Where's
@Seppi for this? Right in his(her?) wheelhouse.
Perhaps amphetamine/meth after uptake through DAT and VMAT, is driving VMAT reversal (see nature comm vs. review paper below), relatively locking a preferential outward flow of DA, but is partially modulated in a feedback loop by TAAR1 in terms of some sensitivity/end rates? Perhaps something akin to L-type Ca2+ channels (compare DAT) linked to VMAT and TAAR (compare IP3R and ryanodine receptors, but sort of a different feedback) releasing more Ca2+ (DA from vacuole instead of Ca2+) from sarcoplasmic reticulum with feedback (say from TAAR) driving SERCA pump (but instead Meth overrides channel preventing previous return). Has to be some kind of feedback cycle there, but I wonder where the balance lies. OCTs like OCT3 could be a secondary valve for DA and such if VMAT was fully inhibited or something?
Maybe the TAAR1 knockout lack that regulation/typical feedback , the tuning down of the DA signal over time rather than overall DAT number. Could be some oligomerization alteration, or that DAT gets 'stuck' in the reversed form more. Could be more DATs on the cell surface, or maybe more DATs don't get internalized over time due to lack of TAAR tuning (via G13 through RhoA). TAAR auto-inhibitory circuit.
I wonder if other transporters are involved to some degree beyond VMAT and DAT. Amphetamine/especially meth do diffuse some (some other papers certainly imply a degree of diffusion even if elements are blocked), especially in the cytosol to more acidic vacuoles. Differences in plasmalemmal vs. vacuole membrane kinetics. Even though it says some effects are blocked by DAT inhibitors like cocaine and methylphenidate, that doesn't seem to match other papers entirely and clinical uses.
Preferential Rho-signaling activity from TAAR1 in non-lipid rafts was interesting compared to epinephrine's PKA activation in lipid rafts. Phosphorylation and internalization targets.
I would be curious to see some sort of sequential experiment, say a BRET-FRET for DAT and VMAT2 in presence of amphetamine as modulated by VMAT2 inhibitors, TAAR1 agents. V-ATPase inhibitor as well. Co-localization, activation of D2, A2A as well.
Various papers that were free or open access
General review, transport cycle model
Amphetamines are known to enhance extracellular dopamine levels, but the underlying mechanisms are unclear. Utilising a new pH biosensor for synaptic vesicles, the authors show that amphetamines diminish vesicle pH gradients, disrupting dopamine packaging and leading to increased...
www.nature.com
Some mechanisms of amphetamine action - highlights DAT - VMAT tandem, vesicle alkilization by amp in MPP+ model
Trace amines (TAs) such as β-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for...
www.nature.com
Overexpression of TAAR1 - Decreased sensitivity to amphetamine, negative regulatory interaction
The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of i…
www.sciencedirect.com
Wider, multi TAAR review
Trace amines and their receptors (trace amine-associated receptors; TAARs) are an emerging pharmacological target for the treatment of human disorders. While...
www.frontiersin.org
As above, wider TAAR review, immuno focused but nice developmental history and evo
The trace amine-associated receptor 1 (TAAR[1] ) is an aminergic G protein-coupled receptor (GPCR) potently activated by 3-iodothyronamine (1), an endogenous derivative of thyroid hormone. Structure activity relationship studies on 1 and related agonists ...
www.ncbi.nlm.nih.gov
TAAR1 molecular level inquiry
Impulsivity is an important personality trait associated with several clinical syndromes including drug abuse. While repeated drug exposure is known to increase certain behavioral responses, such as locomotion, to subsequent drug exposure, few studies ...
www.ncbi.nlm.nih.gov
Meth and TAAR1 agonist, interesting acute vs. chronic
AMP-EAAT3 internalization given insight by your posted TAAR paper
Vesicular monoamine transporters (VMAT) are responsible for the uptake of cytosolic monoamines into synaptic vesicles in monoaminergic neurons. Two closely related VMATs with distinct pharmacological properties and tissue distributions have been characterized. ...
www.ncbi.nlm.nih.gov
VMAT
Amphetamine abuse is a major public health concern for which there is currently no effective treatment. To develop effective treatments, the mechanisms by which amphetamine produces its abuse-related effects need to be fully understood. It is well known that amphetamine exerts its actions by...
www.nature.com
OCT3 and amphetamine
Our previous work suggested a role for oligomerization in regulating dopamine transporter (DAT) internalization, with d-amphetamine dissociating DAT oligomers and monomers being endocytosed. This model was put to detailed testing in the present work with ...
www.ncbi.nlm.nih.gov
DAT oligomers and amphetamine
Not gonna pretend I actually know the topic, I mostly downloaded the papers today waiting for a corticosterone shot and some people. Interesting stuff though.