Releasers and Reuptake Inhibitors

[blueberries]

Ok,
I've forever been puzzled by this and need a proper answer without the shit surrounding it. I have UTFSE and I've had multiple answers (also it's pretty difficult to search for!). So basically: "Can you use neurotransmitter releasers and reuptake inhibitors together?".

I've always believed that you cannot as they would both cancel each other out. However recently I've come to see that they can, even enhancing each other (which would be the most logical conclusion, however logic doesn't seem to apply when it comes to neuroscience!). Compounds such as the APB's and APDB's utilise both releasing mechanisms and reuptake inhibition. At the end of the day though, if each were to potentiate each other, wouldn't they be more potent than straight releasers like MDMA and MDA? Or is the reason they have similar potencies due to the agonism that MDx provide (which the APx's make up for with reuptake inhibition)?

So what is the real answer? I'm on both a releaser and a reuptake inhibitor at the moment (speed and 3F-phenmetrazine) and they seem to be syncing pretty well but is there any danger of losing activity (or gaining for that matter)?

 

[Solipsis]

Isn't it true that:
- they competitively block the synaptic transporter, also depending on whether they block by binding to the same site on the transporter and if not: which action is stronger. But the releaser can also reverse the transporter. The transporter can only bind to one at a time so the reuptake inhibitor would competitively take away some of the action. But compensating for that is probably that there is a greater total action at the transporters happening.
- only the releaser inhibits / phosphorylates and reverses the vesicular transporter.

So I don't believe it is as black and white as 'canceling each other out' or only synergy but rather a complex mix of interactions.

These actions may not be the same at all neurotransmitter systems so drugs with multiple actions may see asymmetrical changes perhaps causing relatively more effect or instead more side-effect, depending on what you're looking for.

As always I'll wait for the opinion of the real pharmacology buffs

 

[endotropic]

There is no such thing as a "straight releaser", any compound that causes transporter mediated neurotransmitter efflux will also prevent reuptake of said neurostranmitter by causing the transporter to work in reverse.

You need to think about transporter occupancy to understand whether a releaser and a reuptake inhibitor will enhance each other or cancel each other out. For SSRI's to have an effect they need to inhibit something like 90% of the total serotonin transporters in the brain. That means when you try to take MDMA after your SSRI you'll find that the serotonergic effects of the MDMA are essentially non-existant as all of the transporters have already been taken up by the SSRI, meaning the MDMA has no opportunity to release serotonin.

Now let's say you're prescribed a low dose of ritalin and you decide to use some dextroamphetamine. The ritalin only needs to occupy a small percentage of the dopamine and norepinephrine transporters to have a therapeutic effect, so when you take the d-amph there's a whole boatload of spare transporters available for the amphetamine to act on and cause release. In that case the effects are additive or even synergistic since neither the d-amph or the ritalin can affect all of the transporters on their own. There could be a situation where you took so much ritalin that the d-amph didn't have anywhere left to act, but people usually start to suffer cardiac complications before they get to the point of total NET/DAT occupancy.

 

[specialspack]

people usually start to suffer cardiac complications before they get to the point of total NET/DAT occupancy.

Interesting - is there any evidence that points to a rough tipping point for a %age of occupancy that might lead to cardiac issues?

 

[endotropic]

Interesting - is there any evidence that points to a rough tipping point for a %age of occupancy that might lead to cardiac issues?

This study had 50% occupancy at around .25mg/kg cocaine and bumped up to 80% at 1mg/kg, and they say that dose range produced "subjective high": http://www.ncbi.nlm.nih.gov/pubmed/10485970

So you might need something like 3-4mg/kg to get ~100% occupancy, which is ~280mg for a 70kg adult.

Really I meant more things like racing heart and high blood pressure at high occupancy than having a heart attack or something. Although 280mg pure cocaine probably wouldn't be exactly safe, that probably has more to do with its local anaesthetic effects and NET action.