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"Effects of DXM on DA release in NAcc: Interactions with Morphine"

D

DotChem

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Nov 24, 2015
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Does that mean you can have your cake and eat it too?? DXM potentiate acute morphine induced DA release while AT THE SAME time attenuates its reinforcing?


  • Pretreatment with dextromethorphan (20 mg/kg s.c., 20 min prior) potentiated the effects of acute morphine(~150% of baseline..)
  • while attenuating the effects of chronic morphine on nucleus accumbens DA level

Effects of dextromethorphan on dopamine release in the nucleus accumbens: Interactions with morphine. Steinmiller CL1, Maisonneuve IM, Glick SD. Pharmacol Biochem Behav. 2003 Mar;74(4):803-10. http://www.ncbi.nlm.nih.gov/pubmed/12667894

Dextromethorphan has been reported to decrease the self-administration of several drugs of abuse, including morphine, methamphetamine, cocaine, and nicotine. Most drugs of abuse increase extracellular levels of dopamine (DA) in the shell of the nucleus accumbens. The effects of dextromethorphan on DA release in the nucleus accumbens of nai;ve rats and of rats treated acutely and chronically with morphine were studied using in vivo microdialysis. DA dialysate levels were evaluated by high-performance liquid chromatography with electrochemical detection.
Acute morphine (5 mg/kg i.p.) treatment increased the levels of DA in the nucleus accumbens to approximately 175% of basal levels.
Chronic morphine (20 mg/kg i.p. daily for 5 days) increased DA release in the nucleus accumbens to 250% of basal levels.
Acute treatment with dextromethorphan (20 or 30 mg/kg s.c.) alone did not alter nucleus accumbens DA levels.

Pretreatment with dextromethorphan (20 mg/kg s.c., 20 min prior) potentiated the effects of acute morphine, while attenuating the effects of chronic morphine on nucleus accumbens DA levels. These results with dextromethorphan suggest that the mechanism mediating the effects of dextromethorphan on drug self-administration involves modulation of the dopaminergic mesolimbic pathway.
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DXM has no effect on DA level in the NAcc? I thought it has decent DAT inhibitory activity, or is it NET/SERT selective?
 
So let's see, opoids can work by binding to opoid receptors on GABA interneurons and turning off those interneurons, while NMDA antagonists can work by binding to NMDA that provides excitatory input to GABA interneurons, so maybe with opoid agonism there is compensation by the NMDA receptors and NMDA antagonism can block that compensation?
 
Well what I'm getting at is that I want to make sure that there is a genuine tolerance reduction rather than just synergism, so when NMDA antagonists work by inhibiting interneurons and opiates work essentially the same way, I'm thinking one of the ways there could be genuine tolerance reduction with NMDA antagonism is if there is an upregulation of NMDAr once the inhibitory interneurons are turned off with opoid agonism
 
DotChem said:
  • Pretreatment with dextromethorphan (20 mg/kg s.c., 20 min prior) potentiated the effects of acute morphine(~150% of baseline..)
  • while attenuating the effects of chronic morphine on nucleus accumbens DA level
Click to expand...
I can confirm this personally. NMDA antagonists can completely block the euphoria and reward from opioids, while potentiating the remaining effects. I speculate that this is at a low, sub-euphoric dosage of the dissociative because with increasing dosages they can become synergistic together. But whilst on memantine, and having virtually no artificial opioid tolerance, even good heroine was actually dysphoric(!) up to the point where it began to seriously depress respiration. No fun at all. None. AH-7921 made a good psychical pain killer and antidepressant.

On the other side, I'd bet much on that dissociatives in general, but especially ketamine and to a lesser extent methoxetamine (this being heavily serotonergic) cause dopaminergic activity that is on par with decent stimulants, by some dubious mechanism. About DXM I can't tell, it's too dirty for me. Maybe the effects a given amount of DA exhibits get amplified- even transiently set the tolerance level some steps down; which we also have against endogeneus DA and thus causing that brain reset effect dissociative-naive people often get (0vers1mpl1f1c@tion of course) For me, low-dosed ketamine is much more reinforcing than plain stimulants, the craving feels quite similarly to the stimulant's (in comparison to opioids, alcohol, etc.).

----

I'm curious about these GABAergic interneurons. Apparently they can be destroyed by too much glutamatergic excitation (in heavy ketamine users, MDMA users someone posted recently here). What do they actually do, and why are they in danger? Somehow like a brake in a car (well, one that has millions of tiny brakes and motors) that's under-sized for the power of the motor, so they get excited and excited without end in the try to do somthing against that heavy excitation to other cells and burn themselves out?
 
theGirlWithBlueHair said:
Dextromethorphan does not affect the dopamine transporter.
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But apparently one or more of its metabolites does affect DAT. I came across study claiming something on that..but I am not sure I'll have to dig it out.

palmanita said:
I can confirm this personally. NMDA antagonists can completely block the euphoria and reward from opioids, while potentiating the remaining effects..
Click to expand...

IMHO the problem with DXM ("the dirtyness") is that unlike other disso it has at least 3 metabolites that are all psychoactives and have rather different pharmacology (binding profile) than DXM: DXO, 3-methoxymorphinan and 3-hydroxymorphinan. Each one is psychoactive. DXO is 10x more potent NMDA antagonist than DXM. So depending if you are fast, slow or no metabolizers, DXM experiences will be different. or if you take D2A4 inhibitors like tonic water before DXM.

I think the common mistake with DXM is to assume that all its psychoactivity is due to NMDA antagonism. Yes its a
pretty potent NMDA antagonist. And even more potent NMDA antagonist is his main metabolite DXO. But it and/or its
metabolites binds to so many other targets ie: nicotinic (alfa3beta4), sigma1. kappa, sodium channels..etc Each one of these targets has its own associated psychopharmacology (like sigma1 agonist = antidepressant, kappa agonists = salvia-like hallucinations..etc)
So one has to be careful reducing in vivo effect of DXM to a single target. I am not sure how rats metabolize DXM!


Cotcha Yankinov said:
I want to make sure that there is a genuine tolerance reduction rather than just synergism
Click to expand...

But DXM alone doesn't affect DA level in Nacc according to the study at least not at the doses used. So if there is synergy, NMDA antagonism should affect DA levels in the nucleus accumbens, would it not?

theGirlWithBlueHair said:
NMDA antagonism increases dopamine release, and by virtue D2 agonism
Click to expand...
possibly at higher doses than those used in the study and/or at other D2 rich brain areas besides the VTA-Nacc axis!

Cotcha Yankinov said:
so maybe with opoid agonism there is compensation by the NMDA receptors and NMDA antagonism can block that compensation?
Click to expand...

imho the effects of DXM on acute and chronic morphine are probably mediated via different pathways. The complicating factor is the different metabolites of DXM that may or may not affect the same pathways..

Yes, as far as antinocipetion effect is concerned, spinal cord MOR (mediate OP analgesia) agonism potentiate presynaptic NMDA but impairs postsynaptic NMDA.


Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408179/
Click to expand...

The question now: is the same mechanism operating with VTA-Nacc neurons that mediate OP euphoria?

The best thing with DXM is if pure DXM DXO MXM and HXM (like as RCs) were available.Because the experiences with
each one them would be different.. would be interesting to see

DXM DXO MXM HXM

2157-7609-S5-004-g002.gif
 
For what it's worth I was under the impression that NMDA antagonists were also shown to induce DeltaFosB in the nucleus accumbens. I don't know if we should hyper focus on dopamine if we're talking about euphoria, but I'm not too well read on that matter.
 
Good reads:

https://www.amazon.com/Dopamine-Receptors-Kim-Neve/dp/1603273328 (highly recommended; actually can't recommend enough if you want to learn everything there is to know about dopamine and the dopamine receptors)

This one will tell you everything there is to know about dopamine and how it interacts with other neurotransmitters, dopamine release, kinetic mechanism of the dopamine transporter and its comparison with with trace amine transporters, distribution of dopamine receptors, dopamine receptor interactions, drug induced depolarizations and inactivation of dopaminergic neurons, growth factors and dopaminergic neurons, INVOLVEMENT OF MULTIPLE OPIOIDERGIC SYSTEMS IN DOPAMINE PHARMACOLOGY:

https://www.amazon.com/CNS-Neurotra...r=1-1&keywords=CNS+NEUROTRANSMITTERS+DOPAMINE
 
If you have any questions about opioidergic ivolvement in in dopamine pharmacology let me know and I will give you information from the book.
 
theGirlWithBlueHair said:
This study begs to differ

http://www.ncbi.nlm.nih.gov/pubmed/
So does this one:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789217/

NMDA antagonists increase dopamine release, regardless of brain region.
Click to expand...

note carefully: the authors of the paper are talking about DXM effect on NAcc specifically
Acute treatment with dextromethorphan (20 or 30 mg/kg s.c.) alone did not alter nucleus accumbens DA levels.(in rats)
Click to expand...
.. Now here is the problem: DXM is NMDA antagonist (among others activities!) .. NMDA antagonism increase DA release regardless brain region..VTA-NAcc is a brain region.. therefore DXM (SHOULD) increase DA release in the NAcc.. do you see the flaw in that?
 
Thank you blue hair :)

I definitely see dotchem's point - it's not like we're talking about a selective NMDA antagonist so interpret with caution.
 
You are correct. But it's effect is the same as any NMDA antagonist so remember that ! :)

If you want.

I can type up the whole chapter of the book, it is very enlightening.

would you want me too> I have insomnia.

Let me know!!!
 
No need to burn out your fingers sweetheart, I appreciate that though :)

I'm sorry about your insomnia, it can be a real demon.. Have you tried much mindfulness meditation?
 
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