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GABAergic withdrawal resembling D2 antagonism?

Jamshyd

Jamshyd

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To be honest I am not well-versed as of now to the interaction between GABA and Dopamine.

However, I did notice that, aside from anxiety (which I assume is largely attributed to GABA receptor downregulation), the effects of GABAergic withdrawals (namely in my experience, benzos and GHB) seem to be very similar to those of D2 antagonists. These effects include:

- Extreme lack of motivation
- Tardive Diskynesia
- Low energy
- Extreme anhedonia

And others, though these are the first to pop into my mind.

I have also personally experienced a MARKED (almost complete) reduction of the euphoric effects of dopaminergic drugs.

Any thoughts? I would appreciate criticism or clarification since I am probably blabbering about something I do not understand very well..
 
This really sounds interesting!! I remember reading about the interaction of dopamine receptors with NMDA, but also with GABAA receptors.
There is a functional crosstalk between the D5 receptor and the GABAA receptors by a direct protein linkage. Tian is the man who wrote much about that. Simply google for Tian, dopamine and GABA.
An other interesting thing crossed my mind: D1/5 antagonists are able to block the euphoric effects of coke.
I hope that helps a little.
 
I dunno, I've never heard of people in GABAergic withdrawal exhibiting the catalepsy that is common with D2 antagonists. Also, the low energy part seems weird too. Usually people in withdrawal from benzos/alcohol are overstimulated, and in serious cases can even have seizures. Maybe its peculiar to withdrawal from GHB, which acts on GABA-B, not GABA-A receptors like benzos and alcohol.
 
Yeah, catalepsy/Tardive Diskynesia are pretty novel side effects when it comes to widthdrawal from GABAergic agonists.

But I mean.. dopamine modulates lots of things, and GABA is ubiquitous, so of course these two systems interact with each other.

The loss of Euphoria from dopaminergic drugs is novel... but, I suppose I should ask: what dopaminergic drugs are you talking about?
 
BilZ0r said:
Yeah, catalepsy/Tardive Diskynesia are pretty novel side effects when it comes to widthdrawal from GABAergic agonists.

But I mean.. dopamine modulates lots of things, and GABA is ubiquitous, so of course these two systems interact with each other.

The loss of Euphoria from dopaminergic drugs is novel... but, I suppose I should ask: what dopaminergic drugs are you talking about?
Click to expand...

Oh I completely agree with you there about the ambiguitiy of just saying "GABA and Dopamine".

The drugs I am refering to were meth and cocaine - I feel all the effects such as peripheral and mental stimulation, but the euphoria is non-existant. There isn't even a mood lift. Now, when a non-schizophrenic person is given a high dose of antipsychotics, I beliece this person would experience anhedonia. What do you make of that?

As 5-HT2 suggested, I think this is more particular to GHB. I am rather confused about the status of GHB in relation to Dopamine. Your paper on this subject, Bilzor, is quite interesting, but I still do not understand how GHB interacts with Dopamine or at least how it affects motivation and euphoria.
 
^I'm very suspect of the putative mechanisms of action of GHB. Taking it myself for the first time only a few years ago, I'm not sure that they are not missing the mark because of how quickly GHB is metabolized. Dopamine levels being depleted is usually a consequence of dopamine being released. I'm not aware of any other drugs that directly lower dopamine levels or act at the synpatic vessicle to stop release. Neuroleptics block D2 receptors, but don't lower DA levels directly. I haven't seen PET or fMRI data on GHB, but I suspect that there is DA release in the Nucleus Accumbens.
 
I am not talking about lowering Dopamine levels per-se though, but rather dopamine desensitization, be it through blocking its release or by blocking its receptors or downregulating them.
 
Think i've experienced this, was using GBL uh probably "too often" heh, and some benzo's as well, after stopping both suddenly, I found that I could eat 30mg hydrocodone, and feel almost 'nothing'... no opiate tolerance..

The opiate buzz was so small that I had to "look for it" to find the very minor buzz that was there, but so weak i had to "look for it". Usually 30mg hydro would not only floor me but well, thats a lot for me, more like "i should be throwing up" instead of "barely feeling it".
 
The dysphoria I feel from neuroleptics/anti-psychotics and the dysphoria I feel from Opiate withdrawal are the same...

This is the only effect anti-psychotics and opiate withdrawal share however... (for me)
 
Wowowowo, back up the truck...

Dopamine levels being depleted is usually a consequence of dopamine being released.
Click to expand...
What with the who now? Who says that GHB depletes dopamine? Dopamine release is constant, and dopamine is being constantly synthesized to counter that... only heavy handed pharmacological manipulations deplete dopamine....

GHB does lower dopamine release, but so does baclofen, and I'd geuss that a GABA transporter inhibitor would as well

GHB%20dopamine%20release.gif
 
^ Interesting.

I may also add that in my case, supplementation with l-phenylalanine did nothing, supplementation with l-DOPA created physical side effects and none of the mental effects.

Would this suggest that IF this is dopamine related, then it would be more due to its antagonism/lack of release, rather than depletion?

To update... yesterday I decided to experiment again. A friend gave me a couple of doses of Heroin as a gift, and I decided to check the status of my euphoric ability. And so I IVed my normal dose (of this same batch), now about 1 month since the abovementioned last trial.

I had a hard time figuring out if I felt a rush, but after a few seconds I felt the typical nausea, itching..etc and I felt comfortable but not blissful as usual...
 
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I mean, when it boils down to it; the major site of action of dopamine is the striatum. Like 90% of the brains dopamine is there, and the majority of the dopamine receptors.... What kind of cells make up the striatum? 95% GABAergic ones.... it could have something to do with that... but I doubt it...

(^ how the fuck did you get L-DOPA?)
 
Mucuna puriens 95% extract. A bit archaic, I know - but I just thought it would be worth the try. Not something I'd ingest often though - I feel without carbidopa it undergoes too much peripheral metabolism.

As for the striatum - I find this interesting as well. You'd expect an increase in firing rate (ie. Dopamine release?) if the inhibitory GABA receptors are downregulated at this site, no? And yet, our problem seems to be related to decrease in dopaminergic transmission...

I do, however, get the impression that dopamine's contribution to behaviour seems to follow a Too Much = Too Little effect. For example, excessive dopamine seems to be linked to delusions, however extreme lack of dopamine also seems to be linked to delusion. Same goes to effects on PD - like mobility problems...

Of course, this is all stabbing in the dark. Anything you Bill or anyone here can provide to clarify this would be helpful. Of course, I will be trying to research it as well.

As an aside.. as if by luck, a friend mentioned that he has a couple of quetiaptine (Seroquel) pills left over. Now, I have never personally taken any Dopamine antagonists. I am thinking of taking one just to see if the feeling matches the reading I have done and if my comparison is a sound one. However - I don't think that now would be the right time, since I still seem to be under the influence of this withdrawal...

----

Another aside I forgot to mention: While I find that Ketamine's dissociative effects are unaffected, its antidepressant effects (as I noted many times elsewhere) seems to have been lost during this period, and an IV of about 100mg (my avarage dose) produced almost no rush or euphoria but the same expected dissociative anaesthesia. However, in the case of Ketamine, I seem to be slowly getting the nice effects back...

Serotonergic drugs that I've used at the time (Tianeptine, MDMA, DPT - not all together of course!) seem totally unaffected.
 
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As for the striatum - I find this interesting as well. You'd expect an increase in firing rate (ie. Dopamine release?) if the inhibitory GABA receptors are downregulated at this site, no? And yet, our problem seems to be related to decrease in dopaminergic transmission...
Click to expand...

Well, if striatal GABA receptors were down-regulated, then they were fire faster... if GABA receptors on their targets were down-regulated, then they would fire faster..

But it gets complicated... by down-regulating GABA receptors, you stop the cells of the striatal from essentially having their effect.

It's all very complicated... I mean, if you tell me what the neural substrate of pleasure is, then we can discuss this a lot easier.
 
Oh, I definitely see the difficulty there. I would think that pleasure is an emergent property of any given moment in the biochemistry/electrophysics of the entire brain.

I just thought it was interesting how these two seemingly unrelated states have so much in common. Thanks a lot for clarifying :)

Btw, do you happen to know why Urethane anaesthesia causes this increase in Dopamine levels after GHB administration?
 
^It's hard to know... Anaesthesia vastly changes the state of the brain (obviously). It must have something to do with the role of GABA-B receptors in the awake vs anaesthetised animal. Probably there is less GABA release in the VTA/SN when the animal is knocked-out, and hence presynaptic GABA-B receptors will be playing less of a role.

...Maybe...
 
BilZ0r said:
What with the who now? Who says that GHB depletes dopamine?
Click to expand...

My point is that GHB appears to have some sort of curvilinear dopaminergic effect, where low doses inhibit release and high ones increase it. In this case, "low" includes even very high recreational uses. It is commonly theorized that the release of stored dopamine that occurs when GHB wears off is the cause of the alert wakefulness that follows 3-4 hours upon GHB-induced sleep in some people.
 
^ Who says high doses of GHB increase dopamine release?

The common theory is fucking bunk. I've had this on Erowid for nearly 3 years, and people are still going on about that dopamine rebound idea...
 
BilZ0r said:
^It's hard to know... Anaesthesia vastly changes the state of the brain (obviously). It must have something to do with the role of GABA-B receptors in the awake vs anaesthetised animal.
Click to expand...

Why do you say GABA(B) and not GABA(A)? What is known about the molecular site(s) of action of urethane?
 
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