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callemann
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5-HT2A agonism and memory function
#19190298 - 11/26/13 03:09 AM (10 years, 2 months ago) |
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Hi!
I haven't seen a lot of discussion on this subject, but this has actually been a subject of quite a lot of scientific scrutiny. An extensive amount of studies link the serotonergic system intimately to memory formation in the hippocampus, and the 5-HT2A receptor(to which psilocybin is an agonist) is often postulated to be essential.
Here is a relatively new study discussing the possibility of manipulating the 5-HT2a receptors to enhance memory function. The viability of low dose ht2a-agonists for treatment of dementia for instance which initially showed promising results, turned out to be problematic, possibly due to receptor down-regulation during long term use. Here they propose to use a 5-ht2a antagonist to increase receptor up-regulation and increased long term activity. For those with access:
http://www.sciencedirect.com/science/article/pii/S107474271300049X
Abstract:
Animal studies have established that drugs activating the serotonin 2A (5-HT2A) receptor can enhance learning and memory in a variety of classical and operant conditioning tasks. Unfortunately, long-term agonism typically results in receptor downregulation, which can negate such nootropic effects. Conversely, chronic antagonism can act to increase receptor density, an adaptation which, in principle, should enhance cognition in a manner similar to acute agonism. In this study, we questioned whether chronic treatment with the 5-HT2A receptor antagonist, SR 46349B, a drug known to increase 5-HT2A receptor density in vivo, would improve cognitive performance in normal mice. To address this question, we administered SR 46349B to mice for 4 days following initial training on a simple rule-based reward acquisition task. We subsequently tested their recall of this task and, finally, their ability to adapt to a reversal in reward contingency (reversal learning). For comparison, two additional groups were treated with the 5-HT2A/2C receptor agonist, DOI, which downregulates the 5-HT2A receptor. SR 46349B improved retention of the previously-learned task but did not affect reversal learning. Subjects treated with SR 46349B also completed trials faster and with greater motor efficiency than vehicle- or DOI-treated subjects. We hypothesize that long-term drug treatments resulting in 5-HT2A receptor up-regulation may be useful in enhancing recall of learned behaviors and, thus, may have potential for treating cognitive impairment associated with neurodegenerative disorders.
From the article:
"Activation of 5-HT2A receptors via acute 5-HT2A receptor agonist treatment enhances learning in classical conditioning paradigms and decreasing receptor activity via inverse agonist treatment impairs learning in similar models (see Harvey, 1996, 2003 for review). Serotonin 2A receptors also modulate mnemonic processes (Meneses, 2002a,b, 2007; Terry, Buccafusco, & Bartoszyk, 2005; Wingen, Kuypers, & Ramaekers, 2007)"
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Caddilac
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Re: 5-HT2A agonism and memory function [Re: callemann]
#19190323 - 11/26/13 03:24 AM (10 years, 2 months ago) |
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WOO hahahahahaaahahaaa
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Cyclohexylamine
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Re: 5-HT2A agonism and memory function [Re: Caddilac]
#19190549 - 11/26/13 05:56 AM (10 years, 2 months ago) |
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Thank you OP for this study, quite interesting.
-------------------- Yes this is tymo - I just changed my name Have you ever had a dream that you were so sure was real? What if you were unable to awake from that dream? How would you know the difference between that dream world and the real world? There is NOTHING better than feeling that warm dissociative fuzz creeping up your body from IM K Something abut that anaesthetic rush... Qualitative Research Chemical Effects and Experiences The Wonderful World of Methoxetamine The 3-Meo-PCP Chapters, Part One
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badchad
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Interesting, but I remain cautiously skeptical.
Indirect 5-HT2a agonists in the form of SSRI's and other antidepressants have been used clinically for more than a decade, with minimal (if any) effect on memory.
5-HT2A antagonists in the form of atypical antipsychotics have also been marketed for quite some time (with little to no effect on memory). Even selective 5-HT2A antagonists have failed clinical trials.
-------------------- ...the whole experience is (and is as) a profound piece of knowledge. It is an indellible experience; it is forever known. I have known myself in a way I doubt I would have ever occurred except as it did. Smith, P. Bull. Menninger Clinic (1959) 23:20-27; p. 27. ...most subjects find the experience valuable, some find it frightening, and many say that is it uniquely lovely. Osmond, H. Annals, NY Acad Science (1957) 66:418-434; p.436
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nooneman


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Re: 5-HT2A agonism and memory function [Re: badchad]
#19190569 - 11/26/13 06:13 AM (10 years, 2 months ago) |
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As the study says, long term or strong agonism leads to downregulation and you end up with the opposite effects that you want which is exactly why they're looking at antagonists rather than agonists.
It's really ironic, a single small dose of an agonist leads to improvements in memory and learning, but repeated or strong doses lead to downregulation resulting in just the opposite effect. May explain some longterm health effects of regular heavy users of psychedelics while also explaining the benefits new users sometimes report.
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Cyclohexylamine
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Re: 5-HT2A agonism and memory function [Re: badchad]
#19190641 - 11/26/13 07:01 AM (10 years, 2 months ago) |
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Quote:
nooneman said: As the study says, long term or strong agonism leads to downregulation and you end up with the opposite effects that you want which is exactly why they're looking at antagonists rather than agonists.
It's really ironic, a single small dose of an agonist leads to improvements in memory and learning, but repeated or strong doses lead to downregulation resulting in just the opposite effect.
Yup. It is ironic in a way.
Quote:
badchad said: Interesting, but I remain cautiously skeptical.
Indirect 5-HT2a agonists in the form of SSRI's and other antidepressants have been used clinically for more than a decade, with minimal (if any) effect on memory.
5-HT2A antagonists in the form of atypical antipsychotics have also been marketed for quite some time (with little to no effect on memory). Even selective 5-HT2A antagonists have failed clinical trials.
SSRIs are not 5-HT agonists or antagonists. They are SSRIs (selective serotonin re-uptake inhibitors). There is a difference in how the two work.
-------------------- Yes this is tymo - I just changed my name Have you ever had a dream that you were so sure was real? What if you were unable to awake from that dream? How would you know the difference between that dream world and the real world? There is NOTHING better than feeling that warm dissociative fuzz creeping up your body from IM K Something abut that anaesthetic rush... Qualitative Research Chemical Effects and Experiences The Wonderful World of Methoxetamine The 3-Meo-PCP Chapters, Part One
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badchad
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Re: 5-HT2A agonism and memory function [Re: badchad]
#19190689 - 11/26/13 07:17 AM (10 years, 2 months ago) |
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Quote:
tymoteusz3 said:
SSRIs are not 5-HT agonists or antagonists. They are SSRIs (selective serotonin re-uptake inhibitors). There is a difference in how the two work.
SSRI's block the reuptake of serotonin, thereby increasing the concentration of 5-HT in the synaptic cleft (at least acutely). It's no surprise that serotonin acts as an agonist at the 5-HT2A receptor. Thus, when you increase 5-HT you increase agonist effects at the 5-HT2A receptor, albeit indirectly. Hence my statement:
Quote:
badchad said:
Indirect 5-HT2a agonists in the form of SSRI's...
-------------------- ...the whole experience is (and is as) a profound piece of knowledge. It is an indellible experience; it is forever known. I have known myself in a way I doubt I would have ever occurred except as it did. Smith, P. Bull. Menninger Clinic (1959) 23:20-27; p. 27. ...most subjects find the experience valuable, some find it frightening, and many say that is it uniquely lovely. Osmond, H. Annals, NY Acad Science (1957) 66:418-434; p.436
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morrowasted
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Re: 5-HT2A agonism and memory function [Re: badchad]
#19190851 - 11/26/13 08:26 AM (10 years, 2 months ago) |
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Quote:
badchad said: Interesting, but I remain cautiously skeptical.
Indirect 5-HT2a agonists in the form of SSRI's and other antidepressants have been used clinically for more than a decade, with minimal (if any) effect on memory.
5-HT2A antagonists in the form of atypical antipsychotics have also been marketed for quite some time (with little to no effect on memory). Even selective 5-HT2A antagonists have failed clinical trials.
I'm with you. I've been taking SSRIs for almost 10 years with no marked difference in memory. Then again I have taken a lot of drugs similar to DOI
edit: apparently SSRIs don't count?
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KingKnowledge
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Re: 5-HT2A agonism and memory function [Re: morrowasted]
#19190899 - 11/26/13 08:41 AM (10 years, 2 months ago) |
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Quote:
morrowasted said:
Quote:
badchad said: Interesting, but I remain cautiously skeptical.
Indirect 5-HT2a agonists in the form of SSRI's and other antidepressants have been used clinically for more than a decade, with minimal (if any) effect on memory.
5-HT2A antagonists in the form of atypical antipsychotics have also been marketed for quite some time (with little to no effect on memory). Even selective 5-HT2A antagonists have failed clinical trials.
I'm with you. I've been taking SSRIs for almost 10 years with no marked difference in memory. Then again I have taken a lot of drugs similar to DOI
edit: apparently SSRIs don't count?
SSRI's do exactly what they say: they selectively inhibit the re-uptake of serotonin. That has nothing to do with the activation of 5-HT2 receptors, just with the re-uptake transporter proteins.
This is quite an interesting read. Previous research has implicated NMDA action (glycine, glutamate, and d-cyclocerine are all agonists) in memory, but not much has been studied about serotonin.
Lots of implications with regards to tripping balls.
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aperson444
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Re: 5-HT2A agonism and memory function [Re: KingKnowledge] 1
#19193849 - 11/26/13 07:49 PM (10 years, 2 months ago) |
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Quote:
SSRI's do exactly what they say: they selectively inhibit the re-uptake of serotonin. That has nothing to do with the activation of 5-HT2 receptors, just with the re-uptake transporter proteins.
Wut.
If you block 5HT reuptake, you increase the amount of 5HT in the synapses. Since 5HT is a full agonist at all serotonin receptor subtypes, downregulation would eventually occur. Typically the mechanism of SSRIs promotes downregulation of 2a/1a receptors as well as the 5HTd subtype autoreceptors that modulate 5HT release.
SSRIs thus water down the effects of psychedelic drugs, primarily through downregulation of 5HT2a receptors.
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Dakotaap0



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Re: 5-HT2A agonism and memory function [Re: aperson444]
#19193925 - 11/26/13 08:08 PM (10 years, 2 months ago) |
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Thanks OP! Great article
-------------------- "We
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KingKnowledge
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Re: 5-HT2A agonism and memory function [Re: aperson444]
#19194833 - 11/27/13 12:35 AM (10 years, 2 months ago) |
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Quote:
aperson444 said:
Quote:
SSRI's do exactly what they say: they selectively inhibit the re-uptake of serotonin. That has nothing to do with the activation of 5-HT2 receptors, just with the re-uptake transporter proteins.
Wut.
If you block 5HT reuptake, you increase the amount of 5HT in the synapses. Since 5HT is a full agonist at all serotonin receptor subtypes, downregulation would eventually occur. Typically the mechanism of SSRIs promotes downregulation of 2a/1a receptors as well as the 5HTd subtype autoreceptors that modulate 5HT release.
SSRIs thus water down the effects of psychedelic drugs, primarily through downregulation of 5HT2a receptors.
It is true that SSRI's force more serotonin to stay in the synapse, but I was thinking more along the lines of activating 5-HT2a receptors through the use of non-serotonin agonists like psilocyban and LSD, etc. This article has nothing to do with SSRI's ability to cause down-regulation.
In the sense I was referring to, I don't really care about serotonin being an agonist (which, of course it is). I care about activating 5-HT2a receptors using psychedelic drugs and seeing their effect on memory, which is what I think the posting of this article was supposed to hint towards on a forum for drugs. This is the shroomery after all
Edited by KingKnowledge (11/27/13 12:36 AM)
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callemann
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Re: 5-HT2A agonism and memory function [Re: KingKnowledge]
#19220564 - 12/03/13 02:59 AM (10 years, 1 month ago) |
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Hi again! I encountered another similar interesting article from 2003 today. Highly interating ideas. It is also open access
Role of the Serotonin 5-HT2A Receptor in Learning
http://learnmem.cshlp.org/content/10/5/355.full
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Into The Woods
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Re: 5-HT2A agonism and memory function [Re: callemann]
#19220667 - 12/03/13 04:31 AM (10 years, 1 month ago) |
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So healthy use of mushrooms not only encourage brain cell growth, but now they improve memory too.
Well that ought to help if they're to be legalised one day.
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