CNS stimulants (9)

What are the 4 stimulants discussed?

Cocaine, amphetamines, ecstasy ans caffeine

What were detected in the wastewater samples?

New drung variants, which were mostly stimulants

Where does cocaine come from?

The cocoa plant leaves

Which form of cocaine is sniffed and injected?

Cocaine HCl

Which form of cocaine is smoked?

The free base

What was cocaine first used as?

Chewing a few leaves allowed to keep south american workers’ hunger away for longer → anasthetic

Was there really cocaine in the original Coca-Cola?

Yes + caffeine from the Kola plant

When was cocaine removed from Coca-Cola?

Early 1900s (4 years)

What are cocaine’s 2 mechanisms of action?

1. Inhibits reuptake of neurotransmitters

2. Blocks sodium channels in peripheral nerves and the heart

What happens when the Na+ channels are blocked?

No axonal conduction → Less propagation of the electrical impulse → anasthesia

Which NTs’ reuptake does cocaine disrupt in the brain? (3)

Dopamine, noradrenaline and 5HT

Which NT’s reuptake does cocaine disrupt in the sympathetic NS?

Noraderenaline

Therefore, which major dopaminergic pathways are affected by cociane?

All 3 of them

Characteristics of dopamine receptors (3)

1. GPCR

2. 5 types in the brain

3. Cocaine action varies upon type of GPCR

Which receptor is mainly targeted by cocaine?

D2

Oral ingestion of cocaine yields a…

High (75%) first pass metabolism

What happens when cocaine is sniffed?

Intense vasoconstriction which can lead to ulcers

Discuss cocaine distribution

Rapid onset = rapid termination (10min mark)

What allows for cocaine metabolism to have a short half life?

Several human carboxylesterases in the liver

What are the 2 steps of action of human carboxylesterases?

1. Hydrolysis

2. Transesterification with ethanol

Which toxic metabolite is formed after that?

Cocaethylene

Why is cocaethylene dangerous?

Comes from a drug interaction which makes it have a half life that is 3-5x higher and a lower lethal dose (20x death risk)

How long do cocaine metabolites stay in urine?

For days

Where elso do cocaine metabolites accumulate?

Deposits in hair

What are 3 vascular injuries that can occur from cocaine use?

Cardiac arrest, myocardial infarcts and arrythmias

What symptom can affect the CNS within minutes of an injection or smoking?

Seizures

What’s a specific CNS adverse reaction to cocaine?

Agitated delirium

Is agitated delirium caused by an overdose?

No, it does not even require a high dose

Why is agitated delirium dangerous? (3)

1. Individual becomes extremely violent

2. Rapidly fatal

3. Mechanism is not understood from lack of animal model

Cocaine caused lung injury

Crack lung or acute pulmonary injury

Why is dopamine release depleted following chronic use of cocaine?

Bc of decreased reuptake

What is observed in humans even 3 months after last use?

Hand tremors and impaired reaction time

What are cognitive impairments linked to when it comes to cocaine consumption?

Changes in cell density

Symptoms linked to cocaine addiction

1. Irritability

2. Dysphoria and despair (dopamine depletion)

3. Severe anxiety, insomnia

How is long term craving shown in the brain?

The amygdala is activated when a cocaine video is shown vs nature video

What does chronic use of cocaine cause in dendrites?

Their rapid growth

In which region of Canada are metamphetamines a major problem?

Western Canada

How do amphetamines target neurons?

By increasing dopamine and NAD release WHILE blocking their reuptake

What can amphetamins do at low doses?

Provide a limited therapeutic use (adderall)

What special kind of tolerance can amphetamine use lead to?

Differential tolerance (No more delayed response but still affects motor activity)

What’s the smokable form of methamphetamine called?

Ice

How does meth lead to neurotoxicity in DA neurons?

Ox. stress in microglia and astrocytes, neurons of the synapse

While dopamine transporters appear to recover…

Cognitive function does not (no new neurons → Parkinson’s)

What is ecstasy (MDMA)?

An amphetamine derivative

What are ecstasy’s main symptoms?

Hallucinations as part of the CNS stimulant effects

On what neurons does ecstasy act?

5HT and DA neurons and their transporters

What organelle is affected by ROSs from MDMA?

Mitochondrion leading to dysfunction

What’s an interesting adverse effect of ecstasy?

Jaw-clenching

What are life-threatening effects of ecstasy?

1. Hyperthermia

2. Arrythmias

3. Renal failure

What does caffeine’s rapid absorption mean for babies?

That they have a really high half life (82H)

What is the PD description of caffeine?

Competitive antagonist to adenosine receptors (A1)

What is adenosine’s job?

Neuromodulator: inhibitor of NAd, DA, Ach, glutamate and GABA

What does that result into in the brain’s networks?

Lower activity in cholinergic stimulatory networks

How is caffeine tolerance described?

Rapid due to increased A1s