Amphetamines (Stimulant #2) Flashcards
What is the structure of amphetamines and how does it resemble that of catecholamines?
The image of the structure
What are the 3 different forms of Amphetamines?
Also, is it True or False, that all forms are HCl salts?
True or False: All forms are derived from KHAT which contains cathinone and methcathinone –> which is a mild stimulant.
There is the Powder version “Crank”
Crystal Meth
Pill
The answer is True, all forms are HCl salts.
False, All forms are all synthetic products
What is the route of administration of Amphetamines?
Also, what is the half-life?
Amphetamines can be
Snorted (Crank version)
Smoked
IV
or Orally ( it is tolerated in the GI tract, not like cocaine)
Also, for orally, Amohetamines is used therapeutically for example used for narcolepsy (sleep disorder), treat obesity (acts as anorectics), and used for Attention Deficits
The half like is 7 + hours.
What is the mechanism of action of Amphetamines?
Hint: Think about the normal mechanism and then see how Amphetamines can disturb this conservation.
Follow up question-based on MOA of AMPH?
Yes or No: Does Cocaine also work in a way, if there are NT receptors that are not releasing a bunch of NT?
True or False: AMPH activation will occur if the pre-synaptic cell is inactive. It will turn DAT into an exchanger (exchange intracellular DA for AMPH) and when a vesicle is released with AMPH it can bound again to the DAT or diffuse away in the blood.
What happens if DAT is knockout?
Normal Mechanism
First, let look at a normal mechanism that is completely pre-synaptic. Tyrosine convert to DA, DA is packed in a vesicle with VMAT protein. The VMAT protein moves DA against the gradient, so it requires energy and it uses the proton gradient that is created by using ATP to move H+ against the gradient. Once the neuron is excited, DA is released to the synaptic cleft and DAT performs reuptake.
AMPH in the system
AMPH is competing with DA for the DAT. When AMPH binds with DAT it will increase affinity for intracellular DA. Once intracellular DA bind to the DAT, it will induce conformation change which will transport AMPH inside the cell and transport DA out of the cell.
(Blocking the reuptake of DA, But also releasing it)
AMPH can diffuse in the membrane and also enter the vesicle. When AMPH is in the vesicle, it will bind with H+ and weaken the driving force to bring DA into the vesicle. This will increase intracellular DA concentration which the DAT has a high affinity towards, and more DA is release.
No, cocaine only works if there is a tonic release of the ligand.
True: AMPH activation doesn’t matter if the pre-synaptic cell is active or not.
AMPH can “go back for seconds” for DAT, which is why I believe why it has a high half-life.
AMPH will still work, induces hyperlocomotion in DAT-KOs, and induced Condition Performance Placement.
Now that we know the Mechanism of Action of AMPH.
What are the acute and long term effects of AMPH?
Here only focus on the acute effect of AMPH.
Acute effects
Similar to Cocaine
Physiological (sympathomimetic)
the primary effect includes: vasoconstriction which increases blood pressure and increases heart rate
Brondchioldilation
Increase temp
Pupil dilation
Anorectic (lessen the appetite)
increase plasma glucose by breaking down fat
Attention (a stimulant)
Includes
high alertness
high ability to concentrate (that is a belief)
and lessen fatigue
Movement( psychomotor)
activates motor pathways (nigrostriatal pathways)
In low doses
Your movement, talking fidgeting, and pace increase
In high doses
repetitive movements
Also, an increase in extracellular monoamines (turn the DAT into an exchanger)
Now that we know the Mechanism of Action of AMPH.
What are the acute and long term effects of AMPH?
Here focus on the long-term effects of AMPH.
Long Term
Affect on the DA system
loss of terminals and probably axons; spare cell soma (they can route back to the original synapse but it won’t form a functional synapse) (This is a 1999 study, but there is a 2015 study that questions of DA terminal loss are the caused by AMPH) (check the image in the flowchart)
the greatest effect in the Nigrostriatal pathway (dopamine pathway)
The lesser effect in mesolimbic and mesocortical pathways
and Hypothalmic path completely spared
Affect on 5-HT system
loss of terminals; spare cells
Terminal loss in cortex, striatum, and hippocampus
(Check the image on the flowchart)
Compensatory changes in the brain
increase GFAP which is a marker for gliosis (a glial response to trauma)
Decrease tyrosine hydroxylase (the rate-limiting enzymes for DA) which lower DA content, DA metabolites, and DAT.
(Check the image on the flowchart)
What are the risks of Amphetamines’ use?
Hint: Mechanism of Amphetamines Neurotoxicity
Part 1
What are the consequences of Oxidative Stress, Inhibition of Mitochondrial Activity and Cytosketal Damage, Excitotoxicity?
What is the effect of AMPH on the BBB?
Mechanism of Amphetamines Neurotoxicity
There are two different pathways
- Increase in the Dopamine pathway. which creates a variety of components, DA Quinones that increase ROS and -OH, increase RNS. Both, ROS and RNS perform Protein Oxidation, protein nitration, lipid peroxidation, and DNA oxidation all lead to oxidative stress.
- Increase in the Glutamate pathways, which are induced indirectly and cause high levels of ATP which can be toxic, that activates NMDA, and increase Ca2+.
Ca2+ can activate Ca2+ dependent protease which increases septin TAU and MAP-2 that leads to Cytoskeletal Damage (Excitotocity) (Apoptotic pathway) Also, Ca2+ can inhibit the mitochondrial activity, increase ATP utilization and decrease O2 consumption. Finally, Ca2+ can activate NOS which increase RNS and contribute to Oxidative Stress (seen in the DA pathway)
The consequences are VMAT-2-loss, DA, and/or 5HT Terminal Damage, and increase blood-brain barrier (BBB) permeability.
Meth induced “opening” of BBB, has quick effects take minutes which include increase vesicular release and degradation of tight junctions. Meth also has slower effects take hours which can be chronic like inflammation and cytokine release from neural damage, microglia, and leukocytes. Also, Meth induced can affect the MMP (metric metalloproteinases) which degrades endothelial cell-basement membrane and phosphorylates and cleaves tight junctions
What are the risks of Amphetamines’ use?
Part 2
Psychosis
a paranoid state characterized by hallucinations and delusions and occasionally violent behavior
Physical Deterioration most common skin ulceration and meth mouth. Proposed cause of meth mouth
Lack of drive to keep up basic hygiene
increase motor activity grind teeth (bruxism)
Thirst and hunger (high consumptions of sugary carbonated drinks)
dry mouth from the change in pH and bacteria
What do we know of TARR1 and its relationship to the effect of Amphetamines?
Hint: Agonists?
Two ways TAAR1 is related to the action of AMPH
We know that TAAR has nine receptors but we only study TAAR1 in this course. These receptors are expressed in the body and brain (check flow chart for specific locations)
The TAAR1 Agonist consists of the endogenous ligands, B-phenylethylamine, B-tyramine, p-octopamine. Other ligands consist of DA and pyschostimulus like AMPH, METH, MDMA (ecstasy), PDHA. TAAR1 Agonists are known to play a functional role in ADHD, Depression, and Schizophrenia.
Relationship to the effect of AMPH
Negatively modulators AMPH-like stimulants
Look at two models, the TAAR1 overexpression model which decreases AMPH self admisntarion, AMPH-induced hyperlocomotion, and decrease cue-induced reinstatement of drug-seeking. The TAAR1 KOs model which is hyperdensity to AMPH-induced locomotion augmented (make greater) METH-induced CPP, and increase DA release in the striatum.
DAT enhances TAAR1 mediated signaling
Increased cAMP/PKC signaling in TAAR1/DAT preparations
TAAR1 is associated with DAT internalization
Binding of ligands to TAAR1 induces translocation to the membrane
(look at the flowchart for the images)
Remember that a study from 1999 concluded that the long term effects of AMPH effect the loss of DA terminals and probably axons. Now a study from the 2015 question if this conclusion is truthful.
What is the neuroadaptation induced by amphetamine exposure?
What evidence do we have that amphetamines exposure causes or does not cause neural damage?
The neuroadaptation is that AMOH leads to terminal loss (less DAT). This is the conclusion from the 1999 study.
In the 2015 study, they propose two models for their correlation study, is the number of DAt expressed changing based on the amount of dopamine in the synapse? The first model is the conclusion from 1999, AMPH leads to terminal loss, less DAT measure, less DA. The second model is that AMPh leads to the internalization of DAt so decrease DAT but increase Dopamine.
(look at the graph on the flowchart)
Conclusion: the results are more consistent with the second model than the original model.
