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GHB Analogs Journal Article Request

hussness

hussness

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Mar 12, 2005
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Western U.S.
Would someone mind pulling this up for me? My institution doesn't have access to it:

Wellendorph, Petrine, Hog, Signe, Greenwood, Jeremy R., de Lichtenberg, Anne, Nielsen, Birgitte, Frolund, Bente, Brehm, Lotte, Clausen, Rasmus P., Brauner-Osborne, Hans
Novel Cyclic {gamma}-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain
J Pharmacol Exp Ther 2005 315: 346-351


Thanks!
 
^ Exactly. GABA-B makes the GHB experience... well; GABA-B is the foundation, the GHB-Receptor just tops it off. The GHB-receptor agonist t-HCA is not very fun.
 
So where exactly is this putative GHB receptor? I assume it can't be on the same on the same membrane protein from what you're saying, but does binding to the GHB receptor hyperpolarize the same cells?
Is it just me who's confused on this, or is there a general lack of consensus?
 
^^^there seems to be a general lack of consensus. The specific GHB receptor is not that well characterized, though some claim to have isolated it.
 
so you could do tests on rats to assess the reinforcing activity of GHB administered with a selective GHB receptor antagonist (if such a drug exists,) and you hypothesis, bilzor, is that because the primary 'enjoyable' effects of GHB are GABA-B mediated, rats administered with the antagonist concurrent to GHB wouldn't experience such strong DA mediated?
Where are GABA-B receptors located in the limbic system / medial forebrain bundle? Do they interact with opioidergic signalling pathways?
Surely there are selective GABA-B antagonists... do these block the reinforcing effects of GHB?
Personally I don't find GHB (well, actually 1,4-butanediol) to be very euphoric at all. Relaxing, yes, sedating, yes, but I find alcohol to be more enjoyable if I'm in the mood to stomach it.

I'm a little out of the loop with neuropharm. I've been doing xray crystallography, and I dearly miss studying teh brain. I'll try and get a tech job in the neuroanatomy labs next year.
 
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GABA-B receptors are everywhere, and I think you should go easy on talking about the medial forebrain bundle, a lot of things go through there that aren't related to reward (histamine, orexin...)

GHB%20receptor%20localization.GIF

Putative GHB receptor mRNA distribution.

The electrophysiology of the GHB receptor is very poorly known. The paper that cloned the protein above, expressed it in CHO cells, and got what looks like a GHB receptor mediated Na+ current, but I don't trust that bit as far as I can throw it.

Something more relativent is this paper that shows a GHB-receptor mediated glutamate release in the brain. Though that paper claims that the GHB-receptor mustn't be a GPCR, where that mRNA localization paper above is looking at a GPCR. this paper on the other hand showed that in GABA-B knockouts, GHB has no effect of GTP turn over, (or on dopamine synthesis) so that is more evidence that the GHB receptor is not a GPCR.

GHB%20autoradiography.JPG

Autoradiography of another (or maybe the same) GHB receptor.

As far as I am aware, no one has looked to see whether GABA-B or GHB antagonists block the reinforcing effects of GHB, only whether this modifies GHBs sedative effects (where GABA-B antagonists block it and GHB receptor antagonists don't do anything).
 
As far as I am aware, no one has looked to see whether GABA-B or GHB antagonists block the reinforcing effects of GHB, only whether this modifies GHBs sedative effects (where GABA-B antagonists block it and GHB receptor antagonists don't do anything).
Click to expand...

Hmm there's a MSc project for someone... I'd love to do that.

Oh hey look at thess:
http://www.ncbi.nlm.nih.gov/entrez/..._uids=15940094&query_hl=1&itool=pubmed_docsum
"Resuscitative effect of a gamma-aminobutyric acid B receptor antagonist on gamma-hydroxybutyric acid mortality in mice."

http://www.ncbi.nlm.nih.gov/entrez/..._uids=12606639&query_hl=1&itool=pubmed_docsum
"The role of GABAB receptors in the discriminative stimulus effects of gamma-hydroxybutyrate in rats: time course and antagonism studies."

And on a slightly different note,
http://www.ncbi.nlm.nih.gov/entrez/...t_uids=9512074&query_hl=1&itool=pubmed_docsum
"Gamma-hydroxybutyric acid decreases intravenous cocaine self-administration in rats."

That is really interesting... I wonder if its because its more 'satisfying,' perhaps because the same level of 'euphoria' is produced from a smaller amount of the drug, if GHB and cocaine were to act in synergy (or even a simple additive effect) on the VTA-NAc, as one might expect? But then if it were more satisfying it would be more reinforcing which would mean it would *increase* self-administration. So the obvious deduction is that GHB reduces the reinforcing effects of cocaine in rats. Which is wierd. I'm going to check out what they have to say in the discussion of this paper. Or I would, if we had access to it. That is really strange... I'm sure I've accessed "Pharmacology, Biochemistry & Behaviour" before. Can anyone please give me a pdf of this? Bilz0r maybe you could put it up on your site if you can get it.
 
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BilZ0r said:
^ Exactly. GABA-B makes the GHB experience... well; GABA-B is the foundation, the GHB-Receptor just tops it off. The GHB-receptor agonist t-HCA is not very fun.
Click to expand...

What effect does GABA-B have on the dosage? Does it lower the risk of overdose? Also what about the interaction with ethanol, is t-HCA potentiated by ethanol (like GHB)?
 
BilZ0r said:
huh?
Click to expand...

Sorry, I meant, "what effect dose GABA-B agonism have on the dosage (compared to GHB)?"

But since you answered the other question it doesn't really matter.
 
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