psyt 301: issues in drug dependence (lecture 5 - alcohol)

what is alcohol (chemical name + formula)

ethanol - C2H6O and is produced by fermenting sugars with yeast

List the possible reasons for alcohol consumption decline

• increasing health concerns

• inflation and affordability

• rise of no or little to none alcohol percentage (ex. 0%)

• cannabis substitution

• immigration

• reduced use by youth

Why might province by province drinking rates differ?

1) Legal drinking age is different (18 in only QC, AB, Manitoba, 19 everywhere else in Canada)

2) Accessibility is different (ex. QC and Ontario have legalized selling alcohol in grocery stores / convenience stores, whereas other provinces it isn’t this available, must go to liquour store)

when does the risk to drink start?

at the first drop of alcohol

what kind of disorder is AUD?

medical disorder

what impact does AUD have on society?

Leading risk factor for death and disability worldwide —> contributes to more than 200 diseases, injuries, and health conditions

• risk goes up, the more you drink

Government revenue is LESS than the societal costs from alcohol use (alcohol use costs the government billions annually)

what is the level of consumption that minimizes alcohol health loss?

NONE - no safe level above ZERO that minimizes health loss

Is this true: adolescents drink less often than adults, but when they do drink they drink way more

TRUE

Explain adolescent BAC (blood-alcohol level) threshold, physical sensitivity and risks associated with these factors

Adolescents require less drinks to reach the legal BAC of 0.08% (meaning they have a low BAC threshold)

• On the other hand, they have lower physical sensitivity > adults, and would require more drinks to feel more physically impaired (loss of coordination, slurred speech, slowed movement)

• This lower physical sensitivity makes them more likely to binge drink which leads to VERY high BAC levels

What are adolescents more vulnerable to (cognitive effects of alcohol)> adults?

memory disruptions, disrupted brain plasticity

what are overall risks associated with adolescent alcohol use?

1) death and major injuries (both direct: overdoses, and indirect: drunk driving)

2) impaired judgement and risk taking

3) impaired functioning and long term outcomes (legal involvement, poor academic performance)

what are the pre-existing neurobiological markers associated with adolescent alcohol use?

1. gray matter atrophy before alcohol use

2. pre-existing family SUDs can cause youth to have altered brain structure

3. differences in frontostriatal white matter microstructure predicts which youth > other youth are more likely to binge drink

biological consequences of alcohol use in adolescents

impaired PFC development

Higher sensitivity to alcohol-induced neuronal death

Hippocampal neurogenesis (that occurs in adolescence) = more sensitive to alcohol toxicity

increase in reward responsiveness of DA system to alcohol later in life (alcohol becomes more salient later)

describe ethanol as a molecule

• a lipophilic molecule that’s highly soluble in water

• absorbed by the stomach and small intestines and from the GI tract

• undergoes first-pass metabolism in liver

• distributed to ALL body tissues and crosses ALL biological membranes (permeable everywhere in the body)

what is alcohol pharmacokinetics? what factors affect it

how the body processes alcohol through different mechanisms of metabolism, excretion, absorption etc.

Factors affecting alcohol pharmacokinetics:

• Amount of alcohol

• Type of alcohol

• Sex, age, body size, weight

• Total body water%

• Metabolism, food, drinking experience

• liver function

Describe alcohol metabolism in 2 steps

1. Alcohol —> acetaldehyde (by alcohol dehydrogenase - ADH, and in large alcohol amounts by CYPE1)

   1. This step happens in cytosol

2. Acetaldehyde —> Acetate (by aldehyde dehydrogenase - ALDH)

   1. This step happens in the mitochondria)

Lastly: Acetate —> H2O + CO2

Reduced co-factor in the process: NAD+ —> NADH

Where is ADH and ALDH enzymes expressed almost exclusively in?

Liver and digestive tract

What biological mechanism causes hangover effects

acetaldehyde buildup (bc/ it’s aversive and toxic = a protective factor against heavy drinking, to make us STOP)

• Acetaldehyde buildup causes side effects such as:

  • Flushing, vasodilation (widening blood vessels), palpitations

When consumed regularly, what happens to ADH and ALDH production

they become up-regulated

What polymorphisms of ADH / ALDH increase risk of alcohol use disorder (AUD)

1. low activity ADH2*1 and ADH3*2

2. High-activity ALDH2*1

Both activity contribute to overall low acetaldehyde buildup = reducing the aversive side effects (hangover effects) that serves as a protective factor against more drinking - so if drinking causes little aversion, higher incentive to drink + greater risk of developing AUD!

what population has a lower risk of AUD and what biological factor causes this?

Asian population - they have special ALDH2*2 variant allele that produces intense acetaldehyde aversion that causes nausea, vomiting, dizziness, headache, vasodilation, and facial flushing —> high aversion makes them less likely to drink more

• ALDH2*2 makes Asians metabolize alcohol slower than other populations

single most important predictor of developing AUD

heritability - if a first-degree relative has AUD

• proven by adopted out studies (kids with biological parents with AUD get adopted into non-AUD environment, still likely to get AUD)

• proved by cross-fostering studies (kids without biological parents with AUD get adopted into homes with parents with AUD, still less likely to get AUD)

Although alcohol is mainly heritable what environmental factors effect likelihood of AUD?

• socioeconomic status

• education level

• religion (religious prohibitions)

• occupation

• family integrity (family stability)

• trauma

• temperament / personality

Which is true:

1. alcohol produces sedating effects only

2. alcohol produces both stimulant and sedating effects

2. alcohol produces both stimulant and sedating effects

But alcohol is classified as a depressant still

Describe when alcohol produces stimulating vs. sedating effects

Stimulating effects: Small alcohol doses —> peaking at BAC: 0.05 (produces mood elevation, euphoria)

Sedating effects: Larger alcohol doses —> peaks at BAC: 0.40-0.75 (can produce heavy sedative effects: mental clouding, slurred speech, unconsciousness, coma, to even death)

Describe the dose-dependent effects of alcohol in plasma concentrations:

30-100mg/dl:

• euphoria, anxiolytic, sedation, mood altering, impaired coordination, impaired judgement

100-200mg/dl:

• mental clouding, ataxia, slurred speech, memory impairment, impaired balance, drowsiness

200-300mg/dl:

• stupor (little consciousness), unconsciousness

>300 mg/dl:

• disordered breathing, coma, death

Acute vs. chronic alcohol effects

Acute:

• impaired cognition, loss of inhibition, risky behaviour, increased aggression, vomiting, hangover, driving accidents

Chronic:

• cirrhosis, fatty liver, liver failure

• Chronic alcohol use causes constant acetaldehyde buildup = produces fat cell proliferation and inflammation

• Besides the liver, chronic use can also spread and affect:

  • Cardiovascular system - more hypertension

  • Cancers - in the upper GI, lower GI, liver > breast

  • GI system irritation, inflammation, bleeding, nutritional deficiencies

  • CNS: cerebral atrophy, cerebellar degeneration, peripheral neuropathy

What is Wernicke-Korsakoff Syndrome

a rare neurological disorder made up of 2 distinct disorders and ultimately caused by the lack of Vitamin B thiamine

• Alcohol misuse/ AUD= leading cause of this disorder

• Contributing disorders that make up the syndrome:

  • Wernicke’s encephalopathy

  • Korsakoff’s Psychosis

What is Wernicke’s encephalopathy (WK syndrome)

Severe but temporary atrophy to the thalamus, hypothalamus, hippocampus, and cerebellum

• Causes lack of muscle coordination, affecting posture and balance

• Involuntary movements (tremors)

• Vision problems (cross eyed, drooping, abnormal eye movements)

• Confusion

What is Korsakoff’s Psychosis (WK syndrome)

• irreversible memory impairment such as anterograde amnesia (can’t form new memories)

• making up new memories or innacurate versions of memories that don’t exist (confabulation)

• Hallucinations, lack of motivation, emotional apathy,

• repetitious actions + speech

• Problems with decision making, planning, organizing, completing tasks

What is alcohol’s main neurotransmitter target in the brain?

enhances GABA A receptors (which inhibits GABA, produces different effects depending on location of GABA affected)

but also inhibits glutamate by blocking NMDA receptors non-comptetively (reduces excitation)

Acute vs. chronic neurobiological effects of alcohol

Acute: decreased excitability (decreased Glu), sedative responses, more reward reinforcement effects (increases in DA) and disinhibited behaviour

Chronic: increased excitability (increased Glu), decreased DA activity, less motivation, more withdrawal (neg. reinforcement)

In one study, does increased [C]raclopride (radiotracer) mean higher or lower DA activity?

increased [C]raclopride = lower DA activity

Lower / more displaced [C]raclopride = higher DA activity, bc/ that moelcule and DA are competitive for one binding site, so if less of that molecule, that means more DA is binding and more active

• Alcohol increases DA release and thus displaces [C]raclopride in these radiotracer studies

Do men or women show more DA release to alcohol in the ventral striatum?

Men

• and only men showed positive correlation between DA release and subjective effects of alcohol

How does alcohol reduce pace of brain activity

1) by boosting (enhancing) inhibitory actions of GABA at GABA receptor

2) decreasing excitatory actions of Glu at NMDA receptor

Note: “disinhibition” of GABA only occurs in reward areas (VTA), but overall alcohol cellular effects = enhances GABA inhibition which produces typical slurred speech, slurred and sedative responses

How does alcohol show different allosteric modulating effects depending on GABA’s location?

Alcohol binds GABA receptors no matter what - but some GABA receptors enhance GABA, others inhibit GABA depending on where these GABA receptors are located

• In the hippocampus, thalamus, and cerebral cortex, alcohol binds GABA receptors that enhance GABA’s inhibition —> causing slurred movement, anxiolytic effects, slowed speech, sedative effects = depressant effects

• In the VTA, alcohol binds to inhibitory GABA receptors that inhibit GABA’s inhibition and cause increased dopamine firing

So in some brain areas, alcohol makes GABA activity increased (cerebral cortex, hippo/thalamus), or GABA activity decreased (VTA —> NAcc)

• Alcohol also stimulates release of more B-endorphins which inhibit GABA, and cause more VTA dopamine release (a secondary pathway to promoting more VTA dopamine release)

how does alcohol inhibit glumatate through NMDA receptors?

Alcohol binds NMDA receptors non-competitively, and inhibits influx of Na+ and Ca2+, preventing Glu release

• Reduction of Glu signalling and lowered excitatbility causes key effects:

  • Lower synaptic plasticity

  • Worse memory and learning

  • Alters reward circuitry and increases DA signalling in NAcc

How does chronic alcohol use neurobiology look different?

1. Hyperexcitability (increased Glu signalling)

2. Decreased GABA function

Why?

1. Upregulation of NMDA receptors (system is always being depressed, brain adapts to add more receptors to detect smaller traces of Glu so it can not be so depressed)

2. Downregulation GABA receptors (system is always being depressed, brain adapts to decrease depressing GABA receptors, so less depression effects occur, and less rewarding effects occur)

   1. Less GABA enhancement in cerebral cortex, thalamus, hippocampus

   2. Less GABA inhibition (called disinhibition) in VTA

Alcohol withdrawal symptoms

alcohol craving, autonomic hyperactiity (tremors), vomitting, profuse sweating, tachycardia (fast heart rate)

what are the life threatening symptoms of withdrawal

grand mal seizures (from hyperexcitability)

delirium (transient, visual ad auditory illusions, hallucinations)

describe two ways for alcohol withdrawal management

1. Benzodiazepines (to control agitation, decrease seizure risk - can only be used short term)

2. Medical intervention (if hallucinations, delirium, seizures, or persistent tachycardia occur)

#1 alcohol comorbidity (name others too)

1. Smoking (nicotine/tobacco use disorder)

Others: depression, anxiety, cocaine use disorder = these others may be secondary to AUD

3 types of alcohol tolerance

1) metabolic tolerance (increased induction of microsomal enzymes, increased alcohol metabolism)

• pharmacokinetic

2) functional tolerance (increased sensitivity and number of Glu /GABA receptors - think upregulation/downregulation)

• pharmacodynamic

3) situational tolerance (increased alcohol tolerance in familiar drinking environments, triggered by cues, and is learned and context-dependent)

behavioural treatments for AUD

• brief counselling, motivational enhancement therapy, CBT, community reinforcement approach, social skills training, peer-supported recovery (AA, TSF)

What 3 pharmacological interventions used to treat AUD

1. Disulfuram (induces intense aversion by blocking ALDH, after alcohol converts to acetaldehyde, it can’t convert out of acetaldehyde —> acetate, so strong aversion kicks in)

2. Naltrexone (mu opioid antagonist - blocks opioid release, blocking GABA disinhibition in VTA, reduces cravings)

3. Acamprosate (GABA receptor antagonist, blocks GABA inhibition, causes excitation - thought to balance excitatory and inhibitory responses in people with AUD)

Note: naltrexone = different from naloxone, in that naltrexone blocks rewarding effects of alcohol and opioids long-term, whereas naloxone is a fast acting opioid antagonist that immediately reverses opioid release

What kind of treatments are NOT approved for AUD treatment

Gabapentin, Nalmefene, anxiolytics, baclofen, varenicilin, semaglutide (GLP-1A agonist)

GLP-1 agonist

GLP-1 = glucagon-like peptide receptor agonist = ozempic = semaglutide

• GLP-1 receptrs are a gut-brain peptide released from intestinal L cells and neurons in the NTS (nucleus tractus solitarius) in the brainstem that is supposed to control cravings and produces less desire to drink (based on anecdotal reports)

• We naturally express them widely in reward brain regions in the VTA NAc, PFC, and amygdala