Chemicals causing release or inhibition of Neurotransmittors

Concerning serotonin, norepinephrine, and dopamine:

I'm searching for non-euphoric, non-recreational substances that cause a release or inhibition of each of these. For example, one chemical that causes (directly or indirectly) the release of serotonin (another chemical that does the same for norepinephrine, and a third for dopamine). Second, I'm looking for non-euphoric, non-recreational substances that cause inhibition of reuptake of these neurotransmitters. For example, one that inhibits reuptake of serotonin, one for norepinephrine, and one for dopamine.

On the inhibition of reuptake:
Serotonin: SSRIs - Paxil, Prozac, Zoloft, etc.
Norepinephrine: SNRIs- Reboxetine, Strattera
Dopamine: SDRIs - Wellbutrin

So I guess I answered half my question about substances that inhibit reuptake. Out of all these antidepressants or any other substances, what seems to be the MOST POTENT inhibitor of reuptake of each neurotransmitter?

Same goes for release; what causes the MOST RELEASE of each neurotransmitter?

Remember, I'm looking for substances that are not euphoric or recreational. Thanks.

Edited for grammatical error.

The releasers of those chemicals will all be euphoric and recreational to a degree...

MDEA is largely a pure serotonin releaser
(-)Ephedrine is largerly a pure NA releaser, though it has poor acccess to the brain, (-)-Phenmetrazine is the same, (-)Methamphetamine is also largely NA selective... probably the most selective out of the ones I've mentioned.

I can't think of a pure DA releaser.

Of course, serotonin releasers all cause dopamine release through 5-HT2 receptors... I'm pretty sure its 5-HT2A.


Have a look at this table, pick the drugs as you wish

Well amineptine is a dopamine reuptake inhibitor that's used as an antidepressant that's not supposed to be recreational (but then again, with side effects like spontaneous orgasm...). I think it's specifically dopamine over the other two normal targets. It's a tricyclic, so it might have some anticholinergic activity; I've no idea whether it has or it hasn't.

Amineptine is probably more selective for NET than DAT (1).

It's strange, there are quite a few sites that cover clinical antidepressants that I've looked at, and all they seem to focus on regarding amineptine's action is the inhibition of dopamine reuptake. Perhaps it's because amineptine is categorized as having a small abuse potential, so that's why they seem to be overly concerned with dopamine reuptake

Yeah, well a lot of sites tell you that methamphetamine or cocaine are selective for dopamine... so it's always hard to tell.

I'll tell you one thing is that ritalin where at the 3,4 positions the benzene ring has been extended into a napthalene ring is allegedly very good. Although it binds strongly to the dopamine receptor, it does not significantly impact on dopamine release to anywhere near the same extent. Hence it is believed to have anti-addictive properties and is being considered as a treatment agent to combat cocaine addiction and the like.

Blizor, I saw the source on that table you provided but if you could provide me with an online link, that would be greatly appreciated. Also, if you know where I could find the full text (if it isn't online, such as where to look in a library), that'd be very helpful as well.

Diethylpropion was one chemical that intrigued me...if anyone know where I can find more information on this, it could be very much appreciated.

Thanks a lot to all. Blizor, you are a HUGE asset to this new forum and I'm glad it got started...it has definitely proved to be extremely informative in the short time it's been up. Thanks again.

Edited for info. about diethylpropion

Well if you online access to the European Journal of Pharmacology, you can find that article here... If you have access to a scientific/medical library, the articles references is Eur J Pharmacol. 2003 479(1-3):23-40, which is a whole issue dedicated to the action of psychstimulants which act on transporters.

Now, is there any way of telling which of the drugs on that chart cause tolerance to develop? For example, the SSRIs don't but methamphetamine does, which would mean the values listed for the SSRIs would be (roughly) the same after 1 years while the values listed for meth-amp. would be significantly lower, right?

Assuming tolerance didn't occur with any of these, wouldn't the one with the highest values also provide the most antidepressant effects, such as phendimetrazine and diethylpropion?

If we ignore the antidepressant effects of SSRIs (as we don't really know why they happen), then one can safely say that tolerance occurs to SSRIs.

I would say that tolerance occurs to all of them.

As we don't know the mechanism behind antidepressants, I feel we can't predict them... though most people would say that anything that inhibits the uptake of NA and/or 5-HT with little effect on DA would be a good antidepressant.

Why do you say "with little effect on DA would be a good antidepressant?" I was under the impression that Wellbutrin could be classified as a SDRI (selective dopamine reuptake inhibitor) and that it's primary (if not, only) mode of action was on dopamine...and this seems to be a fairly effective treatment for depression. Please clarify why you think little effect on DA would be important for antidepressants.

From what little we know about the precise actions of antidepressants and reasons why they relieve symptoms of depression, what actions would be ideal in releaving these symptoms?

It has been suggested an SSRI plus a 5-HT1A antagonist could prove to be more effective than an SSRI alone. "In-vivo L-792239 was seen to increase rat hippocampal extra-cellular 5-HT (up to +400% of basal levels), 30 minutes after injection [67]. This is comparable to the enhancement of 5-HT efflux found by the combination of WAY 100635 plus fluoxetine, which effectively doubles the increase in extra-cellular 5-HT in the frontal cortex poduced by fluoxetine alone [68]." (http://www.bentham.org/sample-issues/cmc9-8/spinks/spinks-ms.htm)

What is an example of a 5-HT1A antagonist that is currently available in the US? I believe certain atypical antipsychotics may be.

The newest approved A/D is Cymbalta, a dual reuptake inhibitor that affects reuptake of both serotonin and norepinephrine. Similar to Effexor, but more 'potent' in its reuptake of norepinephrine (more equally acting, while Effexor still primarily affects serotonin, and norepinephrine to a much lesser extent at higher doses. This suggests that NA may play a larger role than initially thought in treatment of depression.

As mentioned, Wellbutrin's primarly acts on dopamine. This would lead me to believe a serotonin/norepinephrine/dopamine reuptake inhibitor would be the most effective treatment against depression (possibly with the addition of a 5HT1A antagonist). So wouldn't Cymbalta + Wellbutrin + 5HT1A antagonist be a GREAT treatment options? Now this may cause some concern about triggering manic episodes, so why not throw in the first FDA-approved drug for bipolar since Lithium, Lamictal? Or use lithium itself?

I guess I'm just looking for what "cocktail" of drugs that are currently available in the US you would prescribe for the most severe case of bipolar disorder, depression, panic disorder, generalized anxiety disorder, and OCD (all in one patient)? Currently, I'd think Cymbalta, Wellbutrin, Lamictal (and possibly lithium), Gabitril, and possibly an atypical antipsychotic (Geodon) would be a great combo.

After editing this for the fourth or fifth time, I'm off to bed. But I strongly suggest reading the internet link I provided before replying as it seems to be very useful (I still haven't finished reading it).

Well, you see, firstly, I'm kinda in the camp that antidepressants, on average, are startlingly inneffective drugs. While in some people, it would seem, they work very well, in active placebo controlled clinical trials, on subject to meta analysis or not, they only just reach significance, and sometimes don't...

I also feel that a line needs to be drawn between euphoriants and antidepressants... I personally suspect that SDRIs (as some people like to call them) and MAOIs are euphoriants. I also think that if you changed their pharmacokinetic properties, so that they were rapidly absorbed, you would get a very addictive drug.

You want to know a fast absorbed 5-HT/NA/DA uptake inhibitor? Cocaine.

I think that an SSRI plus a 5-HT1A antagonist is a fucking recipe for disaster clinically... I don't know whether you'd get hallucinations, anxiety, psychosis, or all three... but you'd definatly get something because of massive cortical excitation.

Somehow you're under the impression that flooding the brain with 5-HT or some other monoamine is the answer to depression... and I am certain that it is not.

When ever I get into this kinda discussion, I always want to say "the best pharmacological treatments are always etiological" or something, i.e. Good drugs effect causes. I'm not sure if there are many examples that back me up though. I suppose it depends on your scope. Morphine is probably one of the best drugs ever. It doesn't treat the damage, or the inflammation or the generation of pain signals, but it does stop a lot of them from entering the brain, so in one sense you can say they are treating the cause of the pain, which is pain signals getting to the brain. The mack daddy of all drugs, are the antibiotics: Majoratively side effect free, huge success rate; they are definatly causative. When it comes to psychopharmacology, we don't have causative drugs (apart from maybe MS and Myasthinea Gravis probably some others too). There is no evidence for low monoamines in depression, and I think the evidence for a dopaminergic link to schizophrenia is weak. SO, in my opinion, until we find the cause of depression (and I doubt it will be classically neurochemical), we wont be able to treat it well, especially if we have too many more non-imaginative people like Spinks wasting research funding.

I might add that this kind of massive co-morbidity that you often see in depression shows to me at least, that what we have is a massive psycho-neurological failling and if anyone thinks classical systems pharmacology is gonna help, they're gonna have to wake up.