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GABA Receptor Antagonists

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c0rt3x

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I'm looking for a suitable GABA antagonist in order for experimental reversing the damages of alcohol dependency.

The only one readily available was Thujon - but this substance has probably to much other pharmacological effects.

Does anyone know a "clean" GABA-Antagonist?

Or has anyone another idea of how to reverse ethanol induced damages to the brain?
 
I don't think a gaba antagonist will just reverse the damage caused by ethanol abuse. I think a lot of the damage is from a down regulation of gaba receptors among other things combined with damage from over excitation of neurons during the withdrawal / hangover but I could be wrong. A gaba antagonist might help upregulate receptors again but it would be really uncomfortable while you're on it.
 
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There are two main subtypes of GABA receptors, GABA-A and GABA-B.

However GABA antagonists are considered to be really bad things. GABA is one of the main inhibitory systems in the brain so GABA antagonists result in excessive neuronal stimulation, leading to cell death from overstimulation, convulsions, seizures, anxiety, etc. Not good.

The prototypical GABA-A antagoist is bicuculline. Other drugs considerd to be "antagonists" are actually negative modulators - flumazenil is the prototypical one and acts similar to the opposite of a benzodiazepine. Pentylenetetrazol is another one used to induce seizures experimentally.

I don't think GABA antagonists are your solution. What "damages" are you trying to reverse, and what is the proposed mechanism? As far as I know a simple balanced diet, antioxidant/vitamin supplementation, and excercise are enough to effect recovery in most cases of mild neurotoxicity.
 
Bicuculline is actually self administered and apparently addictive under some conditions.

I would definitely not recommend this, though. Flumazenil is really the only compound that should even be considered and only if you're dead-set on it.

Whatever damage your brain has is unlikely to be related to GABAergic mechanisms! Look how long and difficult it is to become physically dependent on ethanol compared to alprazolam or any of the barbs (a physical dependency that substitutes well for benzodiazepines)- I don't think it's causing serious changes to your GABAergic system.
 
GABA-B receptors interest me a lot. You should read the "Opioids and GABA-B agonists" thread.

In that thread are links to a couple of papers. The first suggests that opioid induced euphoria comes from reduced activity at the the GABA-B receptor which results in increased dopamine release (GHB activates this receptor and inhibits dopamine release). The second suggests that GABA-B receptors are important for Modafinils DRI effects, but is a little more confusing...

Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release

1. Zheng-Xiong Xi1 and
2. Elliot A. Stein1,2,3,4

+ Author Affiliations

1.
Departments of 1Cellular Biology, Neurobiology, and Anatomy (Z.-X.X., E.A.S.), 2Psychiatry and Behavioral Medicine (E.A.S.),3Pharmacology (E.A.S.), and 4The Biophysics Research Institute (E.A.S.), Medical College of Wisconsin, Milwaukee, Wisconsin

Abstract

An emerging hypothesis to explain the mechanism of heroin-induced positive reinforcement states that opiates inhibit γ-aminobutyric acid (GABA)-ergic interneurons within the mesocorticolimbic dopamine (DA) system to disinhibit DA neurons. In support of this hypothesis, we report that the development of heroin self-administration (SA) behavior in drug-naive rats and the maintenance of SA behavior in heroin-trained rats were both suppressed when the GABAB receptor agonist baclofen was coadministered with heroin. Microinjections of baclofen into the ventral tegmental area (VTA), but not the nucleus accumbens, decreased heroin reinforcement as indicated by a compensatory increase in SA behavior. Additionally, baclofen administered alone or along with heroin dose-dependently reduced heroin-induced DA release. This effect was blocked partially by intra-VTA infusion of the GABABantagonist 2-hydroxysaclofen, suggesting an additional, perhaps GABAA receptor-mediated, disinhibitory effect. Taken together, these experiments, for the first time, demonstrate that heroin-reinforced SA behavior and nucleus accumbens DA release are mediated predominantly by GABAB receptors in the VTA and suggest that baclofen may be an effective agent in the treatment of opiate abuse.
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The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism.

Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K.

Institute of Pharmacology, University of Ferrara, Italy.
Abstract

The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.

PMID: 8813612 [PubMed - indexed for MEDLINE]
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Other drugs considerd to be "antagonists" are actually negative modulators - flumazenil is the prototypical one and acts similar to the opposite of a benzodiazepine
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For what it's worth, Flumazenil is actually a silent antagonist. It binds to the receptor but it doesn't produce an effect either way. Well, there may be some decrease in GABA's efficacy, but I don't know that it's statistically significant.

There are a whole lot of inverse agonists, many beta-carbolines, for instance, that do the opposite of benzos, and these are the drugs you'd really want to avoid. A silent antagonist like flumazenil is relatively safe by comparison.
 
Hammilton said:
For what it's worth, Flumazenil is actually a silent antagonist. It binds to the receptor but it doesn't produce an effect either way. Well, there may be some decrease in GABA's efficacy, but I don't know that it's statistically significant.

There are a whole lot of inverse agonists, many beta-carbolines, for instance, that do the opposite of benzos, and these are the drugs you'd really want to avoid. A silent antagonist like flumazenil is relatively safe by comparison.
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A silent antagonist, interesting. I know that its used to alleviate symptoms of benzodiazepine withdrawal but not much else about it. Don't beta-carabolines usually double as MAOI inhibitors?

sekio said:
Doesn't flumazenil bind at the benzodiazepine site?
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Yeah.

OP: in terms of a "clean" GABA-A antagonist flumazenil seems to be your best bet, but it does not increase GABA the same way alcohol does. As for reducing damage caused by ethanol, no drug so far as I am aware is in usage. Looks like you found promising information though. Good Luck.



Just how Flumazenil alleviates symptoms instead of what sounds logical on the outside (aggravating withdrawal) is a mystery, though I'm sure it has something to do with the profile Hammilton related.
 
I don't entirely understand the question, I'm sorry. Yes, Flumazenil binds at the BZD site, as an allosteric site, the agonistic or antagonistic (or inverse agonistic) activity is measured by their ability to potentiate or reduce the effect of GABA when it binds. Clonazepam, for instance, nearly doubles the effect of GABA. Flumazenil more or less leaves the effect of GABA unaltered. Inverse agonists, like many beta carbolines, significantly decrease GABA's effect when it binds.

Yeah, some beta carbolines are MAOIs. Nowhere near all of them though. There are many compounds from the family, just like there are many compounds from the phenethylamine family, and they can have rather variable effects.
 
I was under the impression that if you gave flumazenil to a benzo-dependent person they would go into snap withdrawals, a bit like giving naloxone to an opioid head.

As far as I can tell, supressing one of the main inhibitory circuits in your brain is not wise...
 
sekio said:
I was under the impression that if you gave flumazenil to a benzo-dependent person they would go into snap withdrawals, a bit like giving naloxone to an opioid head.
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If I'm understanding Hammilton right and Flumazenil is essentially a silent allosteric modulator (doesn't increases or decreases the effect of the orthosteric ligand) then it should only have an effect when another compound is bound to the BZD site and Flumzenil competes it off.

If the person still had benzos on board the Flumazenil would compete them off and cause GABA to work at normal efficiency instead of the benzo amplified efficiency, sending the person into withdrawals. I think the proposed usefulness for treating withdrawal symptoms comes later when the receptor has lost sensitivity to GABA, and Flumazenil somehow "resets" the receptor.
 
Well, I agree about the last part, but I'm not sure about the former.

The BZD receptor isn't the 'real' receptor on the site. The BZD site doesn't really do anything unless GABA is bound, and then it acts to potentiate the effect of GABA. If you give naloxone you're blocking the actual receptor site, not some allosteric binding site as is the case here.

I'm guessing it wouldn't feel good, but it won't be the same as naloxone in a junkie
 
Poodles! said:
GABA-B receptors interest me a lot. You should read the "Opioids and GABA-B agonists" thread.

In that thread are links to a couple of papers. The first suggests that opioid induced euphoria comes from reduced activity at the the GABA-B receptor which results in increased dopamine release (GHB activates this receptor and inhibits dopamine release). The second suggests that GABA-B receptors are important for Modafinils DRI effects, but is a little more confusing...
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GHB releases glut trough the ghb receptor, besides that i think its selective for presynaptic gabab wich increases da.
That said its mu that causes "liking", da just causes wanting.
 
"Are you looking for something to help you through the acute withdrawal phase of alcohol dependence or something to reverse long term changes following abstinence?"

I want to reverse long term damages after many years of abstinence.

I do not understand why Flumazenile would alleviate withdrawal symptoms of GABA agonists or positive modulators, too.
It was actually more reasonable to expect a serve worsening of the symptoms.

Maybe thus beta-carbolines (in very low doses of course) would be the more effective substances for my special purpose. But I agree that GABA-Antagonists are all but fun in general and highly dangerous, too.

However I consider one to two weeks of taking low dose GABA-Antagonists (which btw after that time should lead to a quite enjoyable withdrawal :) as the lesser evil compared to the inability to enjoy any GABA related substance for the rest of my life...

@Hammilton: Which beta-carboline would you consider to be the most matching opposite of ethanol in its pharmacological profile?
 
Reversing long term damages by ingesting probable excitottoxins ain't smart - you won't find any help with GABA agonists.

And in pharmacology sometime one plus negative one doesn't always equal zero. Drug effects aren't as simple as finding the "opposite" of another drug and using it. What "long term damages" are you speaking of, are they percieved or medically documented, and what other drugs do you take / lifestyle do you lead?
 
This thread is like someone saying they got chemical burns from potassium hydroxide years ago and that they're now trying to remove the scars with conc. sulfuric acid...

Also, unless one has been drinking heavily on a daily basis for years, notable alcoholic brain damage isn't very likely.
 
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