SUD Pathophysiology + Pharmacology

1) What is the primitive brain (old)

2) What is the neocortex brain (new)

3) What is “stronger” / harder to override

4) Which one is the primary pleasure / reward system

5) Which one has strong learning paths? How do they react to change?

1) Primitive (old) brain

• Primary pleasure/reward systems

• Strong learning paths formed that are resistant to change

• Irrational, instinctual, emotional

2) Rational, logical, thinking

3) Primitive is stronger / more powerful

4) Primitive

5) Primitive; resistant to change

1) What is the motivated adaptive behaviour

2) Explain classical conditioning’s role in this

1) Process of learning/adapting to maximize access to resources —> survival advantage

• Survival of the fittest 

2) Cues predict valuable resources

1) Dopamine: ___(__) detection , makes you ___ behaviours, reinforces ___

2) Glutamate: Excitatory! Builds ____ ___ via (___/___), directs ___ - making

3) GABA: Inhibitory, What does it do to

• a) glutamate

• b) DA

1) Novelty detection, approach behaviours, reinforces learning

2) Builds neuronal pathways via NMDA/AMPA, directs choice-naking

3) a) Can oppose glutamate; b) Can activate DA

Physiological Mechanisms of Enduring Neuroplasticity

1) Dopamine release promotes the release of what?

The answer to #1 binds to NMDA and AMPA receptors…

2) What do NMDA receptors do

3) What do AMPA receptors do

4) Repeated dopamine and ___ (Q1) activation leads to enduring changes which are strong ____ ____

1) Glutamate

2) NMDA = Memory encoding, long term potentiation

3) AMPA = Memory retrieval 

4) DA + glutamate = enduring changes = strong learning pathways 

Pathological Dysregulation with Acute & Chronic Substance Use

ACUTE/INTERMITTENT USE

1) Massive release in what

2) Are neuronal changes temporary or long-term

3) What is the substance encoded as? (to the brain)

1) Massive dopamine release

2) Temporary changes (hours-days)

3) Highly valuable resource

Pathological Dysregulation with Acute & Chronic Substance Use

CHRONIC USE:

1) ___-driven neuroadaptations maintains long-term ___ ___

2) What do substance cues do to brain activity

3) What do conventional cues do to brain activity

4) How long do cravings persist for

5) DURING WITHDRAWAL: 

• What gets dysregulated during withdrawal?

• What does this do to sympathetic activation

• What does this do to parasympathetic activation

• What happens do DA/5-HT/opioid neurotransmitters?

1) Glutamate-driven neuroadaptations maintains long-term craving pathways

2) Substance = INCREASE

3) Conventional = DECREASE

4) Basically forever

5) During withdrawal:

• HPA axis = dysregulated

• Increased sympathetic activation

• Decreased parasympathetic activation

• Decrease in DA/5-HT/opioid neurotransmitters 

What is the central role of motivated behaviour in SUD?

1) Substances hijack ___ learning systems —> the brain ends up encoding them as excessively ___

2) What is craving

3) What happens to craving pathways? They remain ____

4) ___ can trigger relapse by activating craving ___

1) Substances hijack adaptive learning systems —> brain codes them as excessively valuable

2) Craving = powerful, enduring motivator, directs behaviour toward substance seeking

3) Craving pathways remained hardwired

4) Stress can trigger relapse by activting craving circuits

1) Which neurotransmitter ensures our survival and success by alerting us to 

• The appearance of a novel resource (new) + wanting to learn about it

• The possible appearance of a familiar resource (learned thru associations)

____ 

2) When this NT gets released and activity levels rise, does it create a preference for novel or familiar resources 

1) Dopamine 

2) Preference for novel (new) resources (we feel brave + take risks) 

1) __ promotes neuronal changes (learning), and stimulates __, which CREATES learning pathways

1) Dopamine promotes neuronal changes and stimulates

2) Glutamate which creates learning pathways

How does glutamate ensure our survival + success

1) Stimulating growth of neural ___ for ___

2) ___ our behaviour towards more ____ ___(s)

1. Stimulating growth of neural pathways for learning

2. Directing our behaviour towards more valuable resources

Motivated Adaptive Behaviour & SUD

1) What’s the leading NT in intermittent/acute use

2) What’s the leading NT in repeated + regular use

1) Dopamine

2) Glutamate

The Significance of Craving: Directs behaviour by modifying activity in the brain

1) Cues associated with the substance do what?

2) Cues associated with more conventional resources (food/sex) do what

** FOR METABOLIC ACTIVITY

1) Increase metabolic activity

2) Decrease metabolic activity (inhibited)

1) Rewarding effects (high) for ppl with no SUD (acute/intermittent use)

2) Craving effects for ppl with no SUD (acute/intermittent use)

3) Rewarding effects (high) for ppl with SUD (chronic/repetitive use)

4) Craving effects for ppl with SUD (chronic/repetitive use)

1) VERY HIGH increase DA; very rewarding

2) Low craving (satiation)

3) Increased rewarding effects (not as much)

3) INCREASED CRAVING (that hit wasn’t enough)

Key Pharmacological Factors in Addiction Potential

1) What are the 3 factors drug wise

2) Out of the 3, which.2 are more important in determining addiction potential

3) Rank from greatest addiction to least out of route of administration

1) Factors:

• Achieved Dose = HOW MUCH substance gets in the brain

• Time to peak concentration = HOW FAST substance levels rise in brain

• Intermittency = HOW OFTEN levels rise and fall in the brain

2) Time to peak concentration + intermittency

3) IV > Smoked > Intranasal > Oral

Alcohol GENERAL INFO

1) When does peak serum concentration take place? This makes it a ___ release

30-90 minutes; delayed release

ALCOHOL

MOA:

1) ___ GABA activity, ___ glutamate activity (via NMDA receptor ___)

2) What receptor does it stimulate? What does this release? (2)

3) Decreases ___ hormone release; this ___ urine production which can lead to ____, making it a ___

4) ___ occurs which makes it so that you lose body heat despite staying warm

5) Chronic effects of alcohol: Which one is temporary

6) Chronic effects of alcohol: Which one is permanent

7) For Q5 and Q6, what are these due to

8) What is a super serious complication related to ALCOHOL WITHDRAWAL

9) Who does this typically happen in ^

10) What are the symptoms of this ^^

11) Onset and durtion of this ^^^

1) Increase GABA; decrease glutamate (NMDA inhibition)

2) Stimulates mu opioid = release 5-HT and DA (pleasure effect)

3) Decreases antidiuretic hormone release; INCREASES urine, lead to dehydration = DIURETIC

4) VasoDILATION

5) Temporary = Wernicke’s acute encephalopathy

6) Chornic = Korsakoff’s psychosis

7) Due to thiamine (vitamin b1) deficiency

8) Delirium tremens —> Delerium + Tremors

9) Typically occurs w/ sudden reduction/abstinence in people who have a history of heavy + chronic alcohol use

10) Delerium, Tremors, Severe agitation + autonomic hyperactivity (increase HR, BP, RR)

11) Onset = 3-5 days since last drink; Lasts 5-10 days

1) Which opioid receptor subtype do we care about the most in SUD

2) This receptor ___ GABA activity which leads to ___ ____

3) Which neurotransmitters does this end up decreasing (4)

1) Mu

• Analgesia

• Sedation, decrease respiration

• Decrease GI transit

• Modulate hormone + NT release

2) Decrease GABA; Increase dopamine

3) Glutamate, ACh, NE, 5-HT

Opioid Acute Effects:

• Euphoria + apathy

• Sedation / Nodding

• Cognitive impairment

AND

__ pupils, __ bowel sounds, slow regular __ , slurred speech, constipation 

1) Restricted

2) HYPOactive

3) Respiration 

Heroin

1) A Mu receptor ___

2) Although it has some binding to __ receptors

3) It’s a prodrug and is metabolized into ___

4) ___ groups encourage passage across ___ meaning it’s ___philic

5) Heroin is removed in the brain via ___

1) Agonist (Selective; high binding affinity)

2) K receptor

3) Morphine

4) Acetyl groups → allows thru BBB ; lipophilic

5) Esterase removal

Opioid Overdose

1) Signs/symptoms (4)

2) What is respiratory depression due to

1) Signs/Symptoms:

• Respiratory depression (severe)

• Pale/bluish skin

• Pupil constriction (miosis)

• Coma

2) Due to body’s decrease response to CO2 and O2 blood levels; this decreases the drive to breathe

Fentanyl: Why is it SO dangerous

• Increased potency 

• Increased lipid solubility (more rapid increase level in brain bc it can cross BBB even faster)

• Overdose can occur within 5 minutes

• You need to KEEP giving naloxone since fentanyl has SUCH a high receptor affinity 

Opioid withdrawal syndrome

1) Short term (5)

2) Long term (4)

Short term:

• Nausea / Vomiting / Diarrhea

• Muscle aches

• Lacrimation or Rhinorrhea

• Pupil dilation

• Sweating

Long term:

• Anxiety

• Dysphoria

• Anhedonia

• Insomnia

Stimulants

1) Lipophilic or lipophobic? Why is this relevant

2) How is MOA different from opioids

3) Cocaine MOA for how it increases DA, NE, 5-HT levels

4) Methamphetamime MOA for how it increases DA

5) MDMA on how it increases DA, NE, 5-HT

1) Lipophilic —> Crosses BBB

2) Increases DA via DIRECT stimulation of neurons

• whereas in opioids/alcohol, it’s an indirect increase in DA through decrease GABA

3) DA = Decrease reuptake (same for NE, 5-HT)

4) DA = Decrease reuptake AND INCREASES RELEASE

5) MDMA = decreases reuptake of all 3 NT

Cocaine

1) Rank from most preferred NT to least

2) Crack vs powder: which is more concentrated? Because of what

3) Which route of administration (2) leads to decrease onset time, increase intensity, decrease duration

1) DA > NE > 5-HT

2) Crack is bc of the salt removal

3) IV or inhaled (smoked)

1) Methamphetamine’s preferential neurotransmitter rank

2) MDMA’s preferential neurotransmitter rank

3) MDMA is eliminated ____ and can ___ CYP2D6 enzymes, beware of ___toxicity

4) What is a FATAL ADR of all stimulants

5) How is ^ ADR amplified by MDMA

6) CHRONIC EFFECTS OF STIMULANTS (2)

• What due to excitotoxicity (increased glutamate release)

7) Stimulant withdrawals (5)

1) DA > ( NE + 5HT )

2) 5-HT > (DA + NE)

3) Hepatically; Inhibit; Hepatotoxicity

4) Hyperthermia

5) MDMA induces vasoconstriction which blocks sweating

6) Chronic Effects:

• Neuronal cell death (of 5-HT and DA) due to excitotoxicity of increased glutamate release

• Microglial overactivation

7) Withdrawal

• Dysphoria

• Fatigue / Insomnia / Hypersomnia

• Hyperphagia

• Abdominal cramps

• Bradycardia