Glutamate receptors other than NMDA

[Deleted member 170540]

There are several kinds of glutamate receptors... Three of these, NMDA, AMPA and kainate receptors are ion channels and then there are metabotropic glutamate receptors (MGluR:s).

The anesthetic and recreational effects of NMDA antagonist like ketamine, PCP or MXE are well known, but there is less knowledge about the effects of drugs that bind to other glutamate receptors.

AMPA/kainate antagonists like tezampanel have been shown to be analgesic and to suppress opiate withdrawal symptoms, but they do not seem to cause effects similar to NMDA antagonists even in large doses.

The metabotropic glutamate receptors have a lot to do with the dopaminergic activity in the nucleus accumbens, which is related to abuse potential of drugs. I found some confusing info about them. Surprisingly, both agonists and antagonists of MGluR:s seem to reduce drug-seeking behavior in alcohol- or cocaine-addicted rats. Of course one has to remember that there are several subtypes of MGlu receptors and the different ligands tested didn't have the same subtype selectivity.

The MGluR antagonist fenobam was tested in the 1970s and was found to be effective as an anxiolytic, but the tests were discontinued because of side effects.

In animals, fenobam stimulates locomotor activity like psychostimulants, see: http://jpet.aspetjournals.org/content/330/3/834.long

Previous studies of MPEP and the related mGlu5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine have reported locomotor side effects at analgesic doses (Zhu et al., 2004). In the present study, administration of fenobam at the analgesic dose (30 mg/kg) but not at lower doses (3 and 10 mg/kg) resulted in an increase in spontaneous locomotor activity in an open-field assay. The increased locomotor activity is interesting in light of findings reported in one clinical trial (Friedmann et al., 1980) that fenobam may have psychostimulant properties.

Is it possible that fenobam or some other compound which is an agonist or antagonist at MGlu receptors has any potential for recreational use? Fenobam was developed as a non-addictive alternative for benzos, but as you know, many times in history a new drug has been presented as a non addictive alternative and has actually been even more addictive than the previous drugs (think heroin, or even tramadol)...

 

[atrollappears]

mGlu2/3 antagonists are being investigated as possible treatments for major depression/treatment resistant depression and Alzheimer's.

 

[skillet]

And group 2 mGluR agonists are being investigated as anxiolytics and antipsychotics, which sort of makes sense as group 1 and 2 receptors should have opposite effects, at least according to this, I need to do some more reading to really understand why.

Hopefully some of the group 2 agonists/antagonists will become available soon, so we can really get an idea if they might have more interesting effects in people than the specific effects shown in animal studies.

Unlike most of the group 2 ligands, fenobam is a really simple structure, simple enough for investigation by grey market manufacturers. It could be nice if they'd take a bit of time to look into stuff like that rather than just cranking out cathinones and PCP derivatives.

Also I can't find any studies on weather the compounds are self-administrated by animals, just effects on self-administration of other drugs.

 

[Deleted member 170540]

Unlike most of the group 2 ligands, fenobam is a really simple structure, simple enough for investigation by grey market manufacturers. It could be nice if they'd take a bit of time to look into stuff like that rather than just cranking out cathinones and PCP derivatives.

Also I can't find any studies on weather the compounds are self-administrated by animals, just effects on self-administration of other drugs.

The lack of tests of self-administration of these compounds was what got me interested in this... There's lots of MGluRs in the 'reward centers' of the brain, so I'd bet that some MGluR ligand (either agonist or antagonist) would be self-administered...

The synthetic steps for fenobam (shown in wikipedia) look simple enough that someone could pull that off in a clandestine lab. Especially as the main precursor is sold as a dietary supplement for bodybuilders.

 

[skillet]

It's kinda frustrating that several people will have actually tried some of them in clinical trials, but we'll never get to hear of their experiences.

Hehe yeah, I looked at the fenobam synth and was like oh shit! Then I was like aaww

 

[Deleted member 170540]

In this study, it was found that another mGlu5 antagonist MPEP potentiates the 'rewarding' effect of ketamine and heroin (measured by conditioned place preference), but does not cause CPP by itself...

http://www.sciencedirect.com/science/article/pii/S0014299909000296

Abstract

The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been shown to reduce intravenous self-administration of ketamine and, to a limited extent, heroin in rats. We investigated whether MPEP affects the rewarding effect of ketamine and heroin as assessed in a conditioned place preference (CPP) paradigm. Sprague Dawley rats were subjected to a standard unbiased CPP protocol. Rats were conditioned with either ketamine or heroin (0.316–31.6 and 0.0125–0.5 mg/kg i.p., respectively), in combination with MPEP (10 mg/kg, i.p.) or its vehicle. The effect of MPEP (10 mg/kg) on the duration of extinction and on reinstatement of ketamine- and heroin-induced CPP was also examined. Ketamine and heroin induced CPP with a minimal effective dose (MED) of 10 mg/kg and 0.25 mg/kg, respectively. MPEP (1–31.6 mg/kg) did not induce CPP by itself; however, co-treatment with MPEP resulted in a 10-fold and 5-fold leftward shift in the MED of ketamine and heroin for inducing CPP, respectively. MPEP slowed extinction of ketamine-induced CPP, but not of heroin-induced CPP, and once extinction was achieved, was able to reinstate CPP in both groups. These findings indicate that a moderate dose of MPEP (10 mg/kg i.p.) potentiates, rather than attenuates, the rewarding effect of ketamine and heroin. Moreover, these data suggest that the attenuating effect of MPEP on ketamine and heroin intravenous self-administration is due to an increase, rather than a decrease, of the rewarding/reinforcing effect of these compounds

 

[Epsilon Alpha]

We need to keep in mind that glutamate has tons of non-CNS effects in the body, tezampanel for one is being researched as a anti-thrombosis medication, granted this is by Raptor Pharma... the same people attempting to cure the Asian flush.
I'd hate to see some anxious cutter attempt to self medicate with that stuff

Also look at the effects of ketamine (NMDA antagonist) on mTOR in non-CNS cells... now that will take a few years off your life.
But I recall Roche investigating a mGluR5 antagonist as an antidepressant (phase I last time I checked).

 

[Deleted member 170540]

I found more interesting studies...

According to http://www.sciencedirect.com/science/article/pii/S0014299909001174 , rats learn to self-administer the mGlu5 antagonist MPEP intravenously...

Abstract

We recently reported that the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduces intravenous self-administration of ketamine and, to a lesser extent, heroin in rats. We also found that MPEP potentiates conditioned place preference induced by these drugs, suggesting that the reduction of self-administration results from an MPEP-induced potentiation of the rewarding effect of the self-administered drug. The aim of the present study was to examine whether MPEP has intrinsic positive reinforcing and rewarding effects. In experiment 1, rats were trained to self-administer either ketamine [0.5 mg/kg/infusion, 2 h sessions, fixed-ratio (FR) 3] or heroin (0.05 mg/kg/infusion, 1 h sessions, FR 10), followed by a number of substitution sessions with MPEP (1 mg/kg/infusion) or saline. In experiment 2, drug-naïve rats were allowed to acquire intravenous self-administration of MPEP (1 mg/kg/infusion, 2 h sessions, FR 3) or saline. In experiment 3, rats were subjected to a single-trial unbiased conditioned place preference protocol with MPEP (0.3–10 mg/kg i.v., 20 min conditioning). It was found that (1) substitution with MPEP in rats which had learned to self-administer ketamine or heroin resulted in stable self-administration behavior, whereas substitution with saline resulted in a typical extinction profile, (2) drug-naïve rats learned to self-administer MPEP, but not saline, and self-administration remained stable for at least 7 sessions, and (3) MPEP induced dose-dependent place preference with a minimal effective dose of 3 mg/kg. These data clearly demonstrate that MPEP has (weak) positive reinforcing and rewarding effects when administered i.v.

This is not surprising because MPEP has also been found to elevate accumbal dopamine (like most drugs of abuse): http://www.ncbi.nlm.nih.gov/pubmed/21790901

EDIT: Epsilon Alpha, I'm not trying to say that these compounds are good for your health, I just find it theoretically interesting to try to find new molecular targets for recreational drugs...

 

[grue]

I like the AMPA agonist domoic acid ... which is found in Cthulhu shellfish and which is a really, really bad neurotoxin, not unlike most other non-partial glutamate agonists at any site.