Catecholamines: Drugs that Affect Dopamine and Norepinephrine

______ is a street drug found to cause Parkinson’s symptoms and resembles dopamine

MPTP

How is MPTP different from dopamine?

Can cross the BBB

Once MPTP is in the blood what does it do?

Signals for MAO to metabolize it

A MPTP metabolite produces ______

MPP+

MPP+ causes ______________ in dopaminergic neurons in the substantia nigra

metabolic dysfunction

Why does MPTP cause Parkinson’s symptoms?

Causes dysfunction in dopamine in the substantia nigra which is responsible for movement

What are 3 possible counteractors for MPTP?

1. Dopamine agonist

2. Precursor for dopamine (DOPA)

3. MAOIs

What can be used as a biomarker for both Parkinson’s disease and MPTP-PD?

Degradation of neurons in the substantia nigra from toxic metabolite MPP+ from MPTP

_______ can be used to inject into rats to test Parkinson’s treatments and understand the disorder better.

MPTP

Increasing of which NT relieves depression?

Norepinephrine

How can MAOIs be used to treat depression?

Inhibit MAO that is responsible for metabolizing norepinephrine so increase norepinephrine release

What are the two areas affected by MAOIs that poses as dangerous?

1. Automatic sympathetic nervous system

2. Liver

What happens if you block norepinephrine transporters on the presynaptic terminal?

More norepinephrine in extracellular fluid

What does a transporter on a presynaptic neuron do?

Reuptake of NT

What does an autoreceptor on a presynaptic neuron do?

Changes NT release and neuronal activity

Which form of cocaine has the smallest amount of cocaine?

Coca leaves

Which form of cocaine has the largest amount of cocaine?

Coca paste

What form of cocaine is cocaine paste converted to and how is it consumed?

Cocaine hydrochloride, snorting

Which form of cocaine is formed from cocaine hydrochloride and how is it consumed?

Freebase, smoked

Which form of cocaine affects the body the fastest?

IV/smoking

Cocaine has a _____ half-life

short

Is cocaine lipophilic or lipophobic and what does this mean for it’s pharmacodynamics?

Lipophilic, passes through the BBB

When do cocaine users experience a high?

5 minutes after administration

Where is cocaine metabolized?

Blood and liver

Why is benzoylecgonine a primary target for drug tests for cocaine?

Metabolite of cocaine with a longer half-life than cocaine so it is in the body still after cocaine itself is excreted

What is cocaines primary mechanism of action?

Blocking dopamine, norepinephrine, and serotonin transporters

What is cocaines secondary mechanism of action?

Increase firing and release of dopaminergic neurons in VTA

What does cocaine do to anesthetics?

Blocks Na+ channels they go into

Which route of administration results in higher likelihood of addiction to cocaine?

IV/smoking = more cocaine in system faster = more addictive potential

Why does the level of baseline dopamine in the mesolimbic pathway impact the level of effect cocaine has on the body?

High levels of dopamine already in system = more dopamine from cocaine blocking transporters = bigger high

What are the 2 dependants for the mood altering effects of cocaine?

1. Rate of transporter (DAT) occupancy

2. Baseline level of dopamine activity in the mesolimbic pathway

Being exposed to a small amount of a drug causing a wanting of more (priming) is a contributing factor of ______ __________

cocaine misuse

longer abstinence = more craving

Incubation of cocaine craving

What is the result of cocaine misuse in the brain?

Down regulation of all things dopamine

Methamphetamine is more potent than amphetamine because it has a _______________

Long half-life

Ephedrine, similar structurally to dopamine, found in decongestants can be used to make _____________

Methamphetamine

Which drug was used in WWII and lead to high levels of misuse due to addiction during war?

Methamphetamine

Amphetamines and Methamphetamines are ___________ of the catecholaminergic system

indirect agonists

How do amphetamine and methamphetamine increase dopamine in the extracellular fluid?

Block dopamine transporters

_____ competes with dopamine and enters the axon terminal via dopamine transporters which it disrupts _____ and causes dopamine to exit the vesicle and enter the extracellular fluid.

Amphetamine, VMAT

AMPH (amphetamines) competes with dopamine and enters the axon terminal via dopamine transporters which it disrupts VMAT and causes dopamine to exit the vesicle and enter the cytoplasm.

What process causes dopamine to be forced into the extracellular fluid of the synapse?

Dopamine receptor phosphorylation

At high doses, what can amphetamines cause?

Prevention of catecholamine metabolism by MAOs

What happens with repeated methamphetamine use?

Methamphetamine blocks DAT = Increase dopamine in extracellular fluid = decrease in dopamine receptors from being overloaded with dopamine