- Response disinhibition involving GABA signaling in the cortico-limbic system is an
important factor in impulsivity
- MS permanently alters expression of various GABA-A receptor subunits
- Use of a chamber for self-administration
- Can we antagonize the effects of operant self-administration?
oSelf-administration of alcohol in maternal separation group was significantly
higher than in controls
- Level of GABA-A A2 expression was significantly higher in the CeA and mPFC of MS rats
compared to controls
- 3-PBC acts as the GABA-A a1/a2 receptor
oReduced operant responding of MS rats for alcohol compared to vehicle
find more resources at oneclass.com
find more resources at oneclass.com
- Data suggests that MS produces impulsivity and excessive drinking these behaviours
were attenuated
- Conclusions
oMS increased expression of GABA-A a2 subunits in central stress circuits
- MS appears to be a risk factor for binge drinking in this animal model, and it is linked to
impulsivity
- Linked to human alcoholism: adverse childhood experiences are an incredibly risk factor
for psychopathologies
oPhysical abuse, childhood neglect, sexual abuse, witnessing violence in the home
oMaternal separation in a rodent model is a relatively mild stressor but impacts
the rodent model greatly
Are Alcohol and Drug Dependence Inherited?
- GWAS and large scale studies have not come to a consistent conclusion
Human genetic studies twin and adoption studies
- Concordance rate for MZ twins = 70%, DZ (32%)
- Ratio of MZ/DZ is close to 2.0
- Concordance between MZ twins is very variable ranges from 26 to 70%
- Very difficult to classify what is MZ, what is DZ, what constitutes alcohol, etc.
oZygosity needs to be determined by computer analysis of DNA
- Weight of the evidence is pointing towards a higher concordance in MZ than DZ
Adoptee Studies
- Depends on when the child was separated from biological parents
- Still dependent on reports that may or may not be accurate
- Risk ratios still observed to be significantly higher for those who are family-history
positive
oRange is still quite variant
- Problems:
oDiagnosis of family history
oDegree of childhood adversity
oMaternal alcoholism wasn’t controlled for in any study potential fetal alcohol
syndrome
Children born with FAS have increased exposure and are more likely to
consume
oWhen children are adopted out but have a family history, they are still more
likely to become alcoholic compared to those with no family history
- In genetic studies: look at what the weight of the evidence suggests, but there are many
factors that make it difficult to be sure
oAlcoholism is likely multi-genic
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Dosing is also irrelevant: blood alcohol concentrations being achieved in model animals would be lethal in a human, 5g/kg. 0. 8 mg is the legal limit for humans: led to multiple cycles of intoxication and withdrawal. Acute intoxication dosage: equivalent to a bolus of 5 drinks for a human: close to lethal dose. For chronic intermittent ethanol treatment, this is the hypothesized model: binding of positive modulators to gabars = overstimulation. Within 1 hour, internalization of delta-containing gaba. Within a few hours, internalization of synaptic gabars. Major increase in surface alpha2beta1gamma1 and alpha4betagamma2. Issue: alcohol is not self-administered but forced brain response is different: also adds to mice being very stressed interaction effects between alcohol and the stress negates forced administration of saline control mice. Maternal separation during infancy causes long-lasting modulation of neurons in the limbic system acts as a stressor. Response disinhibition involving gaba signaling in the cortico-limbic system is an important factor in impulsivity.
