280 replies to this topic

[AMx Workshop]

I always thought Epi andro had a nice effect on mood.....though I'm not entirely sure it was solely that..for all i know, could be piperine. lmao, Just kiddin. DHT's good stuff!

Edited by AMx Workshop, 26 December 2014 - 03:48 AM.

[Area-1255]

I always thought Epi andro had a nice effect on mood.....though I'm not entirely sure it was solely that..for all i know, could be piperine. lmao, Just kiddin. DHT's good stuff!

I found it to be stimulating, but in a good way..strength mostly.

[Ehren Maldonado]

very nice article, my bf would loooove this one!

[Area-1255]

very nice article, my bf would loooove this one!

Thanks, and yeah it's good for any male who is concerned about their health and manhood to read! Most definitely!

[Jbac]

very nice article, my bf would loooove this one!

 

Sounds like you want him to take DHT for the increased stamina and bigger erections

Edited by rwac, 29 December 2014 - 04:50 AM.
[Pokemon hack removed -mod]

[Area-1255]

 

very nice article, my bf would loooove this one!

 

Sounds like you want him to take DHT for the increased stamina and bigger erections
 

Yeah, JavaLizard speaks the truth.

[Area-1255]

See now people, this is a nice stable reminder of how vigilant Area-1255 really is.

 

 

[Area-1255]

Btw, DHEA, PREGNENOLONE AND DHT ALL BOOST NMDA-RECEPTORS FUNCTION

http://www.longecity...ndpost&p=706527

DHEA, PREGNENOLONE; take those as positive allosteric modulators of NMDA-glutamate receptors, and yes, blocking NMDA may worsen OCD for many. Agonizing it should help both schizophrenia and OCD.

 

DIHYDROTESTOSTERONE; as shown below, upregulates NMDA and increases binding...thus

----------------------------------------------------------------------------------------------------------------

THE ANSWER TO ACTIVATING AND UPREGULATING NMDA IS....

--------------------------------------------------------------------------------

DHT, PREGNENOLONE, AND DHEA....good for anxiety, OCD, depression, libido etc

----------------------------------------------------------------------------------------------------------------

• Use creatine and protodioscin to boost DHT naturally.
• You can easily buy pregnenolone and DHEA for cheap online.

 

 

 

http://molpharm.aspe...ontent/40/3/333

http://en.wikipedia....anism_of_action

Book on NeuroSteroids ; NMDA SECTION

Quote

 

Endocrinology. 2005 Apr;146(4):2091-7. Epub 2005 Jan 20.

Dihydrotestosterone increases hippocampal N-methyl-D-aspartate binding but does not affect choline acetyltransferase cell number in the forebrain or choline transporter levels in the CA1 region of adult male rats.

Romeo RD1, Staub D, Jasnow AM, Karatsoreos IN, Thornton JE, McEwen BS.

Author information

 

Abstract

Testosterone, acting through its androgenic metabolite 5alpha-dihydrotestosterone (DHT), can increase dendritic spine density in the CA1 region of the male rat hippocampus. The mechanisms mediating this increase in spines are presently unknown. In female rats, estrogen (E) has been shown to increase spine density, which is in part mediated by increases in N-methyl-d-aspartate (NMDA) receptors in the CA1 region and cholinergic forebrain inputs to the hippocampus. Whether similar mechanisms are responsible for the DHT-induced increase in spines in the male remains to be determined. In the first experiment, we used [(3)H]glutamate NMDA receptor binding autoradiography to assess whether DHT-treated males had higher NMDA receptor levels in the CA1 region of the hippocampus, compared with oil-treated males. In the second set of experiments, we used choline acetyltransferase (ChAT) in situ hybridization and immunohistochemistry to assess whether DHT could affect ChAT cell number in the forebrain. We also investigated the effect of DHT on hemicholinium-3-sensitive choline transporter levels in the CA1 region of the male hippocampus. We found that DHT significantly increased NMDA receptor binding in the CA1 region of males but had no effect on ChAT cell number in the forebrain or hemicholinium-3-sensitive choline transporter protein levels in the CA1 region. These data indicate that, similar to E-induced spinogenesis in females, DHT-induced increases in spine formation in males may require increases in NMDA receptors. However, unlike E-treated females, these data suggest that DHT does not influence cholinergic inputs to the hippocampus.

PMID:   15661864   [PubMed - indexed for MEDLINE]

 

Edited by Area-1255, 06 January 2015 - 08:41 PM.

[Area-1255]

As much as this statement is old, king hyperion is the noble , postured, ubiquitous  poster child of the male awesomeness movement.

[Area-1255]

Any ideas on the next article fellas?

[Area-1255]

Already created an estrogen equivalent, yall seen that yet?

[Area-1255]

Article updated!

[VICREP]

Area-1255,

 

I have been on finasteride for 1 year now for MPB. I'm not happy about having to systemically lower DHT just to fight hairloss, but I feel as if I have no other option.

 

Nizoral, Minoxidil, etc are effective hairloss treatments no doubt, but how  much if a fight can they really put up whilst DHT is still miniaturizing the follicle? What are my best options? RU? 

[Area-1255]

Area-1255,

 

I have been on finasteride for 1 year now for MPB. I'm not happy about having to systemically lower DHT just to fight hairloss, but I feel as if I have no other option.

 

Nizoral, Minoxidil, etc are effective hairloss treatments no doubt, but how  much if a fight can they really put up whilst DHT is still miniaturizing the follicle? What are my best options? RU? 

Minoxidil, zinc, butterbur and rosemarinic acid from life extension. 

You want to lower histamine a little bit, to help lower inflammation.

Also lowering prolactin if it is elevated will help reduce excess DHT.

[BasicBiO]

Ahh DHT. My old friend. Definitely an underrated substance.

 

Has anyone tried TLR's Dehydromestolon-OA? I just made an ETOH suspension 50mg/mL and dosed about 30mg today. Haven't noticed too much beyond extra alertness and perhaps some aggression, but I'm also running SEMAX so it's not a clean trial. I'll try it again when I am off SEMAX et al and report back.

 

 

[Area-1255]

Ahh DHT. My old friend. Definitely an underrated substance.

 

Has anyone tried TLR's Dehydromestolon-OA? I just made an ETOH suspension 50mg/mL and dosed about 30mg today. Haven't noticed too much beyond extra alertness and perhaps some aggression, but I'm also running SEMAX so it's not a clean trial. I'll try it again when I am off SEMAX et al and report back.

No but they seem very reputable and innovative, it sparks my interest...I've heard a lot of good things about them. 

[Area-1255]

I'll be ordering some of the optimized DHT analogue within the next week or so, and I will update this thread & post a new log in sups!

Edited by Area-1255, 03 February 2015 - 01:29 AM.

[BasicBiO]

Day 2 on Dehydromestelone was not-so-great in the mood department. I had lots of energy, but no patience whatsoever and was quite testy. This would have been great for workouts, but the effect seemed to last around 8 hours when I finally took some lemon balm extract to chill the F out. I have to many life variables in play right now to have any anger issues.

 

I'm still holding out hope that this compound will have some use so I am shelving it for the moment and concentrating on my SEMAX run. I suspect my DHT is low due to low energy and libido, but I want to free of other noots before I attempt to try dehydroM again. 

 

Best of luck on your run Area-1255, I'll be watching with interest.

[Area-1255]

Day 2 on Dehydromestelone was not-so-great in the mood department. I had lots of energy, but no patience whatsoever and was quite testy. This would have been great for workouts, but the effect seemed to last around 8 hours when I finally took some lemon balm extract to chill the F out. I have to many life variables in play right now to have any anger issues.

 

I'm still holding out hope that this compound will have some use so I am shelving it for the moment and concentrating on my SEMAX run. I suspect my DHT is low due to low energy and libido, but I want to free of other noots before I attempt to try dehydroM again. 

 

Best of luck on your run Area-1255, I'll be watching with interest.

Strong ITALIAN blood and "Optimized DHT Compounds" - people better hope they don't get in my way.

[Son of Perdition]

 

Day 2 on Dehydromestelone was not-so-great in the mood department. I had lots of energy, but no patience whatsoever and was quite testy. This would have been great for workouts, but the effect seemed to last around 8 hours when I finally took some lemon balm extract to chill the F out. I have to many life variables in play right now to have any anger issues.

 

I'm still holding out hope that this compound will have some use so I am shelving it for the moment and concentrating on my SEMAX run. I suspect my DHT is low due to low energy and libido, but I want to free of other noots before I attempt to try dehydroM again. 

 

Best of luck on your run Area-1255, I'll be watching with interest.

Strong ITALIAN blood and "Optimized DHT Compounds" - people better hope they don't get in my way.

 

same...i have some weird blood..i am part persian and part italian and indian. 

[Area-1255]

 

 

Day 2 on Dehydromestelone was not-so-great in the mood department. I had lots of energy, but no patience whatsoever and was quite testy. This would have been great for workouts, but the effect seemed to last around 8 hours when I finally took some lemon balm extract to chill the F out. I have to many life variables in play right now to have any anger issues.

 

I'm still holding out hope that this compound will have some use so I am shelving it for the moment and concentrating on my SEMAX run. I suspect my DHT is low due to low energy and libido, but I want to free of other noots before I attempt to try dehydroM again. 

 

Best of luck on your run Area-1255, I'll be watching with interest.

Strong ITALIAN blood and "Optimized DHT Compounds" - people better hope they don't get in my way.

 

same...i have some weird blood..i am part persian and part italian and indian. 

 

That's quite the mix....

[Plasticperson]

I really liked reading through the DHT thread and decided to buy some protodioscin. 1000 mg of 80 precent standardized extract. Stuff has some great benefits like extra confidence and increased muscle mass. The only problem is that after 3 weeks of use I've seriously gone into rage mode.  At first it was great, however, after a while stuff like an increased libidio turned into shut the fuck up and take your clothes off already. I've also noticed that I have this angry fog over my thought process some days. Instead of thinking through a problem, like i usually do, ill get this tendency to throw rage fits until a problem is solved regardless of any collateral damage. It's actually kinda funny sometimes. 

 

Very strong stuff the Trib extracts. Going to try a lower dose and see how things go but the anger and mood problems are no fun. Its seems the supp really pushes the line between increased mood/ confidence and narrow minded rage.

[Area-1255]

I really liked reading through the DHT thread and decided to buy some protodioscin. 1000 mg of 80 precent standardized extract. Stuff has some great benefits like extra confidence and increased muscle mass. The only problem is that after 3 weeks of use I've seriously gone into rage mode.  At first it was great, however, after a while stuff like an increased libidio turned into shut the fuck up and take your clothes off already. I've also noticed that I have this angry fog over my thought process some days. Instead of thinking through a problem, like i usually do, ill get this tendency to throw rage fits until a problem is solved regardless of any collateral damage. It's actually kinda funny sometimes. 

 

Very strong stuff the Trib extracts. Going to try a lower dose and see how things go but the anger and mood problems are no fun. Its seems the supp really pushes the line between increased mood/ confidence and narrow minded rage.

Some of it is a learned trait  - you just gotta channel the "rage"...many times easier said that done - DHT sups and increasing it in general will most certainly make you more serious but also more motivated and confident, however, studies show that serotonin and DHT are technical opposites; and androgens DO NOT promote aggression unless coupled with very low serotonin OR genetically HIGHER serotonin type 2 receptors....OR an overall excess of noradrenaline. Also, Androgens do NOT promote offensive aggression, only defensive (aka getting discredited, or someone attempting to attack you or talk down to you).

 

• Androgen dependent aggression is defensive in nature, and dependent on noradrenaline levels.
• Androgens do not cause any aggression if 5-HT1A/1B (!) (!) are consistently or strictly activated (interestingly these are autoreceptors for serotonin).
• If you have genetically higher levels of serotonin type 2A receptors, you are more prone to aggression - regardless of androgen/estrogen balance.
• Serotonin seems to only DULL aggression by the type 1 receptors; and possibly a couple others - at all other receptors serotonin is largely PRO-AGGRESSIVE.
• Think about neurology and physiology, if you have higher DHT you need to also make sure the noradrenaline rush is kept in check....so augmenting DHT can be as simple as adding something like magnolia or gotu kola.

 

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

 

 

 

Eur J Pharmacol. 2005 Dec 5;526(1-3):125-39. Epub 2005 Nov 28.

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

de Boer SF1, Koolhaas JM.

Author information

 

Abstract

More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the predisposition for and execution of aggressive behavior. The dogmatic view that 5-HT inhibits aggression has dominated both pharmacological research strategies to develop specific and effective novel drug treatments that reduce aggressive behavior and the pharmacological mechanistic interpretation of putative serenic drug effects. Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively. The availability of the novel benzodioxopiperazine compound S-15535, which acts in vivo as a preferential agonist of the somatodendritic 5-HT(1A) auto-receptor and as an antagonist (weak partial agonist) at postsynaptic 5-HT(1A) receptors, allows for a pharmacological analysis of the exact site of action of this anti-aggressive effect. It was found that, similar to other prototypical full and partial 5-HT(1A) and/or 5-HT(1B) receptor agonists like repinotan, 8-OHDPAT, ipsapirone, buspirone, alnespirone, eltoprazine, CGS-12066B and CP-93129, also S-15535 very effectively reduced offensive aggressive behavior. Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.

PMID:   16310183   [PubMed - indexed for MEDLINE]

https://notendur.hi....n_ a review.pdf

 

http://www.ncbi.nlm....pubmed/10869883

Edited by Area-1255, 11 February 2015 - 11:35 AM.

[Plasticperson]

 

I really liked reading through the DHT thread and decided to buy some protodioscin. 1000 mg of 80 precent standardized extract. Stuff has some great benefits like extra confidence and increased muscle mass. The only problem is that after 3 weeks of use I've seriously gone into rage mode.  At first it was great, however, after a while stuff like an increased libidio turned into shut the fuck up and take your clothes off already. I've also noticed that I have this angry fog over my thought process some days. Instead of thinking through a problem, like i usually do, ill get this tendency to throw rage fits until a problem is solved regardless of any collateral damage. It's actually kinda funny sometimes. 

 

Very strong stuff the Trib extracts. Going to try a lower dose and see how things go but the anger and mood problems are no fun. Its seems the supp really pushes the line between increased mood/ confidence and narrow minded rage.

Some of it is a learned trait  - you just gotta channel the "rage"...many times easier said that done - DHT sups and increasing it in general will most certainly make you more serious but also more motivated and confident, however, studies show that serotonin and DHT are technical opposites; and androgens DO NOT promote aggression unless coupled with very low serotonin OR genetically HIGHER serotonin type 2 receptors....OR an overall excess of noradrenaline. Also, Androgens do NOT promote offensive aggression, only defensive (aka getting discredited, or someone attempting to attack you or talk down to you).

 

• Androgen dependent aggression is defensive in nature, and dependent on noradrenaline levels.
• Androgens do not cause any aggression if 5-HT1A/1B (!) (!) are consistently or strictly activated (interestingly these are autoreceptors for serotonin).
• If you have genetically higher levels of serotonin type 2A receptors, you are more prone to aggression - regardless of androgen/estrogen balance.
• Serotonin seems to only DULL aggression by the type 1 receptors; and possibly a couple others - at all other receptors serotonin is largely PRO-AGGRESSIVE.
• Think about neurology and physiology, if you have higher DHT you need to also make sure the noradrenaline rush is kept in check....so augmenting DHT can be as simple as adding something like magnolia or gotu kola.

 

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

 

 

 

Eur J Pharmacol. 2005 Dec 5;526(1-3):125-39. Epub 2005 Nov 28.

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

de Boer SF1, Koolhaas JM.

Author information

 

Abstract

More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the predisposition for and execution of aggressive behavior. The dogmatic view that 5-HT inhibits aggression has dominated both pharmacological research strategies to develop specific and effective novel drug treatments that reduce aggressive behavior and the pharmacological mechanistic interpretation of putative serenic drug effects. Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively. The availability of the novel benzodioxopiperazine compound S-15535, which acts in vivo as a preferential agonist of the somatodendritic 5-HT(1A) auto-receptor and as an antagonist (weak partial agonist) at postsynaptic 5-HT(1A) receptors, allows for a pharmacological analysis of the exact site of action of this anti-aggressive effect. It was found that, similar to other prototypical full and partial 5-HT(1A) and/or 5-HT(1B) receptor agonists like repinotan, 8-OHDPAT, ipsapirone, buspirone, alnespirone, eltoprazine, CGS-12066B and CP-93129, also S-15535 very effectively reduced offensive aggressive behavior. Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.

PMID:   16310183   [PubMed - indexed for MEDLINE]

https://notendur.hi....n_ a review.pdf

 

http://www.ncbi.nlm....pubmed/10869883

 

VERY intriguing 

 

Im homozygous CC at the rs6311 snp which boosts the expression of the 5ht2a receptor and heterozygous CT at the s4654748 receptor which lowers blood vitamin b6 concentrations; vitamin b6 is needed to produce gaba and SEROTONIN. I also have the T allele that lowers the amount of MOA-A  resulting in higher level of norepinephrine. Correct me if I'm wrong but i'm under the impression that norepinephrine and noradrenaline are synonymous. Essentially, I'm the perfect candidate for roid rage.

 

Perhaps these specific levels of neurotransmitters predispose someone to a paranoid/anti-social mindset. This type of mindset would make someone way more weary of people and more DEFENSIVE. Combined with increased androgens this could create a defensive personality prone to anger. 

 

Other than gotu kola and magnolia what else do you think would be helpful in ameliorating the RAGE.. I think forskolin might be helpful because it lowers the 5ht2a induced increase in dopamine d2

Edited by Plasticperson, 11 February 2015 - 10:06 PM.

[Area-1255]

 

 

I really liked reading through the DHT thread and decided to buy some protodioscin. 1000 mg of 80 precent standardized extract. Stuff has some great benefits like extra confidence and increased muscle mass. The only problem is that after 3 weeks of use I've seriously gone into rage mode.  At first it was great, however, after a while stuff like an increased libidio turned into shut the fuck up and take your clothes off already. I've also noticed that I have this angry fog over my thought process some days. Instead of thinking through a problem, like i usually do, ill get this tendency to throw rage fits until a problem is solved regardless of any collateral damage. It's actually kinda funny sometimes. 

 

Very strong stuff the Trib extracts. Going to try a lower dose and see how things go but the anger and mood problems are no fun. Its seems the supp really pushes the line between increased mood/ confidence and narrow minded rage.

Some of it is a learned trait  - you just gotta channel the "rage"...many times easier said that done - DHT sups and increasing it in general will most certainly make you more serious but also more motivated and confident, however, studies show that serotonin and DHT are technical opposites; and androgens DO NOT promote aggression unless coupled with very low serotonin OR genetically HIGHER serotonin type 2 receptors....OR an overall excess of noradrenaline. Also, Androgens do NOT promote offensive aggression, only defensive (aka getting discredited, or someone attempting to attack you or talk down to you).

 

• Androgen dependent aggression is defensive in nature, and dependent on noradrenaline levels.
• Androgens do not cause any aggression if 5-HT1A/1B (!) (!) are consistently or strictly activated (interestingly these are autoreceptors for serotonin).
• If you have genetically higher levels of serotonin type 2A receptors, you are more prone to aggression - regardless of androgen/estrogen balance.
• Serotonin seems to only DULL aggression by the type 1 receptors; and possibly a couple others - at all other receptors serotonin is largely PRO-AGGRESSIVE.
• Think about neurology and physiology, if you have higher DHT you need to also make sure the noradrenaline rush is kept in check....so augmenting DHT can be as simple as adding something like magnolia or gotu kola.

 

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

 

 

 

Eur J Pharmacol. 2005 Dec 5;526(1-3):125-39. Epub 2005 Nov 28.

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

de Boer SF1, Koolhaas JM.

Author information

 

Abstract

More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the predisposition for and execution of aggressive behavior. The dogmatic view that 5-HT inhibits aggression has dominated both pharmacological research strategies to develop specific and effective novel drug treatments that reduce aggressive behavior and the pharmacological mechanistic interpretation of putative serenic drug effects. Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively. The availability of the novel benzodioxopiperazine compound S-15535, which acts in vivo as a preferential agonist of the somatodendritic 5-HT(1A) auto-receptor and as an antagonist (weak partial agonist) at postsynaptic 5-HT(1A) receptors, allows for a pharmacological analysis of the exact site of action of this anti-aggressive effect. It was found that, similar to other prototypical full and partial 5-HT(1A) and/or 5-HT(1B) receptor agonists like repinotan, 8-OHDPAT, ipsapirone, buspirone, alnespirone, eltoprazine, CGS-12066B and CP-93129, also S-15535 very effectively reduced offensive aggressive behavior. Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.

PMID:   16310183   [PubMed - indexed for MEDLINE]

https://notendur.hi....n_ a review.pdf

 

http://www.ncbi.nlm....pubmed/10869883

 

VERY intriguing 

 

Im homozygous CC at the rs6311 snp which boosts the expression of the 5ht2a receptor and heterozygous CT at the s4654748 receptor which lowers blood vitamin b6 concentrations; vitamin b6 is needed to produce gaba and SEROTONIN. I also have the T allele that lowers the amount of MOA-A  resulting in higher level of norepinephrine. Correct me if I'm wrong but i'm under the impression that norepinephrine and noradrenaline are synonymous. Essentially, I'm the perfect candidate for roid rage.

 

Perhaps these specific levels of neurotransmitters predispose someone to a paranoid/anti-social mindset. This type of mindset would make someone way more weary of people and more DEFENSIVE. Combined with increased androgens this could create a defensive personality prone to anger. 

 

Other than gotu kola and magnolia what else do you think would be helpful in ameliorating the RAGE.. I think forskolin might be helpful because it lowers the 5ht2a induced increase in dopamine d2

 

Yes, I have the "Warrior Gene" as well which means I have an elevated norepinephrine count as well as dopamine and serotonin to an extent...though serotonin is on the lower end...kinda where I want it....but I "augment" the noradrenaline by drinking pomegranate and taking magnolia daily.

[Area-1255]

DHT also opposes progesterone - which helps explain why it modulates MAPK to a larger extent than regular testosterone does.

Edited by Area-1255, 13 February 2015 - 08:01 PM.

[Area-1255]

If all androgenic hormones can enhance NMDA, then the only reason they are HPTA inhibitory is from eR-Beta cross-activation.

[mindpatch]

If all androgenic hormones can enhance NMDA, then the only reason they are HPTA inhibitory is from eR-Beta cross-activation.

If generalized anxiety can be associated with increased expression at the NMDA level and possible glutamate excitotoxicity, would exogenous TRT alter the NMDA/GABA balance?  I'm currently taking Memantine, which has helped me with anxiety.  

[Area-1255]

 

If all androgenic hormones can enhance NMDA, then the only reason they are HPTA inhibitory is from eR-Beta cross-activation.

If generalized anxiety can be associated with increased expression at the NMDA level and possible glutamate excitotoxicity, would exogenous TRT alter the NMDA/GABA balance?  I'm currently taking Memantine, which has helped me with anxiety.  

 

NMDA doesn't necessarily cause anxiety - in itself, the activation of it actually helps rid fears by increasing fear memory and "fear extinction memory".

The problem comes from excess of glutamate at other receptors, which basically makes NMDA activation useless or NMDA triggers further neuro-toxicity but only because of additive effects; including the addition of more calcium channel mediated voltage issues.

http://www.longecity...6-nmda-agonist/

NMDA antagonist neurotoxicity

 

NMDA activation WITHOUT excess glutamate at other receptors is actually a very good thing - especially for cognitiion, GLUTAMATE is also essential for normal heart beat rhythms, libido, and for cellular energy production...

 

Neuron. 2007 Mar 15;53(6):871-80.

Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex.

Burgos-Robles A1, Vidal-Gonzalez I, Santini E, Quirk GJ.

Author information

 

Abstract

Extinction of conditioned fear is an active learning process requiring N-methyl-D-aspartate receptors (NMDARs), but the timing, location, and neural mechanisms of NMDAR-mediated processing in extinction are a matter of debate. Here we show that infusion of the NMDAR antagonist CPP into the ventromedial prefrontal cortex (vmPFC) prior to, or immediately after, extinction training impaired 24 hr recall of extinction. These findings indicate that consolidation of extinction requires posttraining activation of NMDARs within the vmPFC. Using multichannel unit recording, we observed that CPP selectively reduced burst firing in vmPFC neurons, suggesting that bursting in vmPFC is necessary for consolidation of extinction. In support of this, we found that the degree of bursting in infralimbic vmPFC neurons shortly after extinction predicted subsequent recall of extinction. We suggest that NMDAR-dependent bursting in the infralimbic vmPFC initiates calcium-dependent molecular cascades that stabilize extinction memory, thereby allowing for successful recall of extinction.

 

Edited by Area-1255, 27 February 2015 - 02:48 AM.

[Area-1255]

Another thing to remember is the 5-HT1A serotonin receptor - I call it the "charlatan" of serotonin receptors...you get benefits from stimulating it, and you get benefits from antagonizing it, you get downsides either way, LOL.

 

It's also the main serotonin receptor involved in inhibiting NMDA receptor function and it also is considered the "main" autoreceptor. 

Paradoxically, it's the autoreceptor part of it that has the most significance in depression and anxiety...but the post-synaptics seem to inhibit memory function, declarative and retention.