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Serotonin 5-HT(1)A Receptor and Male Sexual Function / Motivation

serotonin 5-ht1a receptor male sexual function motivation libido agonist antagonist pssd cure

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#1 Area-1255

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Posted 18 February 2015 - 07:05 AM


This is probably about the 10th time I've had to explain this - so I'm posting a topic for all to see.

 

5-HT1A agonism (pre-synaptic) can have it's benefits, namely in reducing excess serotonin - HOWEVER, after persistent agonism - it tends to de-sensitize, which then sends a flood of disinhibited serotonin to the post-synaptic 1A receptors which then can inhibit penile erection and can reduce sexual motivation....especially regarding arousal by female pheromones or presence!

 

5-HT1A agonism, all in all, is far less beneficial in men, than in women - where it tends to release oxytocin more and women have different levels of serotonin receptors anyhow...

 

Ideally, men DO NOT want much , if hardly at all 5-HT1A/1B activation - as they both inhibit male sexual response and performance.

 

So for PSSD, E.D or libido issues - you're better off with an ANTAGONIST - which will have beneficial effects on all hormonal parameter's in men as well...more so when a 1A antagonist is used with a 2A antagonist...

 

In women, the 5-HT1A agonism releases oxytocin which helps their bonding and libido...however, in men, it kills erections at that receptor and causes testosterone to decrease in response to female presence and in general. Read all studies below thoroughly.

 

 

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Psychoneuroendocrinology. 2002 Jul;27(5):609-18.

Involvement of the 5-HT(1A) and 5-HT(1B) serotonergic receptor subtypes in sexual arousal in male mice.
Abstract

The presence of a sexually receptive female behind a partition that prevents physical contact, but not seeing or smelling, increases blood testosterone level and induces the specific behavior in CBA male mice so that they more frequently approach the partition and spend more time near it in an attempt to make their way to the female. Treatment with the selective 5-HT(1A) serotonin receptor agonist 8-OH-DPAT (0.1, 0.25, 0.5 and 2.0 mg/kg) induced a dose-dependent decreasein the amount of time spent by the males near the partition, or "partition time", which is considered the main pattern of sexual motivationThe activating effect of female exposure on the male's pituitary-testicular system was totally blocked, as no increase in plasma testosterone level was observed. The 5-HT(1A) antagonist p-MPPI (0.1, 0.2 and 0.4 mg/kg) itself did not affect behavior or alter plasma testosterone, but attenuated the inhibiting effect of 8-OH-DPAT on behavior and totally antagonised the effect of the 5-HT(1A) agonist on testosterone response. The 5-HT(1B) agonist CGS-12066A (1.0 and 2.0 mg/kg) has no influence on the plasma testosterone increase exhibited by the male in response to female exposure. At the same time, either dose of CGS-12066A significantly reduced the partition time. The conclusion was made that the 5-HT(1A) subtype is involved in controlling both behavioral and hormonal indices of sexual arousal in male mice, while the 5-HT(1B) receptors antagonise sexual motivation, but do not modify the hypothalamic-pituitary-testicular response.

PMID:   11965359   [PubMed - indexed for MEDLINE]

 

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Int J Neuropsychopharmacol. 2009 Sep;12(8):1045-53. doi: 10.1017/S1461145709000406. Epub 2009 May 13.

5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats.
Abstract

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

PMID:   19435548   [PubMed - indexed for MEDLINE]

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J Androl. 2006 Sep-Oct;27(5):679-85. Epub 2006 May 25.

Doxazosin and serotonin (5-HT) receptor (1A, 2A, and 4) antagonists inhibit 5-HT-mediated human cavernosal contraction.
Abstract

Penile erection results from the balance between relaxation and contractile mechanisms of the corpus cavernosum. Only a few studies suggest a role for endogenous contractile agents such as 5-hydroxytryptamine (5-HT). Our aim was to confirm the possible role of 5-HT in human erection. The effect of 5-HT on human cavernosal tissues, as well as those of doxazosin (shown previously to have 5-HT inhibitory action), ketanserin (5-HT (2A) receptor antagonist), NAN-190 (5-HT (1A) receptor antagonist), and SB 203186 (5-HT (4) receptor antagonist) on 5-HT-mediated effects, were assessed using the organ bath technique, including electrical field stimulation study (EFS). Results are presented as median (mg/mg = mg contraction/mg of tissue). Consistent 5-HT-mediated (10(-3) M) contractions were demonstrated (n = 18; 63 mg/mg). These contractions were inhibited with ketanserin by 90% (n = 8), NAN-190 by 68% (n = 12), and SB 203186 by 55% (n = 12). Doxazosin showed a similar 5-HT inhibitory action in a concentration-dependent manner (10(-4) M; 94% reduction; n = 8, 10(-6) M; 68.3% reduction; n = 8). Our EFS studies indicated the presence of neuronally derived 5-HT and that a majority of the nonnoradrenogenic contraction (54%) was mediated via 5-HT(2A) receptors. These findings suggest that 5-HT may play a role in the human detumescence process via 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors. Neuronally released 5-HT is probably an important contractile neurotransmitter in the erectile process. Doxazosin, ketanserin, and 5-HT(1A) and 5-HT(4) receptor antagonists may be useful as part of combination therapy used to treat erectile dysfunction.

PMID:   16728720   [PubMed - indexed for MEDLINE]    Free full text

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Psychopharmacology (Berl). 1992;108(1-2):47-50.

5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.
Abstract

The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections.

PMID:   1357709   [PubMed - indexed for MEDLINE]

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Eur Neuropsychopharmacol. 2004 Mar;14(2):151-5.

Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study.
Abstract
RATIONALE:

Flesinoxan is a highly potent and selective 5-HT1A agonist. In a recent study, in normal volunteers, flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature.

OBJECTIVES:

In order to better define the role of 5-HT receptor subtypes in response to flesinoxan, we assessed the influence of 5-HT1A and 5-HT2 antagonists on hormonal and temperature responses to flesinoxan.

METHODS:

Hormonal and temperature responses were studied in 6 volunteers with or without pretreatment with pindolol (30 mg p.o.), a 5-HT1A antagonist, or ritanserin (10 mg p.o.), a selective 5-HT2 antagonist, using a double-blind crossover design.

RESULTS:

Pindolol significantly antagonized ACTH, PRL, GH and temperature responses to flesinoxan and ritanserin exhibited similar activity on PRL and ACTH responses.

CONCLUSIONS:

These results show the role of 5-HT1A mechanisms in the PRL, ACTH, GH, and temperature responses to flesinoxan, and the role of 5-HT2 mechanisms in PRL and ACTH responses. Therefore, they confirm the interest of flesinoxan as a 5-HT neuroendocrine probe.

PMID:   15013031   [PubMed - indexed for MEDLINE]

 

 


Edited by Area-1255, 18 February 2015 - 07:06 AM.

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#2 StevesPetRat

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Posted 19 February 2015 - 07:14 PM

Can anything besides Rx antagonists to help shift the homeostasis of this system (in the "right" direction)?



#3 jaiho

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Posted 20 February 2015 - 05:22 AM

Wouldn't an antagonist also block oxytocin for males, in turn, reducing feeling of love for a partner?



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#4 NeuroNootropic

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Posted 20 February 2015 - 10:15 AM

Can anything besides Rx antagonists to help shift the homeostasis of this system (in the "right" direction)?

 

Rhodiola Rosea helps me with my anhedonia, low libido, low energy, and motivation and it increases serotonin in the brain. It also increases 5-HT1A receptors: 

Rhodiola rosea has been used for centuries in the traditional medicine to stimulate nervous system, to enhance physical and mental performance and to treat fatigue. It is known that administration of Rhodiola rosea extract elicits antidepressant activity, but the mechanism of action still remains unclear. Evidence from animal models and human studies show that nicotine reduces symptoms of depression and that nicotine cessation induces depressive-like symptoms. We investigated the effects of Rhodiola rosea on nicotine withdrawal signs. Nicotine dependence was induced by subcutaneous nicotine injection (2 mg/kg, four times daily) for 14 days. Another group of animals treated with nicotine (for 14 days) and successively with Rhodiola rosea extract was co-administered with selective 5-HT receptorial antagonist WAY 100635 (1 mg/kg). After nicotine withdrawal animals were evaluated for behavioural parameters (locomotor activity, abstinence signs, marble burying test), diencephalic serotonin metabolism and serotonin receptor-1A expression. Results show a significant increase of 5-HT content in N treated with R. rosea, with a significant increase of serotonin receptor 1A, suggesting an involvement of serotonin in beneficial effects of R. rosea on suffering produced by nicotine withdrawal.

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#5 StevesPetRat

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Posted 20 February 2015 - 04:15 PM

Rhodiola Rosea helps me with my anhedonia, low libido, low energy, and motivation and it increases serotonin in the brain. It also increases 5-HT1A receptors:

I think this may be the opposite of what I want to do...
edit: errr the increase serotonin part. I want the rest. Which all strike me as dopaminergic effects rather than serotonergic ones.

Edited by StevesPetRat, 20 February 2015 - 04:17 PM.


#6 Major Legend

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Posted 20 February 2015 - 08:04 PM

I'm not sure what to make with this - if people were already on an antidepressant , would taking an antagonist at the ht1a destroy the beneficial effects of an antidepressant?



#7 mindpatch

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Posted 21 February 2015 - 03:22 PM

Can anything besides Rx antagonists to help shift the homeostasis of this system (in the "right" direction)?

 

Anyone got any WAY-101405 lying around?

 

If I've been on SSRI based meds for years and, though I've been off for two years now, still suffer from depressed libido, is this caused by the SSRI use, or would you expect things to correct or repair by this time?  



#8 Major Legend

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Posted 21 February 2015 - 06:23 PM

 

Can anything besides Rx antagonists to help shift the homeostasis of this system (in the "right" direction)?

 

Anyone got any WAY-101405 lying around?

 

If I've been on SSRI based meds for years and, though I've been off for two years now, still suffer from depressed libido, is this caused by the SSRI use, or would you expect things to correct or repair by this time?  

 

 

I have heard the depressed libido can be quite permanent. How long were you on them for?

 

Have you had your testoterone levels tested? I have heard people use wellbutrin as adjunct to SRRI to offset the libido side effects.

 

I tend to think clomid and anastrole (or nettle root extract) can work.



#9 mindpatch

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Posted 21 February 2015 - 10:10 PM

I was on them for years.

My test trends to be low normal. I was on try on that wasn't really the answer for the low libido, so I know that the mechanism is different.

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#10 chziime

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Posted 21 February 2015 - 10:54 PM

What effect does Mirtazapine have on this receptor in the long term?

"Indirect α1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α2-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.[5][8][78][79][80] Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor."


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#11 Area-1255

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Posted 26 February 2015 - 10:05 PM

 

Rhodiola Rosea helps me with my anhedonia, low libido, low energy, and motivation and it increases serotonin in the brain. It also increases 5-HT1A receptors:

I think this may be the opposite of what I want to do...
edit: errr the increase serotonin part. I want the rest. Which all strike me as dopaminergic effects rather than serotonergic ones.

 

5-HT1A blockade would enhance sexual response in the presence of a female AKA pheromonal response....it also is involved in the rise of testosterone that causes one to assert themselves or compete for a female and their attention..thus it can be said, that this receptor is an equalizer in sexual motivation...you certainly don't want it stimulated in most cases - if you want to be an "alpha male" , that is.


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#12 Brazzo

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Posted 07 March 2015 - 01:21 PM

 

5-HT1A agonism (pre-synaptic) can have it's benefits, namely in reducing excess serotonin - HOWEVER, after persistent agonism - it tends to de-sensitize, which then sends a flood of disinhibited serotonin to the post-synaptic 1A receptors which then can inhibit penile erection and can reduce sexual motivation....especially regarding arousal by female pheromones or presence!

 

What about Ginko Biloba? Would it be wise for long-term use or could it cause the mentioned de-sensitization?



#13 nowayout

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Posted 07 March 2015 - 02:36 PM


5-HT1A blockade would enhance sexual response ....it also is involved in the rise of testosterone

 

 

How about partial agonists?  I'm thinking of vilazodone, which is the one SSRI-type antidepressant with supposedly negligible sexual side effects.

 

I can't tell if partial agonism in this case causes a net reduction of 5HT-1a agonism or the opposite.


 



#14 Area-1255

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Posted 07 March 2015 - 08:33 PM

 

 

5-HT1A agonism (pre-synaptic) can have it's benefits, namely in reducing excess serotonin - HOWEVER, after persistent agonism - it tends to de-sensitize, which then sends a flood of disinhibited serotonin to the post-synaptic 1A receptors which then can inhibit penile erection and can reduce sexual motivation....especially regarding arousal by female pheromones or presence!

 

What about Ginko Biloba? Would it be wise for long-term use or could it cause the mentioned de-sensitization?

 

Doubtful that it would cause de-sensitization - as it is involved with "preventing/reversing age-related decreases in 5-HT1A receptors" - indicating a protective effect while simultaneously agonizing them.

http://comilac.com.t...f/Kaynak16x.pdf

 

 

Fundam Clin Pharmacol. 1995;9(2):169-74.

Stress-induced 5-HT1A receptor desensitization: protective effects of Ginkgo biloba extract (EGb 761).
Abstract

The effects of sub-chronic cold stress on the functioning of hippocampal 5-HT1A receptors in old isolated rats and the possible protective effects of Ginkgo biloba extract (EGb 761) were investigated. Cold exposure during five days, produced a significant reduction of the inhibitory effect of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity. In contrast, neither the affinity nor the density of hippocampal [3H]8-OH-DPAT binding sites were affected indicating that the reduced sensitivity of 5-HT1A receptors induced by stress is probably due to a modification of their coupling mechanisms to adenylyl cyclase. The stress-induced desensitization of 5-HT1A receptors was prevented by the administration of EGb 761 (50 mg/kg per os/14 days). These results clearly indicate that 5-HT1A receptors are desensitized by stress and point out the reduced capacity of old rats to cope with the adverse effects of a chronic stressor. EGb 761 appears to restore the age-related decreased capacity to adapt to a chronic stressor.

PMID:   7628830   [PubMed - indexed for MEDLINE]

 

Pharmacol Biochem Behav. 1999 Mar;62(3):543-7.

The discriminative stimulus properties of EGb 761, an extract of Ginkgo biloba.
Abstract

Stimulus control was established in a group of nine rats using a dose of EGb 761 of 10 mg/kg, administered i.p., 15 min before training. A two-lever operant task using a fixed-ratio 10 schedule of sweetened milk reinforcement was used. Based upon a criterion for the presence of stimulus control of five consecutive sessions during which 83% or more of all responses were on the appropriate lever, a mean of 24 sessions was required to reach criterion performance. Subsequently, it was observed that EGb 761-induced stimulus control is significantly antagonized by the selective 5-HT1A antagonist WAY-100635, but is unaffected by the 5-HT2 antagonist pirenperone. Furthermore, EGb 761 generalized to the selective 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin [8-OH-DPAT], and this generalization was blocked by WAY-100635. The present results indicate that EGb 761 is able to induce stimulus control when administered via the intraperitoneal route, and that its stimulus effects are mediated in part by activity at the 5-HT1A receptor.

PMID:   10080249   [PubMed - indexed for MEDLINE]

 


Edited by Area-1255, 07 March 2015 - 08:37 PM.

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#15 Area-1255

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Posted 07 March 2015 - 08:47 PM

 


5-HT1A blockade would enhance sexual response ....it also is involved in the rise of testosterone

 

 

How about partial agonists?  I'm thinking of vilazodone, which is the one SSRI-type antidepressant with supposedly negligible sexual side effects.

 

I can't tell if partial agonism in this case causes a net reduction of 5HT-1a agonism or the opposite.

 

 

Right, partial agonist is kinda a vague term - some partial agonists are more selectively antagonistic to the autoreceptors , but most are actually agonistic to them (where you would see reductions in serotonin) - you have to understand the two main effects of serotonin 5-HT1A receptors (the 5-HT5A is almost identical, and interexchangeable)

 

1.) Activation of 5-HT1A reduces cyclic AMP (as it is negatively coupled to G-proteins)

2.) Decreasing serotonin release (pre-synaptic autoreceptors).

 

 

Thus the partial agonist must be examined as to which partitions it exerts agonistic activity and which are antagonistic/partially agonistic.....

 

Most of all 5-HT1A partial agonists are agonists at the post-synaptic side (decreasing  cAMP) and agonistic at the presynaptic side (decreasing serotonin).

 

The net effect of 1A partial agonists is reduction in sympathetic nervous system activity, including noradrenaline and glutamate - and lessened heart rate, constriction of pupils and an anxiolytic/antidepressant effect. As well as increased beta-endorphin release..most drug induced highs including cocaine, amphetamine and other addictive drugs end up hitting/mediating most of their high effect through serotonin 5-HT1A - induced dopamine and beta-endorphin release. Dopamine reuptake inhibition just adds to that effect or indirectly does this indirect signaling itself by downstream pathway alteration.

 

 

 

The problem is though, by inhibiting cyclic AMP we may end up causing issues like reductions in testosterone synthesis despite the benefits of increased prefrontal dopamine release - TAKE NOTE ; just because 1A agonism results in dopamine enhancement in some* areas like the prefrontal cortex, it is also associated with decreases in dopamine in the paraventrical nucleus - which would explain why penile erections and sexual motivation are abolished with 1A agonists !

 

......Because PREFRONTAL dopamine increases would basically mean null in terms of sexual output, and decreases in PVN/MPOA dopamine are going to cause issues in terms of sexual motivation - which is what 1A agonists do.

 

However, the paradoxical increase in libido from 1A agonists is because in these individuals, lowering serotonin over rides the downsides of 1A post-synaptic activation.... in other words, if your issue is to do with classical libido issues such as just a decreased sex drive - then 1A agonism may have it's benefits...but if it is to do with sexual motivation in terms of pursuing and in terms of arousal AROUND a female, and / or erectile problems then 1A antagonism is more useful.

 

**If you feel almost, too NOT aggressive in the way you deal with things in life - meaning you don't stand up for yourself as much and don't assert yourself - then you'd want 1A ANTAGONISM.**


Edited by Area-1255, 07 March 2015 - 08:50 PM.

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#16 GoingPrimal

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Posted 08 March 2015 - 08:18 PM

So do we know of any worthy 5HT-1 antagonists that are natural? Not getting anything from pubmed atm.
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#17 Area-1255

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Posted 09 March 2015 - 12:02 AM

So do we know of any worthy 5HT-1 antagonists that are natural? Not getting anything from pubmed atm.

I've researched thoroughly, nothing that would be potent enough - we need a research chem company or nootropics company to release a 1A antagonist like lecozotan or WAY 100 635, Hopefully soon.  ;)


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#18 Guinga

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Posted 09 March 2015 - 12:40 AM

wow that's very useful information, thanks! i've been having some problems with pssd, and  alrealdy tried a lot of "libidogenic" herbs: catuaba,tribulus,etc. without much effect. i haven't read the whole thing so forgive me if what i'll ask has alrealdy been said. the effects described are due to the upregulation of the 1a  recepetors or due to reduced serotonin in the cleft? in that case tianeptin couldn't  be as helpful as the 1a antagonists?

 


Edited by Guinga, 09 March 2015 - 12:41 AM.

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#19 Area-1255

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Posted 09 March 2015 - 04:16 AM

wow that's very useful information, thanks! i've been having some problems with pssd, and  alrealdy tried a lot of "libidogenic" herbs: catuaba,tribulus,etc. without much effect. i haven't read the whole thing so forgive me if what i'll ask has alrealdy been said. the effects described are due to the upregulation of the 1a  recepetors or due to reduced serotonin in the cleft? in that case tianeptin couldn't  be as helpful as the 1a antagonists?

Not exactly, PSSD is a largely the result of 5-HT(1) autoreceptor DE-SENSITIZATION which leads to that receptor (which regulates serotonin release) being dysfunctional and thus DISINHIBITION of serotonin release. When the pre-synaptic autoreceptor is de-sensitized, tons of serotonin is also moving to the POST-SYNAPTIC 5-HT(1)A receptor - which is totally different than the PRE-SYNAPTIC (autoreceptor) - this post-synaptic side causes depression of the nervous system and heart rate, inhibition of sexual motivation and inhibition of penile erection and reflexes.
 
Additionally, long-term use of SSRI's can cause secondary hypogonadism and thus lowered testosterone....in part due to elevations in prolactin & CORTISOL/ACTH - the chronic elevation of cortisol as with SSRI's (even if it is lowered initially) - ends up causing aromatase enzymes to increase and thus estrogen also goes up - causing further opposition of androgens and other sex hormones as well as neurosteroids such as DHEA/Pregnenolone.
 
SSRI's also distort and some actually COMPETE for neurosteroid sites in the brain and CNS - which means you have a second mechanism for SSRI-induced  DHEA/Pregnenolone deficiencies.
 
Because so many people have DE-SENSITIZED 5-HT1A autoreceptors - I don't recommend buspar as some others would for PSSD - as excessive agonism is what got you to de-sensitized state in the first place, thus, anyone who has taken an SSRI for a period longer than ~3 months should not take buspar as it will continue/amplify the de-sensitized state (buspar is a 1A agonist).
 
My recommendations for PSSD sufferer's are to.
 
1.) Reduce prolactin and cortisol excesses - and correct testosterone deficiency.
 
2.) Exercise daily and take ginkgo biloba and other herbs which may help re-sensitize the receptors...
 
 
A   5-HT-1A antagonist may help for some of the arousal/motivational issues - but one is not available ATM.

 
 
BEFORE people BEGIN SSRI's ,or possibly even whilst on them, one should consider GINKGO BILOBA anyway, as it is shown to prevent de-sensitization of autoreceptors to some extent.
 
http://www.researchgate.net/publication/247669252_Stress-induced_5HT_1A_receptor_desensitization_protective_effects_of_Ginkgo_biloba_extract_(EGb_761)
 

Stress-induced 5HT 1A receptor desensitization: protective effects of Ginkgo biloba extract (EGb 761)

 




ABSTRACT — The effects of sub-chronic cold stress on the functioning of hippocampal 5-HT1A receptors in old isolated rats and the possible protective effects of Ginkgo biloba extract (EGb 761) were investigated. Cold exposure during five days, produced a significant reduction of the inhibitory effect of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity. In contrast, neither the affinity nor the density of hippocampal [3H]8-OH-DPAT binding sites were affected indicating that the reduced sensitivity of 5-HT1A receptors induced by stress is probably due to a modification of their coupling mechanisms to adenylyl cyclase. The stress-induced desensitization of 5-HT1A receptors was prevented by the administration of EGb 761 (50 mg/kg per os/14 days). These results clearly indicate that 5-HT1A receptors are desensitized by stress and point out the reduced capacity of old rats to cope with the adverse effects of a chronic stressor. EGb 761 appears to restore the age-related decreased capacity to adapt to a chronic stressor.

 

 

 


 the effects described are due to the upregulation of the 1a  recepetors or due to reduced serotonin in the cleft? in that case tianeptin couldn't  be as helpful as the 1a antagonists?
 
It's not strictly that any receptor is upregulated - it's that the autoreceptors are de-sensitized and so tons of serotonin is activating the post-synaptic 1A receptors and other receptors..since tianeptine is a reuptake enhancer - it may help by reducing the amount of serotonin activating all receptors...so yes, in theory that could help...

Edited by Area-1255, 09 March 2015 - 04:19 AM.

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#20 nowayout

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Posted 09 March 2015 - 10:23 AM

 

 


5-HT1A blockade would enhance sexual response ....it also is involved in the rise of testosterone

 

 

How about partial agonists?  I'm thinking of vilazodone, which is the one SSRI-type antidepressant with supposedly negligible sexual side effects.

 

I can't tell if partial agonism in this case causes a net reduction of 5HT-1a agonism or the opposite.

 

 

Right, partial agonist is kinda a vague term - some partial agonists are more selectively antagonistic to the autoreceptors , but most are actually agonistic to them (where you would see reductions in serotonin) - you have to understand the two main effects of serotonin 5-HT1A receptors (the 5-HT5A is almost identical, and interexchangeable)

 

1.) Activation of 5-HT1A reduces cyclic AMP (as it is negatively coupled to G-proteins)

2.) Decreasing serotonin release (pre-synaptic autoreceptors).

 

 

Thus the partial agonist must be examined as to which partitions it exerts agonistic activity and which are antagonistic/partially agonistic.....

 

Most of all 5-HT1A partial agonists are agonists at the post-synaptic side (decreasing  cAMP) and agonistic at the presynaptic side (decreasing serotonin).

 

The net effect of 1A partial agonists is reduction in sympathetic nervous system activity, including noradrenaline and glutamate - and lessened heart rate, constriction of pupils and an anxiolytic/antidepressant effect. As well as increased beta-endorphin release..most drug induced highs including cocaine, amphetamine and other addictive drugs end up hitting/mediating most of their high effect through serotonin 5-HT1A - induced dopamine and beta-endorphin release. Dopamine reuptake inhibition just adds to that effect or indirectly does this indirect signaling itself by downstream pathway alteration.

 

 

 

The problem is though, by inhibiting cyclic AMP we may end up causing issues like reductions in testosterone synthesis despite the benefits of increased prefrontal dopamine release - TAKE NOTE ; just because 1A agonism results in dopamine enhancement in some* areas like the prefrontal cortex, it is also associated with decreases in dopamine in the paraventrical nucleus - which would explain why penile erections and sexual motivation are abolished with 1A agonists !

 

......Because PREFRONTAL dopamine increases would basically mean null in terms of sexual output, and decreases in PVN/MPOA dopamine are going to cause issues in terms of sexual motivation - which is what 1A agonists do.

 

However, the paradoxical increase in libido from 1A agonists is because in these individuals, lowering serotonin over rides the downsides of 1A post-synaptic activation.... in other words, if your issue is to do with classical libido issues such as just a decreased sex drive - then 1A agonism may have it's benefits...but if it is to do with sexual motivation in terms of pursuing and in terms of arousal AROUND a female, and / or erectile problems then 1A antagonism is more useful.

 

**If you feel almost, too NOT aggressive in the way you deal with things in life - meaning you don't stand up for yourself as much and don't assert yourself - then you'd want 1A ANTAGONISM.**

 

 

I don't seem to have sexual or libido issues so far on vilazodone (3 weeks), so whatever it is doing, the net effect is either null or somewhat positive at this point.  It maybe too soon though. 


 



#21 Area-1255

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Posted 10 March 2015 - 08:17 PM

One more important bit of information, 5-HT1A activation (POST-Synaptic) seems to precipitate / facilitate hypothermia and hypothermic responses, this includes humans.(low body temp)

 

 

Neuropsychopharmacology. 2002 Aug;27(2):301-8.

Serotonin 1A receptor activation and hypothermia in humans: lack of evidence for a presynaptic mediation.
Abstract

The hypothermia produced by 5-HT1A agonists had initially been claimed to be caused by the activation of cell body 5-HT1A autoreceptors resulting in decreased 5-HT transmission in laboratory animals. In order to address this issue in humans, 12 healthy volunteers underwent a dietary tryptophan depletion paradigm to decrease 5-HT availability, under double-blind conditions, during which body temperature was monitored following oral administration of the 5-HT1A agonist buspirone (30 mg). In addition, plasma prolactin and growth hormone evaluations, two responses that are mediated via the direct activation of postsynaptic 5-HT1A receptors, were determined. The hypothesis was that if responses are mediated by decreased transmission at postsynaptic 5-HT1A receptors, resulting from dampened 5-HT release as a consequence of 5-HT1A autoreceptors activation, then responses to the exogenous 5-HT1A agonist should be attenuated when 5-HT availability has been markedly decreased beforehand. Buspirone produced the same significant increase in prolactin and growth hormone in the tryptophan-depleted state as in the control condition. Similarly, the degree of hypothermia produced by buspirone was not significantly different in the two experimental conditions. In conclusion, these results strongly suggest that the hypothermia and the increases in prolactin and growth hormone produced by buspirone are attributable to the enhanced activation of postsynaptic 5-HT1A receptors, and not to a decrease in 5-HT transmission resulting from the activation of the 5-HT1A cell body autoreceptors on 5-HT neurons.

PMID:   12093604   [PubMed - indexed for MEDLINE]    Free full text

 


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#22 Son of Perdition

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Posted 02 April 2015 - 06:48 AM

veryyy interesting...


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#23 NeuroNootropic

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Posted 03 April 2015 - 01:39 AM

Area-1255, what do you think of Bupropion or Rhodiola Rosea? Bupropion desensitizes 5-HT1A autoreceptors but it usually increases libido. 

Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of alpha2-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.

→ source (external link)

 

Personally, I've used Wellbutrin (bupropion) 150 mg XL in the past and the only day it increased my libido was on the 3rd day, but not on any other day despite taking the drug for more than 5 weeks. It also happened on the 3rd day after I tried going up to 300 mg XL and despite not being able to tolerate the amount of side effects it still increased my libido, but just on that one day.

 

Rhodiola increases 5-HT1A receptors, but the study I linked didn't say if they were autoreceptors or post-synaptic. In any case, Rhodiola also seems to have the same effect as Wellbutrin for me, but lasts a bit longer. It increases my libido a little bit for about a week and then dissipates. Selegiline, Ritalin, Vyvanse, Maca and other substances that have a tendency to increase libido don't increase mine.

 

Given all this, what do you think is more helpful for me, a 5-HT1A agonist or an antagonist? I'm leaning towards the antagonist as the long-term effects of bupropion are not very pleasant, but the initial effects are very desirable.



#24 Area-1255

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Posted 03 April 2015 - 04:39 AM

Area-1255, what do you think of Bupropion or Rhodiola Rosea? Bupropion desensitizes 5-HT1A autoreceptors but it usually increases libido. 

Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of alpha2-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.

→ source (external link)

 

Personally, I've used Wellbutrin (bupropion) 150 mg XL in the past and the only day it increased my libido was on the 3rd day, but not on any other day despite taking the drug for more than 5 weeks. It also happened on the 3rd day after I tried going up to 300 mg XL and despite not being able to tolerate the amount of side effects it still increased my libido, but just on that one day.

 

Rhodiola increases 5-HT1A receptors, but the study I linked didn't say if they were autoreceptors or post-synaptic. In any case, Rhodiola also seems to have the same effect as Wellbutrin for me, but lasts a bit longer. It increases my libido a little bit for about a week and then dissipates. Selegiline, Ritalin, Vyvanse, Maca and other substances that have a tendency to increase libido don't increase mine.

 

Given all this, what do you think is more helpful for me, a 5-HT1A agonist or an antagonist? I'm leaning towards the antagonist as the long-term effects of bupropion are not very pleasant, but the initial effects are very desirable.

An agonist if your issue is in mainframe sexual desire and / or bonding issue or sociability issues...but an antagonist is better if you lack "primal" motivation as in competition, defending, sexual aggression etc ... Also if erectile issues are present, you want an antagonist, not an agonist. 

 

Therefore it's about measuring your personality and history, if you have poor socialization skills and already too much aggression or some sort of vendetta against women, I definitely wouldn't recommend an antagonist...unless you are thinking about being a showcase/participant for Law and Order SVU  (exaggerating a little bit)  ...

 

Re-Iterating in Summary

 

An agonist makes sense in mainly the areas of 

 

  • -generalized anxiety
  • -bonding issues / trust issues
  • -sociability issues
  • -general libido issues as in fantasies or traditional libido gauging
  • -Your nervous system is generally over-excited and heart rate is high.

 

An antagonist makes sense if

 

-You are un-motivated

-You lack primal essence, vigor, aggression etc

-You have circulatory issues or erectile issues apart from libido, or just general lack of nitric oxide production / vasodilation

-You don't get a good pump during workouts

-You feel like you aren't moving forward in life

-You have a tendency to addiction to stimulants or are dependent on caffeine throughout the day.


Edited by Area-1255, 03 April 2015 - 04:40 AM.

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#25 Flex

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Posted 15 April 2015 - 04:21 AM

Bump, whats about Propranolol or any other Rx which might be a relative potnt 5-ht1a antagonist ?

http://en.wikipedia....iki/Propranolol

 

@ GoingPrimal

Here You go

 

Natural 5-HT1A Agonists/Antagonists (PSSD,and Cognitive Function)

http://www.longecity...e-2#entry723282


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#26 Area-1255

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Posted 15 April 2015 - 05:38 PM

Bump, whats about Propranolol or any other Rx which might be a relative potnt 5-ht1a antagonist ?

http://en.wikipedia....iki/Propranolol

 

@ GoingPrimal

Here You go

 

Natural 5-HT1A Agonists/Antagonists (PSSD,and Cognitive Function)

http://www.longecity...e-2#entry723282

Beta-blockers are terrible for sexual function, part of the point of 5-HT1A antagonism is to blunt serotonin's cAMP inhibiting effects...remember cAMP increases test levels, hence why forskolin is sometimes used to raise testosterone and to lean out ---- using something that is a beta blocker as well would contradict the effects of the 5-HT1A blockade.

 

Beta-adrenergic receptors =  positively coupled to adenylate cyclase = + cAMP when activated

5-HT1A receptors              = negatively coupled to adenylate cyclase =  - cAMP when activated.


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#27 Flex

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Posted 15 April 2015 - 11:00 PM

Thank You.

 

Didnt know the implication of cAMP.

 

Heres a list of Agonists and Antagonists of the 5-ht1a receptor:

 

pdsp.med.unc.edu

http://pdsp.med.unc....ry=Submit Query

 

Altough for some reason they dont list Cyproheptadine as an antagonist at 5-ht1a which does also inhibit 5-ht6, 5-ht7 as well as Dopamine D1 D2 & D3

http://en.wikipedia..../Cyproheptadine

 

http://pdsp.med.unc....ry=Submit Query


Edited by Flex, 15 April 2015 - 11:02 PM.

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#28 Area-1255

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Posted 15 April 2015 - 11:07 PM

Thank You.

 

Didnt know the implication of cAMP.

 

Heres a list of Agonists and Antagonists of the 5-ht1a receptor:

 

pdsp.med.unc.edu

http://pdsp.med.unc....ry=Submit Query

 

Altough for some reason they dont list Cyproheptadine as an antagonist at 5-ht1a which does also inhibit 5-ht6, 5-ht7 as well as Dopamine D1 D2 & D3

http://en.wikipedia..../Cyproheptadine

 

http://pdsp.med.unc....ry=Submit Query

No problem, and yeah cAMP is important and works hand in hand with cGMP.

cAMP AND cGMP both are messengers used for the production of testosterone and other hormones AND are messengers used BY hormones and other messengers...

 

Cyproheptadine is more than adequate for serotonin blockade but it's anti-cholinergic and anti-dopaminergic properties make it useless. Ya see how that works?  :-D  :sleep:

 

We need to gain access to more specific serotonin antagonists that LACK properties and affinity concerning other monoamines...it's horrible for research to use mixed compounds lacking specificity...for example, the research & development drug 8-OH-DPAT - it was originally a 5-HT1A full agonist but later was identified to have additional properties as a 5-HT7 agonist and 5-HT1B partial agonist..given the OPPOSITE properties of 5-HT7 and 5-HT1A receptors - this is horribly unfit for research involving only one or other. 


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#29 Plasticperson

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Posted 15 April 2015 - 11:09 PM

i read that ashwagahnda lowers 1a and raises 2a


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#30 Area-1255

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Posted 16 April 2015 - 12:02 AM

i read that ashwagahnda lowers 1a and raises 2a

Yes, that's correct. (!)

 

It can also help block dyskinesia's caused by psychotropics's ; specifically Haldol and other anti-psychotic drugs.

http://online.liebertpub.com/doi/abs/10.1089/109662003322233503
We investigated the role of oxidative stress in the pathophysiology of haloperidol (HP)-induced orofacial dyskinesia and evaluated the beneficial effect of Withania somnifera (Ws) root extract in the amelioration of HP-induced vacuous chewing movements (VCMs) and tongue protrusions in the rat model for TD. Rats were treated for 21 days with intraperitoneal HP (1 mg/kg); on day 22, VCMs and tongue protrusions were counted during a 5-minute observation period. HP-treated rats significantly developed these extrapyramidal symptoms, but coadministration of Ws root extract (100-300 mg/kg) dose-dependently reduced them. Biochemical analysis revealed that chronic HP treatment significantly increased lipid peroxidation and decreased forebrain levels of glutathione and the antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Coadministration of Ws extract significantly reduced the lipid peroxidation and significantly reversed the decrease in forebrain SOD and catalase levels but had no significant effect on the HP-induced decrease in forebrain glutathione levels. These findings strongly suggest that oxidative stress plays a significant role in HP-induced orofacial dyskinesia and that Ws could be effective in preventing neuroleptic-induced extrapyramidal side effects.

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