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Dual dopamine/serotonin releasers

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Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions.
Rothman RB, Blough BE, Baumann MH.
AAPS J. 2007 Jan 5;9(1):E1-10.

We have advocated the idea of agonist therapy for treating cocaine addiction. This strategy involves administration of stimulant-like medications (eg, monoamine releasers) to alleviate withdrawal symptoms and prevent relapse. A major limitation of this approach is that many candidate medicines possess significant abuse potential because of activation of mesolimbic dopamine (DA) neurons in central nervous system reward circuits. Previous data suggest that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is important to consider when developing medications with reduced stimulant side effects. In this article, we discuss several issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, we discuss evidence supporting the existence of a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Then we summarize studies that have tested the hypothesis that 5-HT neurons can dampen the effects mediated by mesolimbic DA. For example, it has been shown that pharmacological manipulations that increase extracellular 5-HT attenuate stimulant effects produced by DA release, such as locomotor stimulation and self-administration behavior. Finally, we discuss our recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine DA-/5-HT-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers might be useful therapeutic adjuncts for the treatment of cocaine and alcohol addiction, obesity, and even attention deficit disorder and depression.

PMID: 17408232

Free article: http://www.aapsj.org/view.asp?art=aapsj0901001

See also related articles for more studies on subject:
http://www.ncbi.nlm.nih.gov/pubmed/17408232
...

Has anyone tested any of these compounds? What are the subjective effects?

4-methylaminorex isn't addictive, but improves a lot of quality of life. Are there available any binding data for it?
 
Very very interesting, that changes everything. Odd how so many people have been addicted to it, though.
 
I'm not buying it.As long as you get your extra dopamine you'll be fine,haha, thats how addiction (or aquired personal dopamine deficits) works.And who says's Naphtylisopropylamine isn't reinforcing?I'm pretty sure it IS,and I'm speaking strictly of humans-at least in ME it WOULD be as its exactly whats I'm searching(craving?) for,a dual Serotonin/Dopamin releasing (or reuptake?) agent.

In the end it boils down to duration of the effects,the longer/slower onset,the better.And yes,hopefully what the paper describes could prove true.But what about potential withdrawals? I know them from Duloxetine,a dual SRI/NRI weak DRI,its fu**ing pain in the ass.

Well this are the words of a biased cynic who in the end would be deeply thankful if indeed something could be found working on the 5-HT and DA axis without running into problems.I know the best AD drug for me would be a SRI/DRI compound,but where are you gonna find one? Minaprine sounds ok,but its not available here.Escitalopram and Methylphenidat would be the closest clean combination to achieve it with two drugs,Citalopram and Bupropion tried many years ago proved to be the best success in vivo.But Wellbutrin sucks.

Maybe I should just try this "bicyclic amphetamine" Napthylisopropylamin?
 
Can we have a dual da-5ht releaser that's non-neurotoxic? Y'know, that's something I look for in maintenance drugs...dunno about anyone else. . .

ebola
 
4MAR has major cardiotoxicity issues I believe. Little affinity for 5ht2b is also a must in my book...
 
Also the DA/5HT toxicity issue is only of major concern if you have significant 5-HT vesicle depletion. In a therapeutic daily use drug the dose would be low enough that this does not happen. MethAmp and MDMA are toxic at all doses because of other toxic metabolites, not just the dual release.
 
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