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LY2456302: KOR antagonist tested in humans - Alternative to JDTic?

jdtic kor kappa ly2456302

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#1 formergenius

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Posted 04 April 2014 - 03:20 AM


I was just checking whether there were any developments on KOR antagonism applied to humans.
This was only published a few days ago.

Most importantly perhaps:

LY2456302 doses were well-tolerated with no clinically significant findings. No safety concerns were seen on co-administration with ethanol.


edit: To clarify; it's orally bioavailable.

Edited by formergenius, 04 April 2014 - 03:26 AM.

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#2 datrat

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Posted 04 April 2014 - 04:00 AM

Great find!

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#3 socialpiranha

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Posted 04 April 2014 - 04:55 AM

nice ! ly is eli lilly isn't it? I'm guessing it's their phase 1 bipolar disorder candidate

Edited by socialpiranha, 04 April 2014 - 05:01 AM.


#4 formergenius

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Posted 04 April 2014 - 10:01 AM

Thanks datrat. Yes socialpiranha, I believe so. No clue whether that's their bipolar candidate; I'm assuming considering the co-administration of ethanol, that it is intended for alcohol addiction treatment.
Regardless, I'd very much like to try it. I wonder if at all it could be significantly cheaper than JDTic?

#5 addx

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Posted 04 April 2014 - 10:34 AM

Nice!

I think they should try playing around with arrestins and kappa opioid antagonist. Arrestins modulate resulting effects from kappa opioid receptor activation inside the cell, I think there are 3 possible pathways and combinations, depending on arrestin presence and I think also the opioid peptide ligand in play, I think one pathway internalizes the receptor.

Also mu-kappa heterodimers also seem interesting. I've seen a study claiming that female pain resistance is due to a larger number of mu-kappa receptor complexes, I think they postulated that the function of mu-opioid receptor in the complex is to antagonize the dyshporic kappa opioid effects while combining with the analgesic effect of both.

Edited by addx, 04 April 2014 - 10:37 AM.


#6 addx

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Posted 04 April 2014 - 02:55 PM

http://www.ncbi.nlm....pubmed/24690494



The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.



I want to see the depression research!


A more general description

http://www.ncbi.nlm....pubmed/24071566

Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t(max): 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED₅₀ = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.


Sounds good!

Edited by addx, 04 April 2014 - 02:58 PM.

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#7 celebes

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Posted 05 April 2014 - 05:55 AM

1 day half-life isn't bad.

#8 neuroatypicow

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Posted 06 April 2014 - 01:08 AM

do any of the full-text papers give its structure?
apart from being possibly less toxic than JDTic may have turned out to be, isn't this a step backwards? don't we WANT a long-acting antagonist, to maximize cost-effectiveness and lessening of potential for cumulative side effects?

#9 addx

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Posted 06 April 2014 - 01:20 AM

Here's the thing that bothers me with kappa opioid receptors.

http://www.ncbi.nlm....les/PMC3727639/

Agonist-activated KOR becomes a substrate for G protein receptor kinase (GRK), which phosphorylates the Ser369 residue at the C-terminal tail of the receptor in the first step in the β-Arrestin-dependent desensitization cascade. Through the use of phospho-selective antibodies developed and validated in the laboratory, we have the tools, to assess with fine cellular resolution, the strength of behavioral stimulus required for release, time course of the release, and regional location of release. We have gone on to show that following KOR activation, both ERK 1/2 and p38 MAP kinase phosphorylation are increased through use of commercially available phospho-selective antibodies. Finally, we have identified that one effector of KOR/p38MAP kinase is KIR 3.1 and have developed a phospho-selective antibody against the Y12 motif of this channel. Much like KOR and p38 MAP kinase, phosphorylation of this potassium channel increases following repeated stress.



I have seen that different endogenous ligands activate different pathways and also in combination with arrestin presence as depicted above.

​There's also the notorious U curve displayed by most opioidergic intervention.

#10 celebes

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Posted 06 April 2014 - 01:29 AM

isn't this a step backwards? don't we WANT a long-acting antagonist, to maximize cost-effectiveness and lessening of potential for cumulative side effects?


It could have been a lot worse, they might have gone for something that's out of the system after 24 hours. Also something with the potential to permanently normalise KOR levels with one dose is never, ever going to come to market. Eli Lilly isn't in the 'cure' business.

#11 neuroatypicow

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Posted 06 April 2014 - 02:28 AM

i agree with everything you wrote, the whole situation is disillusioning.
I'm just perplexed by what's going on with JDTic, how everyone who has gotten a hold of JDTic has reported prohibitive side effects, EXCEPT for that ooonnnneeeee guy, the writer. and yet we supposedly got our hands on some of the same substance from the same source, and no one can tolerate it. 2 out of 6 of the human trial participants had trial-ending v-tach, and yet all the literature on the stuff went on and on about how well-tolerated it was,
and then all of a sudden, it's pharmacy-non-grata. what happened? and how can we know if ly2456302 isn't the same? do we know what the size of the test cohort was, and the duration?
if this is a viable alternative(i hope so, i really do), and if it performs well, would we not expect that, in the absence of reinforcing stressors or re-occurrence of adverse life-events, that once normalized, the antagonized Kappa receptors would stay that way, becoming de facto permanent?
i mean, i'm messed up because i'm messed up, not because i'm continually dealing with deaths, social pressures, early childhood traumas, poverty, etc...
i'm in a supportive stable environment, in otherwise good health, and can intellectualize my past traumas in therapy. wouldn't this undo the primal state 'programming'? if so, then what could the mechanism be for recreating these associations (even assuming a re-agonization of the KORs?)
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#12 celebes

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Posted 06 April 2014 - 03:03 AM

would we not expect that, in the absence of reinforcing stressors or re-occurrence of adverse life-events, that once normalized, the antagonized Kappa receptors would stay that way, becoming de facto permanent?


That's the idea. But it would be a gradual process whereas knocking receptors out should be rapid and definitive. That is assuming JDTic actually does that and it's not just a misconception that cropped up.
And then there is the possibility of kappa upregulation. Buprenorphine for instance does it at 8mg but not at 2mg, both clinical doses.


wouldn't this undo the primal state 'programming'? if so, then what could the mechanism be for recreating these associations (even assuming a re-agonization of the KORs?)


Epigenetic changes. HDACi has promise at neutralising them.

#13 neuroatypicow

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Posted 06 April 2014 - 03:31 AM

ah, i see, thanks.
swell. i fix the hardware, then i'm going to have to talk my genes down off a ledge.
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#14 Steve Zissou

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Posted 06 April 2014 - 06:42 AM

Can someone explain to me why antagonists of the kappa opiod recepters are more favourable than agonists?

#15 addx

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Posted 06 April 2014 - 12:00 PM

Agonism is dysphoric and degrading to the cell in some circumstances. Look at the link I provided, they actually elucidated which circumstances.

The issue with any agonist/antagonist is that presynaptic neurones usually have an opposite effect than postsyntaptic neurones.

I think the issue with opioids is also a multilevel one. I believe opioids in combination with serotonin and dopamine create a layered processing structure in the brain. The emotions of an animal cause subconscious drives which numb pain if need be to be carried out, I think this is facilitated by opioids, higher animals can supress subconscious drives for conscious actions, I do believe the lower drive is "anaesthetised" by opioids to provide a higher conscious drive(PFC). In higher mammals the conscious drive can also be suppressed by "awareness"(vmPFC i think) which may in fact again be regulated by opioids. Each layer may use opioids to supress the "less articulated/thought through" action of the lower layer in order to produce a "smarter" action of the higher evolved layer.

So I believe this is why flooding receptors with opioids gets all kinds of results. I believe the U shape curve is in fact a result of drug working one layer and then a higher dose engage two layers of which the upper one suppresses the lower one creating U type response or something like that. Same thing to be expected with a antagonist I guess.

Edited by addx, 06 April 2014 - 12:02 PM.


#16 addx

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Posted 06 April 2014 - 02:31 PM

Here's the important part:

http://www.ncbi.nlm....les/PMC3096840/

Stress triggers psychiatric conditions including depressive and anxiety disorders. The mechanisms by which stress produces persistent changes in behavior are not fully understood. Here we show in rats that stress (footshock) activates the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens shell (NAS), a brain area involved in encoding reward and aversion. To examine the behavioral significance of altered CREB function in the NAS, we used viral vectors to elevate or disrupt CREB in this region. Elevated CREB produced increases in intracranial self-stimulation (ICSS) thresholds, a depressive-like sign reflecting anhedonia (decreased sensitivity to reward), whereas disruption of CREB function by expression of a dominant negative CREB had the opposite effect. To determine if neuroadaptations that produce anhedonia subsequently affect vulnerability to stress-induced behavioral adaptations, we subjected rats with altered CREB function in the NAS to fear conditioning. While neither elevation nor disruption of CREB function altered the development of conditioned fear, elevation of CREB impaired extinction of conditioned fear. To mimic downstream effects of CREB activation on expression of the opioid peptide dynorphin, we microinjected the kappa-opioid receptor (KOR) agonist U50,488 directly into the NAS. KOR stimulation produced anhedonia but had no effect on expression or extinction of conditioned fear. These findings demonstrate that activation of CREB in the NAS produces multiple behavioral signs (anhedonia, impaired extinction) characteristic of experience-dependent psychiatric conditions such as post-traumatic stress disorder (PTSD). Although CREB activation is a common trigger, expression of these individual signs appears to involve divergent downstream mechanisms.




This is very in line with experience from SSRIs whose clinical benefits after the initial 2-3 weeks are marked by reversal of CREB in the hippocampus. CREB in the hippocampus increases prodynorphin gene expression and I believe KOR gene expression as well. These KORs directly inhibit dopamine in mesolimbic circuits. This is what needs to be antagonised for anhedonia. Flooding the entire CNS may not have the desired consequences.

​I doubt depersonalisation for example has the same pattern although it is possible that KORs are implicated in facilitating it as well.

Anxiety and fear behaviour expression seems related to amygdala KOR functioning as can be seen here

http://www.ncbi.nlm....pubmed/21531393

Edited by addx, 06 April 2014 - 02:38 PM.

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#17 neuroatypicow

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Posted 06 April 2014 - 03:41 PM

thanks for that, it clarifies the mechanisms for me a bit more. this is fascinating, albeit exasperatingly complicated, stuff.

#18 socialpiranha

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Posted 06 April 2014 - 05:24 PM

i'm not sure if the research has been done on ssri's but i know for sure some tricyclics such as desipramine have been shown to reduce stress induced creb phosphorylation in the nucleus accumbens. Unfortunately it's been taken off the market.

#19 addx

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Posted 06 April 2014 - 05:35 PM

Yea, nucleus accumbens, not hippocampus, sorry, dunno why I wrote that.

All SSRI show clinical benefits only as CREB gets reduced in NAS AFAIK. This is infact what's anti depressive about SSRIs. Pushing serotonin gets CREB cycle reduced in NAS in most cases. If it doesn't the AD doesn't work pretty much.


This URL explains it nicely

http://neuroscience....dchromatin.html


It also explains that low CREB in NAS actually causes anxiety and is invoked by prolonged social isolation.
It states ADs can usually normalise both states.

Edited by addx, 06 April 2014 - 05:37 PM.


#20 addx

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Posted 06 April 2014 - 05:52 PM

http://www.ncbi.nlm....pubmed/12740400

Kappa opioid receptor activation in the nucleus accumbens inhibits glutamate and GABA release through different mechanisms.

#21 VERITAS INCORRUPTUS

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Posted 06 April 2014 - 06:26 PM

On duration of action and other facets of kappa antagonists.

Long-acting KOR antagonists including norBNI, JDTic, and GNTI fail to evoke Gbg signaling typical of KOR agonists, but do initiate a Protein Kinase C (PKC) cascade resulting in C-Jun N-terminal Kinase (JNK) activation. Inhibition of PKC by Go6976 blocked norBNI increase in phospho-JNK-ir, and inhibition of JNK by SP600125 or gene deletion of JNK1 isoform blocked the long duration of norBNI antagonism. The JNK phosphorylation site has been localized to the KOR signaling complex, and ongoing site-directed mutagenesis are being used to determine the regulatory site within KOR. Short acting antagonists (e.g. naloxone and buprenorphine) failed to activate PKC/JNK regulation of KOR

http://www.nature.com/npp/journal/v38/n1s/full/npp2012218a.html
(This study as a whole has excellent insights into kappa regulation and the profound impact of the determination of what appears determined strictly arrestin-2 mediated aversive effects of kappa agnonism - well worth the full read with the free full text)

Other great supporting studies:
http://www.ncbi.nlm....d?term=20401607
http://www.jbc.org/c...37332.full.html
http://molpharm.aspe...074195.full.pdf

They are looking to assess LY2 (recommending to abrreviate this one here, LOL) at 10mg and 20mg. The ED50 would seem to indicate potentially a lower dose may be efficacious, perhaps <5mg, though I am certain they have their reasons for these clinical arms for once per day oral dosing.
http://clinicaltrial...how/NCT01913535

One quote I was able to receive for LY2 was at ~$6000/gram.

Pretty impressive portfolio for MOR-mediated analgesia, et. al. sans the negative impact of arrestin induction prevalent with most all existing MOR agonist analgesics; as well as as below the potential for partial KOR agonist activation that does not induce aversive effects within a lack of arrestin-2 induction:
http://www.trevenain...-howitworks.php
http://www.trevenain...eline-kappa.php

Notice how important arrestin involvement is within adverse effects of both MOR and KOR expression.

Edited by VERITAS INCORRUPTUS, 06 April 2014 - 06:34 PM.


#22 VERITAS INCORRUPTUS

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Posted 06 April 2014 - 08:03 PM

http://neuroscience....dchromatin.html
It also explains that low CREB in NAS actually causes anxiety and is invoked by prolonged social isolation.
It states ADs can usually normalise both states.


Does social isolation induce increased KOR/dynorphin expression or exactly what does social isolation trigger?

I'd say it certainly does as a big factor in promoting a KOR-dysregulated/diseased state (reflected in intense pro-depressive and anxiogenic tone)

Interesting for a phenomena that seem so much a 'mild chronic' tonic nature, opposed to more acute, or even chronic, more seemingly severe impact situations.

Notice how once this all transpires the 'habitutated potentiation' creates such a severe sensitivity to inducing anxiety and depression. It can so feed itself, especially within social isolation, which would appear to negates both an escape from 'oneself' and a promotion of the vicious cycle, as well as the positive pathways that are elicited through even simple social interaction, that could enable a positive cascade to balance out the negative cascades.

Indeed, we are intended to be social creatures.

Also one of the reason there can be a craving/need to be with a 'partner'...particularly for those who otherwise are generally not inclined to significant social interaction...

Edited by VERITAS INCORRUPTUS, 06 April 2014 - 08:13 PM.

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#23 addx

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Posted 06 April 2014 - 08:19 PM

Social isolation causes low CREB in NAS meaning.

If high CREB causes high KOR/dynorphin expression than low CREB should be opposite.

I read this as KOR numbs social anxiety into social anhedonia.

Social isolation probably "forgets" the emotional element of social fears since they're not triggered often which probably allows for raw serotonergic social anxiety facilitated by lack of KORs.

Which then grows KORs to numb if triggered often I guess via CREB cycle. Abundance of KOR then provides a tone of anhedonia rather than anxiety. Lack of KORs seem to provide anxiety.

Just guessing...

Edited by addx, 06 April 2014 - 08:21 PM.

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#24 addx

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Posted 06 April 2014 - 08:27 PM

NAS is infact a mammalian construct meaning all success and failure is bound to social status. (this may come as a surprise to many). A mammal can succeed only if there is another mammal that can gain from it. This is altruism hardwired into brains. A human must show off his success to others in order to cause envy(that causes desire to beat - evolutionary selection mechanisms) or to cause learning of those who do not compete. If either is caused success is made. Infact the human is forced to demonstrate his new acquired knowledge or skill either by teaching of performing it. A human can not stop "motivation" until he proves something and it gets validated by others. This ensures that useful knowledge(considered useful by the creator of it) gets shared with the group. Infact the idea of sharing it or using it against the group or getting envy of the group is the only motivating factor of our brains besides the basic urges.

Without other people humans can only be motivated to upkeep.

Edited by addx, 06 April 2014 - 08:29 PM.

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#25 VERITAS INCORRUPTUS

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Posted 06 April 2014 - 08:51 PM

These two herbal studies seem to contradict each other as relates to activity at DOR for epicatechin which makes me speculate into how meritorious the kappa antagonist study on flavonoids actually is:
http://www.ncbi.nlm....93/#!po=21.4286 Flavonoid study on KOR antagonism
http://www.ncbi.nlm....les/PMC2993198/ Epicatechin - DOR agonist mediated effect
(I doubt DOR stimulation could have been some downstream effect...?)

Flavonoid study has low picolmolar Ke for JDTic...not sure if this is supported elsewhere offhand. Indeed it is potent.
Ke in that study for the most potent natural flavonoid compounds are noted 4 orders of magnitude less potent...hmmm...though they still have respectable moderate nM Ke as reported (in contrast though again to low picomolar for the two synthetic long-acting KOR antagonists).

Catechin and amentoflavone might seem promising, if not for some of these factors that appear to make such less potentially successful to engage.

There is a study for the antidepressant effect of Camellia senensis, which regarding (+)-catechin that which was displayed of the flavonoids to have th second most significant antagonist KOR activity at 320nM. It is shown to be orally bioavailable (though not highly) and does cross the BBB as seen in a recent study. Half-life is ~3-4 hours.
http://www.ncbi.nlm....pubmed/10617953 (half-life)
www.ncbi.nlm.nih.gov/pubmed/21773584 (BBB study)

I still highly feel it would be really interesting to see JDTic get trialed in enough number to really get an understanding of the compound and its impact on KOR(JNK1) in this 'KOR crushing' manner (lol) and the resulting effect. Unfortunately, that will not be seen in any clinical setting it appears, and perhaps not otherwise :( A quote I received from a respectable U.S. based research chem supplier was about $2500USD for 250mg; one advantage to hobbyist research costs is the potency is cost effective for dosing your mice or rats.

Though there is a note of one anecdotal report, there are actually two. The jdtic.com report where 100mcg EOD created highly positive effects, though after using 1mg+ dosing for days prior it appears that may skew the bio-assay, and the kappazappa report where 2mg/day was used seemingly successfully.

If the clinical for JDTic that removed this from the pipeline simply used a dose that was higher than necessary, lower dosing may have avoided the v-tach seen in the 2 of 6 in the trial. We may never know. :(

I do not think there will be a U-curve response from KOR antagonists, but extrapolate more research to come to any conclusion that is more solid than a hypothetical speculation.

Edited by VERITAS INCORRUPTUS, 06 April 2014 - 08:55 PM.


#26 VERITAS INCORRUPTUS

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Posted 06 April 2014 - 09:05 PM

NAS is infact a mammalian construct meaning all success and failure is bound to social status. (this may come as a surprise to many). A mammal can succeed only if there is another mammal that can gain from it. This is altruism hardwired into brains. A human must show off his success to others in order to cause envy(that causes desire to beat - evolutionary selection mechanisms) or to cause learning of those who do not compete. If either is caused success is made. Infact the human is forced to demonstrate his new acquired knowledge or skill either by teaching of performing it. A human can not stop "motivation" until he proves something and it gets validated by others. This ensures that useful knowledge(considered useful by the creator of it) gets shared with the group. Infact the idea of sharing it or using it against the group or getting envy of the group is the only motivating factor of our brains besides the basic urges.

Without other people humans can only be motivated to upkeep.


Indeed.
Again, our internal well-being is very heavily tied to our social interactions or lack thereof.
We largely require others intrinsically to reflect back in some manner that which we engage upon ourselves beside simply basic 'upkeep' itself, or we diminish severely as to heightened proneness to dysfunctional states within such isolation.

I do not perceive it is quite as 'absolute' as you are relating such, but it is of very high significance. There is a good deal that one can touch on here, and I do not want to overly derail the thread...this could all get very philosophical as well ;)

Edited by VERITAS INCORRUPTUS, 06 April 2014 - 09:07 PM.


#27 Jbac

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Posted 06 April 2014 - 09:18 PM

Indeed.
Again, our internal well-being is very heavily tied to our social interactions or lack thereof.We largely require others intrinsically to reflect back in some manner that which we engage upon ourselves beside simply basic 'upkeep' itself, or we diminish severely as to heightened proneness to dysfunctional states within such isolation.




Yet another gem from Veritas Incorruptus. It's true that we largely require others intrinsically to reflect back in some manner that which we engage upon ourselves beside simply basic 'upkeep' itself, or we diminish severely as to heightened proneness to dysfunctional states within such isolation. Brilliant.

Edited by Jbac, 06 April 2014 - 09:26 PM.

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#28 addx

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Posted 06 April 2014 - 09:26 PM

I believe a human is motivated by detecting a chance to acquire control of social resources. This is done by the NAS.

For this a human must have a "notion" of social "values"(resources) which is refreshed through socialising.

A human can be motivated by empathy when there is no perceived threat or possibility to control of valued social resources. This schema however is probably not a part of NAS.

#29 VERITAS INCORRUPTUS

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Posted 06 April 2014 - 09:43 PM

CREB/KOR:
CREB reduction acts in a similar manner to KOR antagonists of course within there is an inhibition of dynorphin expression, via directly reducing dynorphin levels and by inhibiting dynorphin from to engaging KOR, respectively.

Exactly in what manner does CREB impair extinction of fear, which is apparently not directly regulated by KOR? What would be the most effective manner to directly inhibit CREB and/or inhibit whatever downstream factor is at play to cause an impairment of fear extinction.

With those in chronic states of anxiety and depression both CREB and KOR are likely highly dysregulated.

Desipramine acts rapidly on depression, which is likely mediated via a pathway other than its reuptake inhibition. Apparently as noted herein by acting in a different manner than other conventional ADs within CREB regulation:
http://www.ncbi.nlm..../pubmed/7603449 Desipramine had no effect on transcription after stimulation by cAMP but blocked the synergistic effect of cAMP and membrane depolarization to the level of stimulation by cAMP alone. Upon membrane depolarization, desipramine reduced the phosphorylation of CREB at Ser-119 and also blocked the depolarization-induced increase in the intracellular free Ca2+ concentration in HIT cells

Some more food for thought if anyone is interested to click:
http://www.jneurosci...6/1855.full.pdf
http://pubmedcentral...les/PMC2740476/
psychcentral.com/news/2007/09/07/a-fast-acting-antidepressant/1246.html (5HT4 agonist showed rapid antidepressant effects, perhaps insight into more directed serotonergic pathways to reducing CREB)

Edited by VERITAS INCORRUPTUS, 06 April 2014 - 10:27 PM.


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#30 formergenius

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Posted 06 April 2014 - 10:00 PM

CREB/KOR:
CREB reduction acts in a similar manner to KOR antagonists of course within there is an inhibition of dynorphin expression, via directly reducing dynorphin levels and by inhibiting dynorphin from to engaging KOR.

Yes, though it seems to be a localized effect. I wrote about this on another forum: "Why not to use the CILTEP stack", if you're interested. Just some crude notes really though.

edit: to quote from "The many faces of CREB":

The transcription factor CREB is best known for its involvement in learning and memory. However, emerging evidence suggests that CREB activity has very different roles--sometimes beneficial, sometimes detrimental--depending on the brain region involved. Induction of CREB in the hippocampus by antidepressant treatments could contribute to their therapeutic efficacy. By contrast, activation of CREB in the nucleus accumbens and several other regions by drugs of abuse or stress mediates certain aspects of drug addiction, and depressive and anxiety-like behaviors. These complexities suggest that strategies that exploit regional differences in upstream factors or that target specific CREB-regulated genes, rather than CREB itself, could make a promising contribution to the treatment of neuropsychiatric conditions.


Edited by formergenius, 06 April 2014 - 10:02 PM.






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