1. I. Considering Genetics/Heredity
How do biological factors contribute to the development of alcohol use disorders?
I. Considering Genetics/Heredity

2. Some Behavioral Genetics Basics:
Genotype ≈ combination of genes
Identical twins have same set of genes
Phenotype ≈ how genes are expressed
genes + environment (shared+ unique)
Even identical twins are never identical
Endophenotypes (per Gottesman & Gould, 2003):
Genetically-influenced phenotype
Identifiable before a disorder develops
Associated with high risk of developing a disorder
Endophenotype = not the disorder, but an intermediate expression of genes that increases/decreases likelihood of developing disorder
Schucket describes 4 endophenotypes that meet these criteria and have been associated with AUD outcomes

3. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
Disinhibited, impulsive, externalizing temperament
Psychiatric comorbidity
(Schuckit, 2009)

4. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Beverage
Alcohol
Acetic acid,
CO2, HzO 
ADH 
acetaldehyde 
ALDH 
ADH1B*2 variant speeds up process
Flushing, nausea,
Vomiting, headache
The ADH1B*2 variant speeds up the process, causes acetaldehyde to build up
Adverse effects = flushing, nausea, vomiting, headache
PROTECTIVE – this variant lower in alcoholics than controls
(Schuckit, 2009)

5. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Lower levels, less aversive
Beverage
Alcohol
Acetic acid,
CO2, HzO 
ADH 
acetaldehyde 
ALDH 
ADH1C*2 variant slows process
ADH1C*2 is less active polymorphism, RISK FACTOR for alcohol dependence
(Schuckit, 2009)

6. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Beverage
Alcohol
Acetic acid,
CO2, HzO 
ADH 
acetaldehyde 
ALDH 
ALDH2*2 variant slows metabolism
(may have 1 allele or 2)
Flushing, nausea,
Vomiting, headache
Having the inactive form of ALDH causes acetaldehyde to build up in blood, leading to aversive physical effects
PROTECTIVE factor
Homozygous (2 mutated alleles) = least likely to develop AUDs because of strong flushing response
Heterozygous (1 mutated allele only) = some flushing but not as protective
(Schuckit, 2009)

7. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
always able to “hold my liquor”
less cognitive/motor impairment
seen in COAs, Native Americans
ability to drink heavily and develop tolerance
A low response level to alcohol is considered a genetically influenced risk factor for later alcohol problems --- endophenotype
At identical BACs, a person with a LRA will
If you aren’t able to recognize the effects of lower doses of alcohol, you are more likely to drink heavy amounts per occasion, which both directly and indirectly increases your risk for alcohol problems,” said Schuckit.
A study in the November 2005 issue of Alcoholism: Clinical & Experimental Research has found that a gene on chromosome 10 – in particular, the KCNMA1 gene – is potentially linked to level of response.
Mechanism is undetermined
(Schuckit, 2009)

8. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
Disinhibited, impulsive, externalizing temperament
nonspecific to drinking
heavier drinking, more problems
early onset of AUDs
gene x environment interaction (more later)
(Schuckit, 2009)

9. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
Disinhibited, impulsive, externalizing temperament
Psychiatric comorbidity (cf. Hasin et al., 2007)
Antisocial personality (adj OR = 1.7, lifetime AD)
Bipolar mood disorder (adj OR = 2.1, lifetime AD)
Schizophrenia
(Schuckit, 2009)

10. Take away messages about the genetics of alcohol use disorders
Genes explain ~ 50% vulnerability (Schuckit, 2009)
Similar genetic contributions in both sexes
AUDs are polygenic
AUDs are multifactorial:
Genes x environments
Gene-environment correlations
Gene–environment interactions refer to situations in which heritable factors influence an individual's susceptibility to adverse environmental exposures or, equally, when environmental contexts affect the expression of genetic predispositions.
Social control (or facilitation) and stress processes are examples of mechanisms that may link social contexts with gene expression and subsequent behavioral and health outcomes (Shanahan & Hofer, 2005).
Gene–environment correlation arises when genetic risk factors affect the likelihood of exposure to environmental risk factors

11. Likely gene-environment correlations in alcoholism (Searles, 1988)
Passive: Environment is not independent of genes
prenatal exposure to alcohol
Parenting, parent/sib role models
Reactive/evocative: certain temperaments precede AUDs and evoke responses from parents, teachers, peers, etc.
high activity level / behavioral undercontrol
emotionality / low soothability / neuroticism
poor attention span / persistence
sociability / extraversion
(Tarter & Vanyukov, JCCP, 1994)

12. Likely gene-environment correlations in alcoholism - cont’d
Active (niche seeking): People actively seek environments that complement/support their genotype
self-selection into “partying” social groups
selection of mates
self-selection away from alcohol involvement (e.g., flushing response)
Genetic influences change over life course
Several pathways to development of AUDs

13. II. Considering Psychobiology/Neuroadaptation
How do biological factors contribute to the development of alcohol use disorders?
II. Considering Psychobiology/Neuroadaptation

14. Alcohol does not have its own receptor system
Alcohol does not have its own receptor system it changes the level, activity, and receptor function of endogenous neurochemicals.
Alcohol alters brain function by changing the level, activity, and receptor function of endogenous neurochemicals
OVER TIME the chronic use of alcohol can change the functioning of the brain

15. Several NT/NM systems are affected by acute doses of alcohol:
dopamine (pleasure, reward, attention)
endogenous opiates (pain perception, mood)
GABA (sedation, anxiety reduction)
êglutamate (excitation, memory, learning)
serotonin (motivation, regulation of attention, emotions)
releases endogenous opiates (naturally occurring opiate-like NT) --> incr. DA activity
Alcohol can be a depressant by enhancing the inhibitory NT (GABA) Or
Reducing the excitatory NT (glutamate, by occupying NMDA receptors, blocking glutamate)
Stimulates serotonin system

16. mesolimbic dopamine pathway
AKA “reward center”
Activity stimulated primarily by NT dopamine
Most drugs of abuse stimulate this pathway
also running, gambling, etc.
Mesolimbic dopamine pathways  reward center of brain
[connects ventral tegmental area to basal forebrain (NA, prefrontal cortex, amygdala)]
Animal studies show that whatever the animal is doing prior to sending an electrical stimulation through this pathway, they will do over and over again!
Activity of these pathways is stimulated primarily by NT dopamine; stimulation produces pleasure and strong positive reinforcement
Drugs stimulate MLD pathways by increasing levels of dopamine in various ways.
Other activities stimulate this pathway also: e.g., running, gambling
Even anticipation of a drug/alcohol can release DA into the nucleus accumbens

17. Many drugs affect the dopamine (DA) system:
Heroin => binds to opiate receptors=> DA release
Alcohol=> triggers endorphins, which bind to opiate receptors => DA release
Methamphetamine => direct release of DA
Cocaine => prevents reuptake of DA after release
Elevated DA levels activate the brain’s reward pathways, reinforcing the associated behavior
With repeated administrations of a drug, can see sensitization to a drug effect
E.g., heightened responsiveness of the DA system, with training, DA receptors become more sensitive to stimulation
Motivational state of wanting or CRAVING when drug levels get low
Contributes to addiction, as alcohol becomes more reinforcing: satisfies craving

18. What happens with regular heavy drinking over time?
The presence of exogenous chemicals can disrupt homeostasis
Synaptic transmission is finely regulated:
In synapse -- enzymes break down extra NT
At presynaptic membrane -- extra NT taken back via reuptake transporter
At postsynaptic membrane -- up-regulation or down- regulation # of receptors
Balance is re-established through neuroadaptation
BUT, excess of anything in a finely regulated system triggers efforts to “rebalance” system: establish homeostasis
With repeated exposures to a drug, brain circuits and synapse activity changes due to:
enzymes in synapse break that down extra NT  more or less enzyme in the synapse
Presynaptic membrane pumps –” reuptake” of extra NT  More or less reuptake into pre-synaptic membrane
Postsynaptic membrane – up-regulation (more) or down-regulation (fewer) of # of receptors
Neuroadaptation = mechanism designed to maintain balance or homeostasis in NT systems (i.e., desensitization)

19. How does alcohol affect NT systems over the short- and long-term?
Acute effect
Chronic effect
ETOH =>
Dopamine  
GABA
Glutamate
DA: long-term effects of alcohol abuse is a lowered level of DA in the brain, making it harder for a person to experience reward or pleasure when sober; craving + dysphoria
GABA:
major inhibitory transmitter (puts breaks on messages sent from neuron to neuron);
Alcohol increases GABA release into synapse and increases receptor sensitivity: slowing down activity in the brain
Chronic drinking reduces GABA activity causing anxiety = overactive nervous system in sober state
Glutamate:
excitatory NT (facilitates firing of neurons, especially via NMDA receptors)
Alcohol puts a damper on glutamate activity (inhibits receptors), resulting in a dampening of neurotransmission (depressant activity)
Over time, neuroadaptation causes the receptors to become very sensitive to glutamate-induced excitation
Leaving CNS in an overly excited state in absence of alcohol
Risk of seizures upon withdrawal
This is one explanation for functional tolerance: The acquired changes in the brain make the brain less sensitive to original levels of alcohol.
The brain has been recalibrated, so to speak, and require more alcohol to achieve the sought-after acute effects.
We can also understand withdrawal as the result of recalibration/adaptation of the brain:
as long as the person continues to drink, these 2 effects are cancelled out, the neuroadaptation effects are only hinted at
As soon as the person stops drinking, s/he is left with fewer receptors, or less production of endogenous NT
The results are a CNS that expresses the “opposite” of the original intoxication effects (find low levels of DA in NA during withdrawal from alcohol, opiates, and cocaine)
. . . Until the brain recalibrates back to its original baseline -- sometimes this is incomplete
In the meantime, during the immediate post-withdrawal period, person is at high risk for relapse
Initial reward is positive reinforcement, but after neuroadaptation, negative reinforcement plays a role -- a person drinks to try to feel better/normal. . .