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Old 01-12-2010, 01:29 PM   #1 (permalink)
 
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Post mGlu5 receptor antagonists as novell anxiolytics?

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In the early 1990s, a new family of receptors were cloned that were found to mediate the intracellular metabolic effects of glutamate via coupling to secondary messenger systems, that is, the metabotropic glutamate (mGlu) receptors. Eight such receptors (mGlu1 to mGlu have been cloned to date, and according to their amino acid sequence, pharmacology and second-messenger coupling, these receptors have been clustered into three groups (I-III). In contrast to the glutamate-gated ion channels (NMDA, AMPA and kainate receptors), which are responsible for fast excitatory transmission, mGlu receptors have been shown to play a modulatory role in the glutamatergic synaptic transmission either by modulating the ion channel activity or by influencing neurotransmitter release. Given the fact that the mGlu receptors are G-protein- coupled, they obviously constitute a new attractive group of "drugable" targets for the treatment of various CNS disorders. The recent discovery of small molecules that selectively bind to receptors of group I (mGlu1 and mGlu5) and group II (mGlu2 and mGlu3) allowed significant advances in our understanding of the roles of these receptors in brain physiology and pathophysiology. The identification of MPEP (2-methyl-6-(phenylethynyl)-pyridine), a highly selective and brain-penetrant mGlu5 receptor antagonist, allowed the exploration of the therapeutic potential of this class of compounds. Subsequent behavior studies revealed that--with the exception of benzodiazepines--mGlu5 receptor antagonists exhibit the widest and most robust anxiolytic activity in preclinical models seen to date. Upcoming clinical studies will soon indicate if the preclinical anxiolytic-like efficacy translates into anxiolytic activity in humans. © 2004 Prous Science. All rights reserved.
The interesting part is that there actually is a pharmaceutical available that acts on those receptors and that is acamprosate.
Acamprosate is currently being prescribed for alcoholism. It was first tought to be a NMDA antagonist but it actually appears to be a mGluR5 antagonist.
Acamprosate is an analogue of taurine.


Quote:
Titre du document / Document title
Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption : relationship to acamprosate actions
Auteur(s) / Author(s)
BLEDNOV Yuri A. ; HARRIS R. Adron ;
Résumé / Abstract
Recent studies have demonstrated that metabotropic glutamate receptor 5 (mGluR5) antagonists decrease alcohol self-administration and suggest that the anti-craving medication, acamprosate, may also act to decrease mGluR5 function. To address the role of mGluR5 in behavioural actions of ethanol and acamprosate, we compared mutant mice with deletion of the mGluR5 gene and mice treated with a mGluR5 antagonist (MPEP) or acamprosate. Lack of mGluR5 or administration of MPEP reduced the severity of alcohol-induced withdrawal (AW), increased the sedative effect of alcohol (duration of loss of righting reflex; LORR), and increased basal motor activity. The motor stimulation produced by ethanol was blocked by deletion of mGluR5, but not by injection of MPEP. Both acamprosate and MPEP increased ethanol-induced LORR and reduced AW. Importantly, the protective effects of both MPEP and acamprosate on AW were found when the drugs were injected before, but not after, injection of ethanol. This indicates that the drugs prevented development of dependence rather than merely producing an anticonvulsant action. No effects of acamprosate or MPEP on ethanol-induced LORR and AW were found in mGluR5 knockout mice, demonstrating that mGluR5 is required for these actions. mGluR5 null mutant mice showed decreased alcohol consumption in some, but not all, tests. These data show the importance of mGluR5 for several actions of alcohol and support the hypothesis that some effects of acamprosate require mGluR5 signalling.

I have got a lot of acamprosate with me now but i wont try it before i tried my memantine (which i'm gonna start next week), anyway i tought this was pretty interesting.
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Old 01-13-2010, 06:22 AM   #2 (permalink)
 
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I wasnt aware of any trials with acamprosate used for anxiety, however i just found this open label trial.

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In this open-label study, acamprosate demonstrated a significant positive effect in decreasing anxiety for most patients. The side effect profile was substantially similar to that reported in the clinical trials. However, these data must be interpreted with caution as preliminary. Limitations to this study include the fact that only 1 clinician was involved in all aspects of the treatment. Although the clinician and the patients rated anxiety separately, the clinician based ratings on interviews with the patients. Thus, there were no truly “blind” raters. In addition, the sample size was modest; however, the effect sizes were substantial.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781041/

Looks interesting.
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Old 01-13-2010, 08:26 AM   #3 (permalink)
 
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Ive just tried a first dose of acamprosate to see what effect it has on me. So far i noticed sedation (which isnt that bad) and my mind seems more clear, i also feel calmer then usual. As far as social anxiety i dont notice a significant effect, but take in mind that i also dont notice anything from benzo's, opiates and other substances unless i'm on amphetamine (my mind is pretty strange to say the least).

So I pretty much expected it to not cause a significant improvement, but i wanted to try it on its own first anyway.

I'm gonna try it in combination with a stimulant to know what it exactly does.
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