Pharmacology of Psychostimulant Treatment

Question 1

What is the public health concern surrounding the increase of methamphetamine use?

Answer 1

METH production is on the rise with increasingly available at lower cost and is one of the most commonly used substance

Also, mental health conditions was identified as one of the underlying causes of problematic methamphetamine use in Canada

Question 2

What are the 3 steps of the molecular mechanism of METH induced neuronal dopamine release?

Answer 2

1. Redistribution of dopamine from synaptic vesicles to cytosol
2. Induction of reverse transport of dopamine through dopamine transporters (DAT)
3. Additional drug effect that impacts extracellular dopamine levels (ex. DAT blockade, metabolism, internalization of DAT)

Question 3

Describe the mechanism of the “redistribution of dopamine from synaptic vesicles to cytosol” as one of the steps of METH induced neuronal dopamine release

Answer 3

METH is a substrate of vesicular monoamine transporters (VMAT1 & 2). VMAT2 gene is preferentially expressed in CNS, with nearly 10-fold higher affinity for METH at VMAT2

Considered to be VMAT competition since METH and dopamine are competing for the uptake site
=DA floods the presynaptic cytosol

Question 4

Describe the mechanism of the “induction of reverse transport of dopamine through dopamine transporters (DAT)” as one of the steps of METH induced neuronal dopamine release

Answer 4

Trace amine associate receptor 1 (TAAR1) signalling alter monoamine transporter function -> changes the conformational property of DAT -> reverse transport (=release DA flooded in the presynaptic cytosol)

Protein kinases regulate DAT function and METH increases protein kinase C (PKC) activity -> PKC activation stimulates DAT-mediated release of dopamine

Question 5

How does dose/concentration of METH affect the mechanism of action?

Answer 5

Low conc. of METH may preferentially release dopamine already resident in the cytosol. Higher conc. are required to redistribute vesicular dopamine to the cytosol

METH at low conc. acts more like a DAT blocker than a reverser

Question 6

What is the striatum and what is it responsible for?

Answer 6

It is a small group of contiguous subcortical structures and is one of the principal components of the basal ganglia

It’s responsible for the movement, reward, and motivation function

Question 7

Summarize the findings of whether METH-use leads to neurodegeneration

Answer 7

Preclinical data predicts that methamphetamine (MA) at an unknown, likely high dose, damages dopamine neurons in the human brain

It was found that METH at doses used by the subjects of the studies, was unlikely to have caused significant damage to brain dopamine neurons. There may be clinical significance to low dopamine levels in recently abstinent METH users if it impacts negatively on cognitive functioning and drug relapse

Question 8

Summarize the main outcome in the dopaminergic imaging index between stimulant users and healthy controls in pre-clinical models

Answer 8

There is consistent reduction in dopamine release in people who have been exposed to chronic stimulant use in contrast to preclinical models of long-term use

Inconsistent preclinical models show no change or increased change in dopamine release after withdrawal

Question 9

What are 3 possible explanations for the reduction in dopamine release?

Answer 9

1. Loss or damage to dopamine neurons
2. Neurobiological adaption (pharmacodynamics tolerance)
3. Premorbid dopaminergic dysfunction

Question 10

Describe the dopaminergic changes in METH use and its effects on the striatum

Answer 10

Dopamine D2 receptors are functionally lower in addiction

METH misuse greatly reduces the binding of dopamine to dopamine receptors in the striatum, a brain area important in memory and movement. With prolonged abstinence, DATs can be restored