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Antipsychotics blocking NMDA antagonist effects?

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Is there any known interaction between typical/atypical antipsychotics and NMDA antagonists?

I've been on 2mg risperidone a day for a few years, because I have had some reactive psychotic episodes and my doctor wants to prevent that from happening again... Before I was on the medication I could get high off 300mg dextromethorphan, but after using risperidone I have to take at least 600mg DXM to get anywhere near the same effects. I don't take DXM many times a year, so I don't think this is caused by tolerance.

I thought this was interesting because one hypothesis links schizophrenia/psychosis with abnormal NMDA functioning in the brain.

The only scientific paper I could find about this is http://www.ncbi.nlm.nih.gov/pubmed/10088132 .

Has anyone else experienced neuroleptics blocking the effects of ketamine or DXM or methoxetamine etc. ?
 
Classical anti-psychotics likely blunt NMDA antagonists' effects downstream, by affecting glutaminergic transmission (glutaminergic transmission is so domain-nonspecific, though, that a hell of a lot of things affect it downstream).

ebola
 
ebola? said:
Classical anti-psychotics likely blunt NMDA antagonists' effects downstream, by affecting glutaminergic transmission (glutaminergic transmission is so domain-nonspecific, though, that a hell of a lot of things affect it downstream).

ebola
Click to expand...

Would Atypical anti-psychotics exert the same effects on NMDA antagonism as "classical" anti-psychotics?

~ vaya
 
Vaya said:
Would Atypical anti-psychotics exert the same effects on NMDA antagonism as "classical" anti-psychotics?

~ vaya
Click to expand...

Well atypical antipsychotics are the first line of attack when someone in a PCP rage is brought in (20mg Zyprexa Zydis here but they may use a shot of Geodon if they have to - they try to avoid using typicals because of the somewhat severe side effects they can have) so while I do not know the details behind it, I can assure you that atypicals work very well on NMDA antagonist blockade.

I personally have experienced the nastiness that ensues when I tried doing ketamine while on Geodon... you end up getting a really fucked up headspace but no "trip" - it is very hard to describe. Geodon itself causes my head to feel weird though.
 
i'm thinking that a whole lot of the subjective effect of arylcyclohexylamine administration is related to dopamine levels. any NMDA blocker (e.g. mk801) will increase dopamine downstream due to reduced glutamatergic thoughput. but with arylcyclohexylamines (PCP, ketamine, MXE, et al.) you have a pronounced DARI effect at bio-relevant doses. the increase in DA throughput due to the combo of reuptake inhibition and upstream dis-inhibition is a perfect recipe for huge dopamine increase. can you say EUPHORIA/PARANOID DELUSIONS??? not that the reduced NMDA signalling is without it's own subjective effect, but it seems like that alone is not enough to produce the strong reinforcing effect common to ACH's. this is why mk801 is not known to be as 'nice' as ket/mxe.

since the typical anti-psych's clinical usefulness is related to DA (mainly D2) blocking, no small wonder that it would change the subjective effect of ACH administration. of course, with the aforementioned combo of DA increasing tendencies, you'd have to be on a large-elephant-tranq dose of thorazine to completely block DA effects, and even then, you'd still have some noise coming thru on the glutmatergic channel. but a raging, paranoid, delusional sh*tstorm might just be quelled enough to allow normal triage.

what is interesting, but not surprising, is that 5ht2a blockage (most atypical anti-psych's do this, no?) can reduce DA levels downstream to be useful not only in non-drug-induced psychosis but also the raging-bull-on-steroids variety produced by ACH use/abuse. 5ht2a must be a really important control point for DA activity. but i suppose that's not exactly news, is it?

still barely on-topic: colleague of mine mentioned a subject who had built up a pretty decent tolerance to mxe due to daily use, while not having used bupropion (or any other stim) for months during this time. maybe 5 hours after a normal 150mg dose of bupropion, subject noticed pretty obvious increase in subjective effect of 35mg mxe. this was first use of bupropion in months, but not an excessive dose.

sorry for jacking up thread, hope maybe some of this rambling mess is useful. if i'm way off base in my tangential processing, i do hope one of the good teachers here will enlighten us further. that's what makes this place great. and thanks for the literature links, that ncbi paper about M100907 is nice because, being a potent 5HT2a antagonist, it should fit nicely when docked with the 5ht2a model structures i like to play with. looking to revive my thread on that, so thanks. and happy holidays, hope all are warm and safe.

peace
 
Yeah I figured dopamine blockade would be the main reason for the reduction of dissociative effects.

How much effect on DA levels does 5-HT2A antagonism have? Have any refs? I figured the lack of selective 2A antagonists as antipsychotics was evidence the effect was minimal. Or maybe reducing DA levels alone isn't enough, and D2 blockade is necessary?

Interesting idea to use a DRI to potentiate a dissociative. Maybe DA release by 2A agonists could account for some of the synergism (think I might have read or written that before)

Hope you have more luck docking MDL than I did :D
 
I found this paper, which seems to say that atypical antipsychotics block the NMDA antagonist effects immediately, but typical antipsychotics do that only after chronic administration:

http://jpet.aspetjournals.org/content/305/3/999.full.pdf

Although there is no universal consensus on precise definitions for typical and atypical antipsychotics, the typical drugs are generally considered those whose primary mechanism is D2 dopamine blockade (e.g., haloperidol, chlorpromazine). The atypical drugs are characterized by having
more complex mechanisms of action, which are not fully understood and demonstrate clinical efficacy with reduced side effects (e.g., clozapine, olanzapine). In a wide range of preclinical models, some of the atypical drugs attenuate effects of NMDA antagonists but the typical drugs do not. For example, clozapine and olanzapine, but not haloperidol or raclopride, attenuate the electrophysiological effects of PCP in brain slices (Arvanov et al., 1997; Wang and Liang, 1998; Arvanov and Wang, 1999). Deficits in PPI and social behavior induced by NMDA antagonists (Bakshi et al., 1994; Corbett et al., 1995; Bakshi and Geyer, 1995) are attenuated by clozapine and olanzapine, but not by haloperidol and raclopride.
However, Mansbach et al. (2001) did find that haloperidol reduced PCP-induced deficits in PPI but to a lesser extent than did clozapine and ziprasidone.
Click to expand...

In some preclinical models, quite different effects are found after chronic compared with acute antipsychotic administration. For example, acute treatment with clozapine and olanzapine enhanced NMDA-evoked electrophysiological responses, but chronic treatment with the drugs reduced NMDA receptor sensitivity (Arvanov and Wang, 1999; Jardemark et al., 2000). Also, chronic haloperidol was shown to reduce PCP-induced alterations in PPI under conditions where acute administration of this typical antipsychotic did not affect PCP-induced PPI deficits (Pietraszek and Ossowska, 1998; Martinez et al., 2000).
Click to expand...
 
Perhaps a psychokinetic approach would be more suiting. I would think about the enzymes that are being up regulated by your medication and drug use. Risperdal actually inhibits an important enzyme to DXM breaking down. I always used 1mg and 2mg (the day of) risperdal to have a great DXM trip without nausea and tons of hallucinations but albeit low doses didn't work very well. But tons of grapefruit juice or just tons of DXM would pretty much fix that.
 
Thanks for your response, MagickalKat277!

nirvus said:
i'm thinking that a whole lot of the subjective effect of arylcyclohexylamine administration is related to dopamine levels. any NMDA blocker (e.g. mk801) will increase dopamine downstream due to reduced glutamatergic thoughput. but with arylcyclohexylamines (PCP, ketamine, MXE, et al.) you have a pronounced DARI effect at bio-relevant doses. the increase in DA throughput due to the combo of reuptake inhibition and upstream dis-inhibition is a perfect recipe for huge dopamine increase. can you say EUPHORIA/PARANOID DELUSIONS??? not that the reduced NMDA signalling is without it's own subjective effect, but it seems like that alone is not enough to produce the strong reinforcing effect common to ACH's. this is why mk801 is not known to be as 'nice' as ket/mxe.

since the typical anti-psych's clinical usefulness is related to DA (mainly D2) blocking, no small wonder that it would change the subjective effect of ACH administration. of course, with the aforementioned combo of DA increasing tendencies, you'd have to be on a large-elephant-tranq dose of thorazine to completely block DA effects, and even then, you'd still have some noise coming thru on the glutmatergic channel. but a raging, paranoid, delusional sh*tstorm might just be quelled enough to allow normal triage.

what is interesting, but not surprising, is that 5ht2a blockage (most atypical anti-psych's do this, no?) can reduce DA levels downstream to be useful not only in non-drug-induced psychosis but also the raging-bull-on-steroids variety produced by ACH use/abuse. 5ht2a must be a really important control point for DA activity. but i suppose that's not exactly news, is it?

still barely on-topic: colleague of mine mentioned a subject who had built up a pretty decent tolerance to mxe due to daily use, while not having used bupropion (or any other stim) for months during this time. maybe 5 hours after a normal 150mg dose of bupropion, subject noticed pretty obvious increase in subjective effect of 35mg mxe. this was first use of bupropion in months, but not an excessive dose.

sorry for jacking up thread, hope maybe some of this rambling mess is useful. if i'm way off base in my tangential processing, i do hope one of the good teachers here will enlighten us further. that's what makes this place great. and thanks for the literature links, that ncbi paper about M100907 is nice because, being a potent 5HT2a antagonist, it should fit nicely when docked with the 5ht2a model structures i like to play with. looking to revive my thread on that, so thanks. and happy holidays, hope all are warm and safe.

peace
Click to expand...

Excellent points of interest, man. I sent you a PM with some further related questions, hopefully you might be able to answer some of them. Way cool tangent, trust me ;)

~ vaya
 
airsh0w said:
Perhaps a psychokinetic approach would be more suiting. I would think about the enzymes that are being up regulated by your medication and drug use. Risperdal actually inhibits an important enzyme to DXM breaking down. I always used 1mg and 2mg (the day of) risperdal to have a great DXM trip without nausea and tons of hallucinations but albeit low doses didn't work very well. But tons of grapefruit juice or just tons of DXM would pretty much fix that.
Click to expand...

one of my friends used to use her brothers risperdal to alleviate her morning nausea (which both her and the brother suffered from)
 
Methoxetamine works by a whole mess of actions, the principal three are antinicotinic action (impaired motor coordination), NMDA & other ion channel blockade (anesthetic/dissociative action), and dopamine reuptake inhibition (stimnulant action). Abilify does block/partially agonise dopamine receptors (responsible for 'feeling good', delusions, and stimulation) & 5-HT2Ar (which may be responsible for some of the 'trippy' effects), so I expect it would reduce the intensity of the trip. I don't think it would block it entirely, except if you are taking high doses of Abilify it may make it not worthwhile to dose.

I do not reccomend using dissociatives if you are prescribed an antipsychotic for mood or cognition disorders.
 
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