Chill pills: why there are no Serotonin 5HT1A selective agonists RCs?

[Cotcha Yankinov]

I don't know how an SSRI would produce chronic agonism of HT2c, either, unless you think elevated serotonin would do that.

Sorry, that is indeed what I meant

What I find interesting about sigma1 agonism is its purported benefit in dementia. Mainly because i've been on sertraline, a sigma1 antagonist, for too long. Has it made me dumber?

There is some tentative evidence that SSRIs themselvesmay slightly increase the risk of dementia (and I would think that this would be the more important factor), however tricyclics seem to reduce the risk of dementia for some reason

 

[DotChem]

.. however tricyclics seem to reduce the risk of dementia for some reason..

Most TCAs are anticholinergics (thus their most common side-effect: dry mouth). They are antagonist at central mAChRs like nicotine (at some central AChR subtypes!). Probably have something to do with the decreased risk of dementia: I read somewhere life-long cigarettes smokers have lower risk of developing dementia than non-smokers (one of the few benefits of tobacco!), unless the studies were $$$$$ by tobacco companie$!! But there is overwhelming evidence central AChR system hold the key to how dementia develop (and basically to how long-term memory is consolidated in and retrieved from the hyppocampus). I am not sure how SSRIs increase risk of dementia.

What I find interesting about sigma1 agonism is its purported benefit in dementia. Mainly because i've been on sertraline, a sigma1 antagonist, for too long. Has it made me dumber? Will it make future treatment with an agonist twice as effective? If sigma1 plays a role in dementia, what are the effects of taking agonists or antagonists long-term in your early retirement years? Or really, any time.

Now, question is: is there interactions between sigma1 and cholinergic receptors? most likely since sigma1 is a chaperone (it functions as modulator/assistant of other receptor and/or transporters proteins especially those in NAC involved in rewards/reinforcing effects of most pyschoactives. The problem is that most psychoactive drugs bind to sigma (one of the most promiscuous protein in the brain). As long as a drug molecule has an amine (almost the only requirement..almost!). So it is really hard to tease out whether observed effect is due to activation/blockade of the chaperone or the receptor/transporter system it is modulating that the drug is targeting. If sigma endogenous ligand(s) were known, then it would make the picture more clear. So far, there is no conclusive evidence as to the endogenous ligand of sigma receptors: DMT has been proposed as the natural sigma ligand but the data is not really convincing. Trace amines like PEA or p-tyramine were also proposed. But as I mentioned, almost ANY molecule that has an amine will most likely interact with sigma!) So until the natural endogenous ligand of sigma is identified, we can only speculate as to the involvement of sigma receptors in dementia.

 

[DotChem]

I have a question re: MDMA, 5HT releasers and 5HT1a agonists: as you all know, one of the biggest (actually the most serious) side-effects of serotonin releasers like MDMA is serotonin syndrome and resulting hyperthermia. Could selective serotonin releasers (SRAs) that are also 5ht1a autoreceptors agonists be safer than those that are just SRAs in terms of hyperthermia? Wouldn't serotonin levels released in raphe be controlled by virtue of 5HT1a autoreceptor activation by the agonist and therefore lower risk of serotonin syndrome/hyperthermia? Do selective post-synaptic 5HT1a agonists induce hyperthermia?? I couldn't find specific literature looking at that. ola me if you do. thx

 

[Scrofula]

I haven't seen any refs to the syndrome after cases like buspirone overdose, but then a lot of the 1a agonists on the market also have adrenergic effects. I think a lot of the toxicity is attributed to the HT2a receptor, actually, and can be blocked with an antagonist like cyproheptadine. I think that's sedating, so it wouldn't help you keep from sweating if it also knocks you out during your drug session.

But really, is the hyperthermia mechanism even known? Seems like a lot of handwaving and then invoking alpha receptors.

As for nicotine, surely after you exclude all the pro-dementia effects of cardiac disease and inflammation from smoking, there's no benefit? I know it's useful therapy during dementia and Alzheimer's. It def. aids memory recall and the study of o-chem until you get hooked and stuck for the next twenty years.

But if the sigma receptor interacts with damn near every drug molecule and is found pretty much all over the brain, what if it's just a red herring and not particularly important (clinically) at all? That would be kind of reassuring really, after a decade of antagonism.

 

[Cotcha Yankinov]

Most TCAs are anticholinergics (thus their most common side-effect: dry mouth).

An especially confusing bit, seeing as there is increasing appreciation for M1 antagonism speeding along dementia

 

[Cotcha Yankinov]

I have a question re: MDMA, 5HT releasers and 5HT1a agonists: as you all know, one of the biggest (actually the most serious) side-effects of serotonin releasers like MDMA is serotonin syndrome and resulting hyperthermia. Could selective serotonin releasers (SRAs) that are also 5ht1a autoreceptors agonists be safer than those that are just SRAs in terms of hyperthermia? Wouldn't serotonin levels released in raphe be controlled by virtue of 5HT1a autoreceptor activation by the agonist and therefore lower risk of serotonin syndrome/hyperthermia? Do selective post-synaptic 5HT1a agonists induce hyperthermia?? I couldn't find specific literature looking at that. ola me if you do. thx

The issue is that releasing agents bypass autoreceptor's inhibitory control. A lot of the hyperthermia is downstream of 5-HT2A activation, which also leads to dopamine release which even further causes hyperthermia. But 5-HT2A seems to be important for a lot of the typical effects of MDMA, however I suppose the clinical efficacy of MDMA/MDAI + 5-HT2A antagonism would be interesting to investigate. I think many of the behavioral effects in animals are linked to 5-HT1B, so even with a 5-HT2A antagonist + MDMA that bit should still be intact, in addition to post synaptic 5-HT1A.

 

[Scrofula]

Is M1 thought to be directly involved with promoting dementia?

I had the impression it was more of a "exacerbates the memory problems" side effect. That's kind of a big deal if it's actively involved, given the number of drugs that antagonize it.

 

[bindingaffinity]

The M1 receptor thing might be Alzheimer's-specific; something to do with amyloid plaques disrupting M1 signal transduction by blocking binding to G-proteins. The absence of M1 dysfunctions of that kind has been observed in, for instance, Parkinson's disease dementia.

As for nicotine, surely after you exclude all the pro-dementia effects of cardiac disease and inflammation from smoking, there's no benefit? I know it's useful therapy during dementia and Alzheimer's. It def. aids memory recall and the study of o-chem until you get hooked and stuck for the next twenty years..

This is neither here nor there in relation to the main subject of this thread, but nicotine has been shown to have neuroprotective effects against Parkinson's disease, and is a more effective and well-tolerated antipsychotic than dopaminergic antipsychotics. (Which is odd, because most studies of nicotinic receptor agonist antipsychotics focus on the alpha-7 receptors... which are not hit by nicotine.)

 

[DotChem]

Updating the ultimate chill pill:.. now besides being best anxiolytics and antidepressants ever (5HT1a Buspar substitutes for benzodiazepines in clinical trials of ppl with anxiety disorders without withdrawal symptoms hell of benzos + it is even better anxiolytic),

Association of 5-HT1A Receptors with Affective Disorders
Extract (p153) ... In this regard, a clinical trial carried out with ambulatory patients diagnosed with generalized anxiety disorder (GAD)found that after weeks 3 and 4, buspirone showed efficacy in relieving patients’ symptoms with a therapeutic effect comparable to that of lorazepam. Also, after discontinuing this therapy, the individuals treated with buspirone showed no withdrawal symptoms, while those medicated with lorazepam saw their symptoms worsen in week 9 after ceasing treatment [58]. Similarly, buspirone (15 mg/day) prescribed for 4 weeks to ambulatory patients with GAD produced a significant reduction of anxiety symptoms compared to alprazolam. Moreover, the patients treated with buspirone experienced fewer adverse effects and symptoms of abstinence than those who received alprazolam [59]. The anxiolytic properties of buspirone have been confirmed in animal models. For example, in a study conducted with Swiss Albino mice that received buspirone at 2.5 and 5 mg/kg, i.p., the drug significantly increased the number of step-through by 46 and 61%, respectively [60]. This demonstrates that buspirone is effective in treating anxiety disorders without causing adverse effects or signs of benzodiazepine dependence.

Not only 5HT1a agonists may be better than benzos as anxiolytics, they may even make you smarter!:D (at least it makes adult rats smarter: 5OH-DPAT increases hyppocampus neurogenesis in rats. This is a big deal actually (I mean adult neurogenesis) Although still in debate, increased hyppocampus neurogenesis is thought to lead to 1. rapid antidepressant action of some fast acting antidepressants like ketamine AND 2. to the nootropic effect of some nootropics like NSI-189 (the current craze among nootropics fans!! This last drug (clinically researched as antidepressant by a company somewhere and developed by US Army research as Nootropic) also leads to increase hyppocampus neurogenesis. So the question is since 5HT1a agonists like 5OH-DPAT increase hyppocampal neurogensis, would they not have Nootropic effect??

Serotonin 1A receptor agonist increases species- and region-selective adult CNS proliferation, but not through CNTF : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438376/
Abstract:Endogenous ciliary neurotrophic factor (CNTF)¹ regulates neurogenesis of the adult brain in the hippocampal subgranular zone (SGZ)² and the subventricular zone (SVZ)³. We have previously shown that the cAMP-inhibiting D2 dopamine receptor increases neurogenesis by inducing astroglial CNTF expression. Here, we investigated the potential role of CNTF in the proliferative response to pharmacological stimulation of the serotonin 1A (5-HT1A)⁴ receptor, which also inhibits cAMP, in adult mice and rats. Like others, we show that systemic treatment with the active R-enantiomer of the 5-HT1A agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)⁵ induces proliferation in the SGZ in rats using unbiased stereology of 5-Bromo-2′-deoxyuridine (BrdU)⁶ positive nuclei......

 

[Limpet_Chicken]

She has PTSD, and we got talking a while back (as I did have it too, after getting sent to a prison, wrongfully, and in a medical state that meant I wasn't fit for trial, could not speak in my defence, and not long after intake, the result was a couple of months of grand-mal tonic-clonic seizures and nearly dying of starvation, because I could not even realize 'food' was being thrown at me, and if I had I could not have physically picked up a knife and fork or hold a plate)

And we were talking, this girl and me about PTSD and the subject of alpha-methyltryptamine came up, as I'd successfully, very successfully, and I need to get in contact with her, as she is interested, and I agreed to help her, since she is somebody I care deeply about, love, even, although she doesn't know that last detail , basically I agreed to help, as a guide, and one that has been there before for the same reason. And assist her in doing the relevant research to make sure the MAOI property is not going to cause problems with her anticonvulsants (she has seizures as well, but the meds I ttake are simpler in nature, just GABA PAMs, one a benzo occasionally used (nitrazepam) the other a barb-site agonist (chlormethiazole, a fairly clean, selective agonist for the GABAaR barbiturate site although lacking the AMPAr negative allosteric modulatory effects of barbs,), basically make sure nothing about the AMT is going to cause her problems. Amazing girl...one of the smartest people I've ever known, and christ is she ever one of the hottest to boot- I'd have a ring on her finger given a femtosecond of a chance

 

[clubcard]

I don't see Tianeptine's 383±183?nM affinity to mu receptors as useful. I presume that MOR and DOR are known to multiply analgesia so 37.4±11.2 ?M at the human DOR receptors gives something of small value.

 

[Cotcha Yankinov]

^I suppose whether or not the affinity of Tianeptine to opioid receptors is appreciable or not is dependent on the other affinities it has/the dosages it can be ingested at, e.g. mescaline has low affinity for 5-HT2A but can be taken in large doses

Seeing as part of MOR agonists' action has to do with shutting off GABA release, a GABA reuptake inhibitor might be a bit antithetical and counter some of that action too..

I've never tried tianeptine, does it have an MOR feel at all?