• N&PD Moderators: Skorpio | someguyontheinternet

What exactly does M-cpp do in the brain?

Yep, Dizocilipine seems to be rather non-selective as an NMDA antagonist, and it also seems devoid from dopaminergic activity [paraphrasing F&B on this one, don't kill me! :D], unlike the known cyclohexamines and amdamantines (amantedine, memantine).

Matt: I actually made at least a couple of threads somehow related to this topic.

Here is an older one: http://www.bluelight.ru/vb/showthread.php?t=258094&highlight=nmda+depression

And here is a newer thread whitch some discussion on NDMA/amygdala http://www.bluelight.ru/vb/showthread.php?t=267675&page=2&highlight=nmda+depression

I'd be happy to hear your input :)
 
Right..here's that reference. I think it's one of the best papers I've read on 5HT2C. If you're interested in 2C, then this is probably one of the best papers to read to get a handle on what 2C it's actually doing in-vivo.
Previously, there'd been alot of electrophysiology papers saying either 2C activity increased or decreased amygdaloid activity.
This paper kinda blew that all away.
Basically, you apply a 2C agonist directly to it's baso lateral amygdala (BLA) and you have a rat in a box, which sulks in the corner, doesn't move very much, squeeks alot more and doesn't respond to new objects.

Also, this involved applying a 2C agonist DIRECTLY to the BLA. So it's not about what might be happening anywhere else

B.M. Campbell & K.M. Merchant Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment. Brain Research 993 (2003) 1-9
 
A number of pharmaceutical companies are developing 5-HT2C agonist as anti-obesity drugs. But the anorexic activity of the 5-HT2C agonist 7-chloro-3-tetrahydrobenzazepine was already reported in a patent in 1968, so it's nothing really new, just that the mechanism of action wasn't known back then.

It's also reasonable to think that the weight gain associated with many antidepressants and anitpsychotics is due to their 5-HT2C antagonistic activity.
 
fastandbulbous said:
Pendant tendancies in me require I mention that it's meta-chlorophenylpiperazine aka 1- (3-chlorophenyl)piperazine for the IUPAC nazis!

BTW do we need to call you Dr Matt the Raver? =D

Yeah, this is what happens when you have a wannabe neuroscientist trying to do organic chemistry (I take your point that meta and methyl are completely different terms!).

and the Dr bit doesn't quite fit cos I bailed on the PhD, but I'll take that as a compliment!
 
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Dr.Heckyll said:
It's also reasonable to think that the weight gain associated with many antidepressants and anitpsychotics is due to their 5-HT2C antagonistic activity.

Actually you can go one step further with this, because 5HT2C knockout mice show no developmental abnormalities, but become obese and are prone to epiletic siezures.

The obesity seems to be simply due to increase food intake, as animals given limited food don't become obese, but will if given free access to food.

Similarly microdialysis studies (in either wild type mice or rats, I can't remember which offhand) have shown that feeding increases dopamine release. 'Desirable' food (shortbread for example) causes greater DA release than normal food.
I think this has something to do with blood glucose levels, although I'm not sure.

So.......less 5HT2C activity=more dopamine
more blood glucose =more dopamine

The two together = lots more dopamine = positively reinforced behaviour and a very fat mouse!

As for the epilepsy, I'm not too sure, as 5HT2C antagonist don't cause seizures
seen in the knock outs.

I have heard 'scare stories' of stimulant induced seizures in people with no previous history of epilepsy. So either knockouts have even higher DA levels than those caused by antagonists.

Alternatively, 5HT2C is very heavily expressed in the hippocampus. I'm unsure if 5HT2C inhibits or stimulates the hippocampal activity, but my hunch is that 5HT2C is inhibitory.

How can DA cause an increase in feeding when stimulants generally inhibit it?

Any drug has what is described as a 'theraputic window' if the dosage is too low, it has no effect. If it's too high, it has unwanted side effects.

Dopamine works in the same way. Too low and you have a lack of response to positive stimuli. Too high and the same thing happens.

Fluctuations in and out of this window either above or below cause addictive behaviour. As will any sudden increases or decreases.

In the case of feeding, the connection between eating and dopamine release becomes learnt, but stimulants will 'uncouple' this as you get the dopamine release without eating (essentially it's tricked you brain into thinking you've eaten).

I don't think feeding's as simple as this, as there are alot of other important factors in feeding such as (CART, agouti, neuropeptide Y etc, etc), I can't substantiate it beyond anecdotally so I kinda have it as a 'work in progress'.
 
An increase in blood glucose levels in the brain will cause dopamine release, yes. It's part of the reward system of which dopamine plays a central part. When the animal eats a food high in glucose, it gets a reward (namely, DA). This reaction conditions the animal to eat more of that food.

5HTC2 antagonists are generally sedating and give men and mice the munchies. Why?--I don't know. That's just the way it is I guess.
 
Helios. said:
5HTC2 antagonists are generally sedating and give men and mice the munchies. Why?--I don't know. That's just the way it is I guess.

This is a paper on the 5HT2C antagonist SB 242084

http://www.sciencedirect.com/scienc...serid=10&md5=ddfdbab8e33a29386b0051ab0e679d78

'SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test) -induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1–1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion'

This paper also claims that while SB242084 inhibits m-CPP induced hypophagia, it doesn't increase feeding.

However, another ref I've got on 5HT2C antagonist called RS-102221 does increae food intake.
 
How can DA cause an increase in feeding when stimulants generally inhibit it?


Could it be that the reward gained from the food causes enough reinforcement - via dopamine release - to cause hyperphagia (ands here we have someone versed in SAR studies/molecular pharmacology guessing at neuroscience!)
 
fastandbulbous said:
Could it be that the reward gained from the food causes enough reinforcement - via dopamine release - to cause hyperphagia (ands here we have someone versed in SAR studies/molecular pharmacology guessing at neuroscience!)

Well yes it does, because D1 and NMDA receptors seem to like holding hands

http://www.ncbi.nlm.nih.gov/entrez/...uids=16719818&query_hl=19&itool=pubmed_docsum

Furthermore Gs (which is activated by D1) and calcium (which is gated by NMDA receptors) promote activation of CamKinase II, which is involved in long term potentiation (LTP), so if D1 and NMDA are co-localised this process will be enhanced.

5HT2C antagonism just increases this by further promoting DA release.

My point is that if DA levels are too high or too low, this process no longer happens.

For example.....trying to eat a burger on speed or E (or seeing someone else doing it) is about the nastiest thing I can think of.

Likewise depression can result in a decrease in food intake.

Having said that.....starting a lab based discussion with the line:

"You know when you're proper pillin', don't burgers seem well mingin'?!?"

Doesn't really seem like a very sensible thing to do, so airing such theories here seems like the best place to do it :p
 
We generally talk about drugs, their chemistry and their effects here. But of course, your biochemical/neurophysiological viewpoint is welcome too.
 
Helios. said:
We generally talk about drugs, their chemistry and their effects here. But of course, your biochemical/neurophysiological viewpoint is welcome too.

Unfortunately, I get really dirty week long come downs off speed. E come downs are even worse. The first week feels like a dirty speed come down, then after that I get a week of confusion and paranoia.

Because of this I've decided that Es are off limits and speed's normally not a good idea.

It also means I try and be a bit more rational about any drug use these days, (cos I reckon my dopaminergic and seratonergic axons have taken a bit of a mangling over the years).
 
Unfortunately, I get really dirty week long come downs off speed. E come downs are even worse.

I'm sure alphamethyldopamine plays a role in the more severe depression from MDMA use (it being a metabolite of methylenedioxy drugs breakdown) as it acts as a false neurotransmitter re dopamine. Also explains why MDA produces the worst comedown of all
 
fastandbulbous said:
I'm sure alphamethyldopamine plays a role in the more severe depression from MDMA use (it being a metabolite of methylenedioxy drugs breakdown) as it acts as a false neurotransmitter re dopamine. Also explains why MDA produces the worst comedown of all

Does this fit in with the idea of oxidative stress (i.e. more oxygen radicals)?

This is off topic...but when I started taking E, I never had a come down. Gradually I started get come downs which got progressively worse. This recovered if I stopped dropping for a while, but came back pretty soon after dropping again.

By the way, by what exactly do you mean by false neurotransmitter?

Oh....and I think you'ld get a similar effect if you had a compound which acted as a 5HT1A/2A antagonist and a 5HT2C agonist, slightly dissociative, sedating
and VERY unpleasant.
 
^Interesting article Matt. I recently attended a conference on drug discovery and a man from Eli Lilly was talking about the applications of glutamate NMDA targets for treatment of CNS degenerative disorders. Very up-to-date and topical. If you can get the full article i'd appreciate a spare copy :)
 
Smyth said:
^Interesting article Matt. I recently attended a conference on drug discovery and a man from Eli Lilly was talking about the applications of glutamate NMDA targets for treatment of CNS degenerative disorders. Very up-to-date and topical. If you can get the full article i'd appreciate a spare copy :)

Do you know his name? If it's an actual journal article you shoud be able to find it on Pubmed. However drugs companies tend to be fairly secretive about their research data. They normally only publish stuff when they've got something to show off about.
 
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