According to the chart on this page(drugs.com about cutting agents) levimesole causes increased D1 receptors. This is listed on the chart called "dangerous effects of cutting agents on the body". I found this to be very interesting, and was wondering if there was anyone who could explain this, as well as if there are any other drugs or ways of increasing D1 receptors without the harmful side effects that snorting levimesole will have.
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N&PD Moderators: Skorpio | someguyontheinternet
Levimesole and increased D1 receptors
- Thread starter Mafioso
- Start date
sekio
Bluelight Crew
I've never heard of this, maybe they mean it's a D1 agonist.
checktest
Bluelighter
Heard about levamisole metabolizing into aminorex, but didn't think that was at clinically relevant levels in humans.
www.ncbi.nlm.nih.gov
This study has levamisole directly inhibiting NET, independent of a metabolite, some DAT. And then aminorex metabolism which is more so. But still, doesn't quite seem unique to levamisole as an agent.
Some amount of MAO inhibition suspected, which could be a factor. D1 v D2. Could modify the sensitivity. Not really quite something.
Ohhh, this is a possible mechanism that could be a factor more unique to levamisole. Inhibition of tissue-nonspecific alk phos. TNAP. Has some CNS expression.
www.ncbi.nlm.nih.gov
www.ncbi.nlm.nih.gov
In model DM rats Levamisole prevented d1 receptor mRNA downregulation by modifying cAMP processing.
www.ncbi.nlm.nih.gov
Early basis for above study. Levamisole blocked d1 receptor downregulation
AMP - adenosine monophosphate
[NOT amphetamine as has sometimes been used]
ATP - adenosine triphosphate
cAMP - cyclic AMP
GPCR - G-protein coupled receptors
NT - Nucleotidase
PDE - Phosphodiesterase
PPi - Pyrophosphate
(P) - Phosphate
So, D1 receptors are GPCRs connected to Gs, a stimulatory g protein that leads to activation of adenylyl cyclase (AC), which catalyzes ATP --> cAMP, leading to PKA signaling and other effects. (This isn't the sole mechanism of D1Rs by any means.)
Adenosine receptors include A1, A2(a,b), A3, are also GPCRs with complex interactions with D receptors (multiple heteromers, etc...). A1 is Gi-coupled and inhibits AC, decreasing cAMP production. A2a is Gs-coupled (similar to D1 increasing AC activity and cAMP).
The bottom two papers suggest that (in their models):
Extracellular cAMP signaling decreases D1R mRNA and protein levels.
Extracellular AMP decreased D1 mRNA
(Adenosine did as well)
[cAMP can be secreted under situations that increase (intracellular cAMP) - Gs signaling / ^AC activity.
This ex-cAMP has a series of fates, including conversion to AMP by ectoPDEs. AMP can be processed to adenosine by ectonucleases like CD73.***]
Levamisole entirely blocked the extracellular AMP-driven D1 mRNA decrease.
(Also inhibitors of other ectonucleotidases)
The decrease of D1 mRNA linked to extracellular cAMP, AMP, and adenosine was (perhaps) via the A2a receptor:
Extracellular cAMP (over 60h but not 24h) led to upregulated TNAP, ectoNT but not A2A.
[This model is based in renal cells of DM rats, and as such is not fully transferable but interesting. Levamisole also reversed D1 downregulation (in the renal cortex) by Streptozotocin ]
***TNAP is a multimodal GPI-linked protein. While the typical described function is as alk phos, catalyzing the extracellular hydrolysis of PPi to (P), broader phosphorylation/dephosphorylation activities are apparent. Processes a form of B6, as well as some activity for ATP --> adenosine (not mentioned as much in the Kuzh papers).
That prurinergic-dopaminergic crosstalk is a possible avenue to target as a regulatory circuit. Say an extracellular cAMP mechanism modulating feedback in addition to typical feedback from other sources. Full release mechanisms and cellular pathways for that.
I mean I thought selective A2A antagonists like a DMPX were more in terms of modifying D2 receptors and that balance, say in Parkinson's and neurodegenerative cases. Relative selectivity. Being studied in addiction as well.
As for this proposed extracellular cAMP aspect and TNAP, more specific neuronal targeting would be necessary to not have some immune and bone effects.
I wonder if this TNAP effect also modifies some BBB/immune/ vascular effect that might be quite tricky to balance.
I mean extracellular cAMP has quite a history and evolutionary use (just look at the pleasingly symmetric development of D. discoideum.)...anyways this tangent has gone on a couple tangents and speculations deep....
I don't know about purinergic signaling, and that P2X7 and other stuff is yet another layer.
As for other D1 receptor upregulation, idk, maybe acetyl-l-carnitine (ALCAR) or something along those lines. Different mechanism though, not even sure of ALCAR's actual use in that regards and ALCAR has issues.
Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters - PMC
We quantified adulterants in street drugs sold as cocaine. We analyzed effects of the most common adulterant levamisole, on neurotransmitter transporters. Differences in the selectivity of levamisole can be explained by homology modelling and ...
www.ncbi.nlm.nih.gov
Some amount of MAO inhibition suspected, which could be a factor. D1 v D2. Could modify the sensitivity. Not really quite something.
Ohhh, this is a possible mechanism that could be a factor more unique to levamisole. Inhibition of tissue-nonspecific alk phos. TNAP. Has some CNS expression.
Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease - PMC
Tissue-nonspecific alkaline phosphatase (TNAP) is one of the four isozymes in humans and mice that have the capacity to hydrolyze phosphate groups from a wide spectrum of physiological substrates. Among these, TNAP degrades substrates implicated in ...
www.ncbi.nlm.nih.gov
The Extracellular cAMP-Adenosine Pathway Regulates Expression of Renal D1 Dopamine Receptors in Diabetic Rats - PMC
Background: Mechanisms that down-regulate expression of renal D1 dopamine receptors in diabetes are not well understood. Results: Inhibiting ectonucleotidases and tissue-nonspecific alkaline phosphatase prevents D1 receptor down-regulation. ...
www.ncbi.nlm.nih.gov
PubMed
PubMed® comprises more than 38 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full text content from PubMed Central and publisher web sites.
www.ncbi.nlm.nih.gov
AMP - adenosine monophosphate
[NOT amphetamine as has sometimes been used]
ATP - adenosine triphosphate
cAMP - cyclic AMP
GPCR - G-protein coupled receptors
NT - Nucleotidase
PDE - Phosphodiesterase
PPi - Pyrophosphate
(P) - Phosphate
So, D1 receptors are GPCRs connected to Gs, a stimulatory g protein that leads to activation of adenylyl cyclase (AC), which catalyzes ATP --> cAMP, leading to PKA signaling and other effects. (This isn't the sole mechanism of D1Rs by any means.)
Adenosine receptors include A1, A2(a,b), A3, are also GPCRs with complex interactions with D receptors (multiple heteromers, etc...). A1 is Gi-coupled and inhibits AC, decreasing cAMP production. A2a is Gs-coupled (similar to D1 increasing AC activity and cAMP).
The bottom two papers suggest that (in their models):
Extracellular cAMP signaling decreases D1R mRNA and protein levels.
Extracellular AMP decreased D1 mRNA
(Adenosine did as well)
[cAMP can be secreted under situations that increase (intracellular cAMP) - Gs signaling / ^AC activity.
This ex-cAMP has a series of fates, including conversion to AMP by ectoPDEs. AMP can be processed to adenosine by ectonucleases like CD73.***]
Levamisole entirely blocked the extracellular AMP-driven D1 mRNA decrease.
(Also inhibitors of other ectonucleotidases)
The decrease of D1 mRNA linked to extracellular cAMP, AMP, and adenosine was (perhaps) via the A2a receptor:
Extracellular cAMP (over 60h but not 24h) led to upregulated TNAP, ectoNT but not A2A.
[This model is based in renal cells of DM rats, and as such is not fully transferable but interesting. Levamisole also reversed D1 downregulation (in the renal cortex) by Streptozotocin ]
***TNAP is a multimodal GPI-linked protein. While the typical described function is as alk phos, catalyzing the extracellular hydrolysis of PPi to (P), broader phosphorylation/dephosphorylation activities are apparent. Processes a form of B6, as well as some activity for ATP --> adenosine (not mentioned as much in the Kuzh papers).
That prurinergic-dopaminergic crosstalk is a possible avenue to target as a regulatory circuit. Say an extracellular cAMP mechanism modulating feedback in addition to typical feedback from other sources. Full release mechanisms and cellular pathways for that.
I mean I thought selective A2A antagonists like a DMPX were more in terms of modifying D2 receptors and that balance, say in Parkinson's and neurodegenerative cases. Relative selectivity. Being studied in addiction as well.
As for this proposed extracellular cAMP aspect and TNAP, more specific neuronal targeting would be necessary to not have some immune and bone effects.
I wonder if this TNAP effect also modifies some BBB/immune/ vascular effect that might be quite tricky to balance.
I mean extracellular cAMP has quite a history and evolutionary use (just look at the pleasingly symmetric development of D. discoideum.)...anyways this tangent has gone on a couple tangents and speculations deep....
I don't know about purinergic signaling, and that P2X7 and other stuff is yet another layer.
As for other D1 receptor upregulation, idk, maybe acetyl-l-carnitine (ALCAR) or something along those lines. Different mechanism though, not even sure of ALCAR's actual use in that regards and ALCAR has issues.
Last edited:
sekio
Bluelight Crew
probably simpler than that...
www.ncbi.nlm.nih.gov
www.ncbi.nlm.nih.gov
PubMed
PubMed® comprises more than 38 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full text content from PubMed Central and publisher web sites.
www.ncbi.nlm.nih.gov
Levamisole: A High Performance Cutting Agent - PMC
Levamisole is an imidazothiazole chemical most frequently used as an antihelminthic agent in cattle. Over the last decade, levamisole has been increasingly encountered as an additive in both powder and crack cocaine. A white powder with a “fish ...
www.ncbi.nlm.nih.gov
checktest
Bluelighter
Yeah I don't know where I was going with that...
A3b4, a4b6 or other nicotinergic agonism (partial) seems pretty good amongst the others for D upreg.
A3b4, a4b6 or other nicotinergic agonism (partial) seems pretty good amongst the others for D upreg.
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