Ethanol/Alcohol

What do a lot of drugs of abuse do?

Disrupt dopamine signaling in brain

Ethanol Def

Produced by the fermentation of sugars from yeast

Comes in various forms depending on production process

Ethanol Forms

1. Liquor

2. Beer

3. Wine

Routes of Absorption for Ethanol

• O (Primary route bc alc is a liquid at low temps: 95% bioavailability)

• IH (highly irritating to throat and nose)

• TM (sometimes administered rectally for rapid onset; can be dangerous in term of dosing)

• IV (not common bc oral route is so easy)

Blood Alcohol Content (BAC)

Amount of alcohol in the system

Size of Ethanol Molecule

Small

Can pass through membranes easily

Is Ethanol hydrophilic or lipophilic?

Both

Can pass through membrane easily bc this + very small in size

When does peak levels of distribution occur when ingested orally?

Approx 50 mins

Where is ethanol accumulated?

Builds up in tissue of blood + water

Primarily brain, liver, kidneys

Who is ethanol more dilute for?

Men, bc they typically have more muscle to fat, which req more blood vessels

2 Primary Enzymes that break down ethanol

1. Alcohol Dehydrogenase

2. Microsomal Ethanol-Oxidizing System

Alcohol Dehydrogenase

Some metabolism begins in gut due to presence of alcohol dehydrogenase

Associated with occasional drinking

Microsomal Ethanol-Oxidizing System

Becomes more active with chronic ethanol consumption to help increase metabolism

Associated with chronic drinking

What do metabolitic enzymes do to alcohol?

Ethanol → Carcinogen Acetaldehyde → Vinegar → Carbon Dioxide + Water

How long does it take to metabolize alcohol in a standard drink?

Roughly an hour

Zero Order Metabolism

Unlike most drugs, ethanol has a relatively constant rate of metabolism

Basically when the drug has constant rate of metabolism

Do female adults need more or less alcohol than men?

Less alcohol

Women have more alcohol with oral ingestion because of metabolic differences; They could have alc dehydrogenase + men have less in blood

How is ethanol excreted?

Maj of unmetabolized alc (approx 5%) is excreted through the lungs

The rest is excreted through urine + sweat

2 mechanisms that promote the same process of depressed activity (how it acts on brain)

1. Allosteric agonism of GABAa receptors to hyperpolarize cells + promo inhibition

2. Allosteric antagonism of NMDA glutamate receptors to prevent depolarization + decrease excitation

What parts of the brain does alc affect?

All; Not one specific part

Ethanol with Dopamine + Opioids

Exact mechanism not clear, but results in disinhibition of dopamine through opioid receptors

Alc promotes release of endorphins

Endorphins

Alters GABA signaling that regulates dopaminergic neuron + directly stim neurons in nucleus accumbens

Helps alc disinhibit dopamine through opioid receptors

Anandamide

Production of this is stimulated by alc; A natural ligand for cannabinoid receptors

Cannabinoid Receptors/Networks

Activate reward pathways

Can further reinforce ethanol with the production of anandamide

Do stressful situations increase or decrease serotonin?

Decrease

Does ethanol increase or decrease serotonin?

Increases through the disruption of serotonin transporter

Indicates that alc is a means of self medication

What does promoting high levels of serotonin do to the motivation to take alc?

Reduces the motivation to consume alc

Does self medicating increase or decrease in stressful times?

Increase

Voltage Gated Calcium Channels

Permits the release of neurotransmitters

What happens to voltage gated calcium channels when there is a high dose of ethanol?

Becomes impaired

Can cause toxic effects in brain

Does ethanol impairment occur in a hierarchy of impairment?

Yes

Ex. Goes from cognitive issues all the way to respitory failure after more drinks; In a specific order

Why does alcohol impairment occur in a hierarchy?

Bc more protection at the later ends, if they fail they can kill you

Also conscious actions build off automatic things (like breathing)

Dont know for sure

Impacts of Ethanol on Cerebral Cortex

1. Impaired judgement + abstract thinking from PFC (decision making impairment + attention disrupted)

2. Sensory + motor systems disrupted (blurred vision, impaired lang comprehension, slurred speech, reduced pain sensation)

How much ethanol is required to reduce reaction time?

Not a lot

Approx 2 ½ standard drinks (brings BAC to .03, legal limit is .08)

Nystagmus

When the eyes begin to display erratic movement; Impairs vision as the brain is not used to rapid movements, so can lead to seeing double + poor visual acuity

Can be seen with low BAC

Relationship b/w BAC and Crashes

Positive Correlation; Higher BAC means more crashes

Impacts of Ethanol on Limbic System

1. Emotional dysregulation from amygdala (increased aggression correlated with BAC)

2. Impairments to memory consolidation through disruption to hippocampus (can lead to blackouts, fragmentary, en blanc)

Low Dose Ethanol on the Limbic System (Feeling Wise bc Amygdala)

Euphoria inducing

Anxiolytic + antidepressant effects

Impacts of Ethanol on Limbic System

Higher Dose Ethanol on the Limbic System (Feeling Wise bc Amygdala)

Dysphoria

Sad or angry

Impacts of Ethanol on Limbic System

What is increased aggression correlated with?

BAC

Blackouts

When the subject is awake + behaving, but will have no recollection of events

Starts at BAC of .13, very frequent at .25

Impacts of Ethanol on Limbic System

Fragmentary

Bits + pieces of memory are missing

Impacts of Ethanol on Limbic System

En Blanc

Total blackout

Impacts of Ethanol on Limbic System

Cerebellum

Inhibitory activity to control movement

Impact of Ethanol on Cerebellum

Discoordination, impairment to balance

Impacts of Ethanol on Brainstem

Decreased respiration + heart rate; Can lead to coma or death

Only occurs at very high doses (at end of hierarchy); > .30 BAC

Chronic Alcohol Use Impacts on Behavior

• Alcohol Intoxication

• Alcohol Liver Disease (ALD)

• Promotes Neurodegeneration

• Inhibition of Adult Neurogenesis

• Neuroinflammation

Does alcohol tolerance counteract the impairments to cognitive function?

No

But they are able to better compensate for their behavioral impairments to help cover it up

How does alcohol age the brain?

Decreases grey + white matter in brain, impairing connectivity

It disrupts most large scale networks (central executive + dorsal attention)

Does NOT recover with cessation

Alcohol + Disruption to Large Scale Brain Networks

Disrupts mostly the central executive + dorsal attentional networks

Can lead to loss of connectivity + cognitive impairment

Anhedonia

When alc inhibits the ability to feel pleasure due to dopamine dysregulation

Coregulated with anxiety + depression

What does chronic inhibition of glutamate receptors due to alcohol lead to?

Production of more glutamate receptors

Problem bc we need glutamate to function

What happens if there are too many glutamate receptors made in response to chronic inhibition due to alcohol?

Cells are hyperexcited bc there are so many glutamate receptors that are not blocked by ethanol

Can lead to tremors, seizures, or death

What can cessation of alcohol lead to?

Tremors, seizures, death

Best Way to break Alcohol Dependence

1. Tapering off dosage

2. Using other GABA agonists (benzodiazepines + barbiturates) with less toxic effects and doses that are easier to control

Are drug therapeutics effective for helping with alcohol dependence?

Good for short term, but many relapse

Is behavioral therapy effective for handling alcohol dependence?

Yes, greatly reduce relapse

Does alcohol have good bioavailability?

Yes, second to caffine

Do women need more or less alc?

Less bc have more metabolites?

What do women have less of?

Alc Dehydrogenase

Why is alc reinforcing?

Disinhib of dopamine

What do opioid peptides dishibit?

Norep + serotonin

What are the metabolites of opioids?

Also opioids

Main cause of opioid death

Respitory issues

How can an overdose be reversed?

Opioid antagonists