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Are there dopamine release agents that don't interfere with VMAT-2?

S

Simfish

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So VMAT2 is the protein that amphetamines interfere with, and this interference is actually a significant component of amphetamine neurotoxicity.

A release agent doesn't necessarily have to be neurotoxic per se. It's only neurotoxic if it results in an increased concentration of dopamine in the presynaptic *terminal* (which is what an interference with VMAT2 does) - in which case the dopamine gets vulnerable to auto-oxidation => this auto-oxidation is what damages neurons. A nice schematic is at http://sphotos.ak.fbcdn.net/hphotos...054514401_100001281229599_327027_386257_n.jpg

By "release agent", I mean, basically an agent that reverses the action of the dopamine transporter (or moves it from the presynaptic terminal into the synaptic cleft).
 
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Hm, I'm not so sure about that.

http://www.bluelight.ru/vb/showthread.php?postid=3473367#post3473367

"Indeed, it is often sited that amphetamines work by inhibiting reuptake, but the actual contribution of amphetamine-induced reverse transport and reuptake inhibition in regards to the increase in free monoamines is hard to calculate but it has been estimated that the majority of the increase in monoamines is due to reverse transport (Schmitz et al., 2001). This conclusion can be easily seen to be true as the maximum increase in free monoamines in the brain caused by amphetamines is well over 1000%, while cocaine causes a maximum increase in extracellular dopamine around 500%. "

It says that reverse transport is really the main mechanism of action.

Reverse transport will also tend to deplete dopamine in the presynaptic terminals
 
I think binding to DAT and DA-release are actions directly connected to each other. See J Neurosci. 1998 Mar 15;18 (6):1979-86. PMID: 9482784
 
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Doesn't amphetamine bind to DAT from the outside of the cell though?

Here's a diagram: http://www.cnsforum.com/content/pictures/imagebank/hirespng/Drug_amphet_low.png

So you could find another way to increase dopamine outside of the cell (inhibit reuptake for example), and then that could increase dopamine to the concentrations necessary to reverse the DAT. When it's outside of the cell, it doesn't have to be neurotoxic.
 
Oh hah, I found a solution! Take Adderall with Ritalin. (although it's probably best to halve one's normal dose of each then)

I'm not even joking =P

http://www.aapsj.org/view.asp?art=aapsj080248#B11

http://jpet.aspetjournals.org/content/304/3/1181.abstract

It has been hypothesized that high-dose methamphetamine treatment rapidly redistributes cytoplasmic dopamine within nerve terminals, leading to intraneuronal reactive oxygen species formation and well characterized persistent dopamine deficits. We and others have reported that in addition to this persistent damage, methamphetamine treatment rapidly decreases vesicular dopamine uptake, as assessed in purified vesicles prepared from treated rats; a phenomenon that may contribute to aberrant intraneuronal dopamine redistribution proposedly caused by the stimulant. Interestingly, post-treatment with dopamine transporter inhibitors protect against the persistent dopamine deficits caused by methamphetamine; however, mechanisms underlying this phenomenon have not been elucidated. Also of interest are findings that dopamine transporter inhibitors, including methylphenidate, rapidly increase 1) vesicular dopamine uptake, 2) vesicular monoamine transporter-2 (VMAT-2) ligand binding, and 3) VMAT-2 immunoreactivity in a vesicular subcellular fraction prepared from treated rats. Therefore, we hypothesized that methylphenidate post-treatment might protect against the persistent striatal dopamine deficits caused by methamphetamine by rapidly affecting VMAT-2 and vesicular dopamine content. Results reveal that methylphenidate post-treatment both prevents the persistent dopamine deficits and reverses the acute decreases in vesicular dopamine uptake and VMAT-2 ligand binding caused by methamphetamine treatment. In addition, methylphenidate post-treatment reverses the acute decreases in vesicular dopamine content caused by methamphetamine treatment. Taken together, these findings suggest that methylphenidate prevents persistent methamphetamine-induced dopamine deficits by redistributing vesicles and the associated VMAT-2 protein and presumably affecting dopamine sequestration. These findings not only provide insight into the neurotoxic effects of methamphetamine but also mechanisms underlying dopamine neurodegenerative disorders, including Parkinson's disease.
Click to expand...
 
Hm here's a question: if amphetamines block the dopamine transporter (they are reuptake inhibitors to some level), then don't they reduce the effects of reversing the dopamine transporter?
 
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