5-HT1A Receptor Agonists May Treat Malaria

haidut

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One of the well-known and safe agonists at the 5-HT1A receptor is lisuride. Maybe something to bring along on that next trip to Africa or other tropical regions?

http://aac.asm.org/content/47/12/3806.abstract

"...Toidentify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels."
 

BobbyDukes

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How can agonizing a serotonin receptor be a good thing, from a Peat perceptive? Maybe this shows that serotonin isn't always the bad guy?
 
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haidut

haidut

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BobbyDukes said:
How can agonizing a serotonin receptor be a good thing, from a Peat perceptive? Maybe this shows that serotonin isn't always the bad guy?

Peat said that "agonizing" certain receptors like 5-HT1 actually has a negative feedback mechanism on serotonin release so it leads to reduced synthesis of serotonin and increase in dopamine. The Wikipedia page sort of backs up this claim of Peat by saying agonizing the 5-HT1 receptor triggers dopamine release, hence the effects of agonists like lisuride and bromocriptine on Parkinson's and schizophrenia.
http://en.wikipedia.org/wiki/5-HT1A_receptor

"...5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.[33][34] As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.[33][35][36] Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects seen upon postsynaptic activation of the 5-HT1A receptor.[37][38]"
 
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haidut

haidut

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Such_Saturation said:
Or methylene blue :mrgreen:

Boom. I completely forgot about this one:):
 

SQu

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So does that mean serotonin plays a significant role in malaria? I've had malaria in a remote place and it would be good to know whether serotonin lowering might assist with symptoms eg fever, headache, diarrhoea, on the way to get help. Might it be an idea to keep cyproheptadine in first aid kit?
 

BobbyDukes

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haidut said:
BobbyDukes said:
How can agonizing a serotonin receptor be a good thing, from a Peat perceptive? Maybe this shows that serotonin isn't always the bad guy?

Peat said that "agonizing" certain receptors like 5-HT1 actually has a negative feedback mechanism on serotonin release so it leads to reduced synthesis of serotonin and increase in dopamine. The Wikipedia page sort of backs up this claim of Peat by saying agonizing the 5-HT1 receptor triggers dopamine release, hence the effects of agonists like lisuride and bromocriptine on Parkinson's and schizophrenia.
http://en.wikipedia.org/wiki/5-HT1A_receptor

"...5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.[33][34] As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.[33][35][36] Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects seen upon postsynaptic activation of the 5-HT1A receptor.[37][38]"

Interesting; the plot thickens!

I had a major interest in the serotonin pathways before I came to this forum. I know 5ht1a has shown benefits for schizophrenics (as has 5ht7 antagonism). It's supposed to be a highly anxiolytic pathway. The definition of a 'parial agonist', to my mind, amost translates as a 'regulator'. So partial agonism doesn't neccesarily mean the receptor is being agonized (for anyone reading). It can go in either direction. Like a modulatory mechanism. I know some of the DA agonists are partial 5ht1a agonists, as you say (abilify being one).

5ht2a agonism and 5ht2c agonism (believe it or not) also increase phasic dopamine. 5ht2a and 5ht2c antagonism increase tonic dopamine flow.

In terms of 5ht1a agonists, I have experimented with buspar, tandospirone and vilaz.

Buspar and tandospirone reduced GAD symptons for me (tandospirone especially). They also increased sexual desire considerably, but had the annoying side effect of penile inhibition (this is in line with what it says on Wikipedia for 5ht1a agonism; and I'm 100% it wasn't placebo). So yes, this was almost like a form of torture for me, being a guy. Adding viagra however, did solve his issue (taken back in the day pre-Peat, before I knew what garbage this drug was, FYI). I wonder how the penile inhibition is caused? Perhaps the increase in prolactin? Maybe that's why you wouldn't potentially have this issue with a drug like lisuride. 5ht1a agonists are supposed to be great horny compounds for females, however. Like, for some females, it makes them insatiably sexual.

Thanks for the links, Haidut.
 
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haidut

haidut

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sueq said:
So does that mean serotonin plays a significant role in malaria? I've had malaria in a remote place and it would be good to know whether serotonin lowering might assist with symptoms eg fever, headache, diarrhoea, on the way to get help. Might it be an idea to keep cyproheptadine in first aid kit?

Yes, it does seem that way and not only for malaria but for many infection diseases. I posted a study more than a year ago showing that the purpose of a fever induced by the organism was to deplete the body of iron and tryptophan both of which are used by several infectious agents for growth and reproduction. The study also theorized that the tryptophan reduction was needed to protect the organism from serotonin overload associated with active infection (stress). So, if cypro can offset some of that serotonin load it would help the body and probably reduce the fever. There are studies on Pubmed showing discussing serotonin, fever and cypro:
http://www.ncbi.nlm.nih.gov/pubmed/15882780
http://www.ncbi.nlm.nih.gov/pubmed/11164765
http://www.ncbi.nlm.nih.gov/pubmed/2087993

The more you read, the more you realize how nasty serotonin is. I just don't understand how with all this information out there doctors still sing its praise...
I personally always carry some cypro when I travel. Between allergies, endotoxin protection, reduction of stress-induced serotonin, and now potential anti-viral benefit I think cypro together with aspirin is great tool for travelers.
 
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haidut

haidut

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BobbyDukes said:
haidut said:
BobbyDukes said:
How can agonizing a serotonin receptor be a good thing, from a Peat perceptive? Maybe this shows that serotonin isn't always the bad guy?

Peat said that "agonizing" certain receptors like 5-HT1 actually has a negative feedback mechanism on serotonin release so it leads to reduced synthesis of serotonin and increase in dopamine. The Wikipedia page sort of backs up this claim of Peat by saying agonizing the 5-HT1 receptor triggers dopamine release, hence the effects of agonists like lisuride and bromocriptine on Parkinson's and schizophrenia.
http://en.wikipedia.org/wiki/5-HT1A_receptor

"...5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.[33][34] As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.[33][35][36] Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects seen upon postsynaptic activation of the 5-HT1A receptor.[37][38]"

Interesting; the plot thickens!

I had a major interest in the serotonin pathways before I came to this forum. I know 5ht1a has shown benefits for schizophrenics (as has 5ht7 antagonism). It's supposed to be a highly anxiolytic pathway. The definition of a 'parial agonist', to my mind, amost translates as a 'regulator'. So partial agonism doesn't neccesarily mean the receptor is being agonized (for anyone reading). It can go in either direction. Like a modulatory mechanism. I know some of the DA agonists are partial 5ht1a agonists, as you say (abilify being one).

5ht2a agonism and 5ht2c agonism (believe it or not) also increase phasic dopamine. 5ht2a and 5ht2c antagonism increase tonic dopamine flow.

In terms of 5ht1a agonists, I have experimented with buspar, tandospirone and vilaz.

Buspar and tandospirone reduced GAD symptons for me (tandospirone especially). They also increased sexual desire considerably, but had the annoying side effect of penile inhibition (this is in line with what it says on Wikipedia for 5ht1a agonism; and I'm 100% it wasn't placebo). So yes, this was almost like a form of torture for me, being a guy. Adding viagra however, did solve his issue (taken back in the day pre-Peat, before I knew what garbage this drug was, FYI). I wonder how the penile inhibition is caused? Perhaps the increase in prolactin? Maybe that's why you wouldn't potentially have this issue with a drug like lisuride. 5ht1a agonists are supposed to be great horny compounds for females, however. Like, for some females, it makes them insatiably sexual.

Thanks for the links, Haidut.

Search the forum for "lisuride libido" and you will see several women discussing how lisuride made them very horny. So, it does seem to have that effect even though I think it's the overall shift towards dopaminergic tone that affects libido in both men and women. FDA is considering approving a female "Viagra" of sorts and the drugs essentially increases dopamine by being mixed 5-HT1 agonist and 5-HT2 antagonist.
http://en.wikipedia.org/wiki/Flibanserin
http://www.npr.org/sections/health-shot ... en-and-sex
"...Flibanserin shifts the balance of three key brain chemicals, Whitehead says. The drug, she says, increases "excitatory factors for sex" — dopamine and norepinephrine — and decreases serotonin, which can dampen the sex drive."

Once again - how can anyone defend serotonin in light of all this "official" evidence for its role in so many pathologies, is beyond me. I think Peatarian.com closed b/c it was overrun by people with serotonin-dominance. JK.
 

bradley

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I'm heading to Africa in a couple weeks, so will definitely be bringing my Blue!
 

SQu

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I'm very grateful for this info haidut. I had already sent my husband off to Indonesia with cyproheptadine for sleep and liver support as he comes back from these long flights very sluggish and dull. I already reach for charcoal when anyone gets sick because I think of endotoxin, and usually nothing more is needed. Now another role for this cheap prescription - free drug that strangely nobody's ever heard of. They keep it under the counter where you can't even see it. So legally you can buy it but only if you know enough to ask. Wonder how many lives it could have saved in Africa for starters.
 
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haidut

haidut

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sueq said:
I'm very grateful for this info haidut. I had already sent my husband off to Indonesia with cyproheptadine for sleep and liver support as he comes back from these long flights very sluggish and dull. I already reach for charcoal when anyone gets sick because I think of endotoxin, and usually nothing more is needed. Now another role for this cheap prescription - free drug that strangely nobody's ever heard of. They keep it under the counter where you can't even see it. So legally you can buy it but only if you know enough to ask. Wonder how many lives it could have saved in Africa for starters.

Yeah, medicine nowadays sure is a strange profession. You'd expect saving the maximum number of lives to be the goal but it's really not. If you add aspirin to the short list of cypro, lisuride and charcoal, you are looking at preventing most of the degenerative conditions, and probably treating a good number of the most lethal ones. All for the cost of about $1/month. Maybe we can start an alternative to the WHO Model List of Essential Medicines:
http://en.wikipedia.org/wiki/WHO_Model_ ... _Medicines

I bet we could shorten the list to about 20.
 

tara

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Quinine is one of the traditional anti-malaria treatments, isn't it? Is this likely to work in a similar way? Is there enough in tonic water for it to be relevant for health?
 

mas

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What baffles me is the US drug regulations requiring Cyproheptadine, which is an older antihistamine, to still require a prescription. Benedryrl and others are OTC.
 
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haidut

haidut

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tara said:
Quinine is one of the traditional anti-malaria treatments, isn't it? Is this likely to work in a similar way? Is there enough in tonic water for it to be relevant for health?

I posted a study showing quinine lowers serotonin synthesis, which likely results in higher dopamine. So, I think that is a more likely explanation of its effects on malaria. Agonists of the 5-HT1A receptor have been shown to increase dopamine so that could be the same mechanism behind both types of drugs.
 

Hugh Johnson

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Yeah, medicine nowadays sure is a strange profession. You'd expect saving the maximum number of lives to be the goal but it's really not. If you add aspirin to the short list of cypro, lisuride and charcoal, you are looking at preventing most of the degenerative conditions, and probably treating a good number of the most lethal ones. All for the cost of about $1/month. Maybe we can start an alternative to the WHO Model List of Essential Medicines:
http://en.wikipedia.org/wiki/WHO_Model_ ... _Medicines

I bet we could shorten the list to about 20.
That list would be really useful for peaters to build family medicine cabinets.
 
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haidut

haidut

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interesting, i was reading about vitex .it antagonizes 5-HT1A.

Interesting.
If that is true it would explain why Vitex seems to have "paradoxically" pro-libido effects in some makes - blocking 5-HT1A lowers prolactin and increases dopamine/libido.
 

PecosRiver

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I've been worried that CBD was anti-peat. Was just reading this article from How CBD Works:

Serotonin Receptors
Jose Alexandre Crippa and his colleagues at the University of San Paulo in Brazil and King’s College in London have conducted pioneering research into CBD and the neural correlates of anxiety. At high concentrations, CBD directly activates the 5-HT1A (hydroxytryptamine) serotonin receptor, thereby conferring an anti-anxiety effect. This G-coupled protein receptor is implicated in a range of biological and neurological processes, including (but not limited to) anxiety, addiction, appetite, sleep, pain perception, nausea and vomiting.

Then I did a forum search for 5-HT1A and found this thread. I felt a definite sense of relief!
 

Frankdee20

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Doesn’t it matter if you’re agonizing on the pre or post synaptic side of 5ht1A ?
 
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