37 replies to this topic

[Jbac]

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.

Where did you read that SSRIs reduce cAMP in the NAcSh and that this reduction shows clinical benefits? This study say the opposite:

http://www.ncbi.nlm....ubmed/19151710/
summary: social isolation lowers cAMP in NAcSh --> anxiety and anhedonia, antidepressants reverse it

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.

That link doesn't cite a source on the claim that antidepressants normalize both high and low cAMP.

I get that you're saying that both high and low cAMP in the NAc is a bad thing and antidepressants fix both cases, but I can't find evidence for the claim that high cAMP is bad and antidepressants lower it, only the opposite case.

Edited by Jbac, 06 April 2014 - 11:25 PM.

[formergenius]

While on the topic of CREB, I'd like to point out that CREM may be an interesting target for future investigation.
Back to LY2 though: $6k for 1g.. Sorry for being lazy, but what's the dose used in humans? I.E. how does it translate to price per day?

[VERITAS INCORRUPTUS]

While on the topic of CREB, I'd like to point out that CREM may be an interesting target for future investigation.
Back to LY2 though: $6k for 1g.. Sorry for being lazy, but what's the dose used in humans? I.E. how does it translate to price per day?

My post above notes clinical trial for LY2 will have 10mg/d and 20mg/day arms.

[VERITAS INCORRUPTUS]

Companions reverse stressor-induced decreases in neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in dentate gyrus.

http://www.ncbi.nlm....pubmed/22832183

[Steve Zissou]

Found this

 

http://www.ncbi.nlm....pubmed/24641310

 

Pharmacology and anti-addiction effects of the novel kappa opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. BACKGROUND AND PURPOSE:

Acute activation of kappa opioid receptors (KOPr) results in anti-cocaine like effects, but adverse effects such as dysphoria, aversion, sedation and depression limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogs have been shown to have potent KOPr agonist activity and may induce a unique response with similar anti-cocaine addiction effects as the classic KOPr agonists but with a different side effect profile.

EXPERIMENTAL APPROACH:

We evaluated the duration of effects of Mesyl Sal B in vivo utilising anti-nociception assays and screened cocaine-prime induced cocaine-seeking behavior in self-administering rats to predict anti-addiction effects. Utilising cellular transporter uptake assays and in vitro voltammetry we investigate the ability of Mesyl Sal B to modulate dopamine transporter (DAT) function and investigate transporter trafficking and kinase signaling pathways modulated by KOPr agonists.

KEY RESULTS:

Mesyl Sal B has a longer duration of action than SalA, has anti-addiction properties and increased DAT function in vitro in a KOPr receptor dependent and PTX sensitive manner. These effects on DAT function require ERK1/2 activation. We identify differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering DAT cell-surface expression.

CONCLUSIONS AND IMPLICATIONS:

These findings show that SalA analogues, such as Mesyl Sal B have potential for development as anti-cocaine agents. Further tests are warranted to explain the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOPr ligands produce both anti-addiction and adverse side effects.

 

 

Really fascinating research this. Explains some of the positive long term effects I've had using low dose salvia extract.

 

 

[addx]

Where did you read that SSRIs reduce cAMP in the NAcSh and that this reduction shows clinical benefits? This study say the opposite:

http://www.ncbi.nlm....ubmed/19151710/
summary: social isolation lowers cAMP in NAcSh --> anxiety and anhedonia, antidepressants reverse it

 

 

Yea, you're right, I guess I confused where and what, I just remembered that SSRI effectivness is timed with its ability to influence CREB, not really sure which direction and where it seems..

 

 

There's a few research links that are of interest for this discussion, involvment of CREB in mood and connection to antidepressant action - from one of many David Pearces webs - http://www.biopsychiatry.com/creb.htm

 

I read all of those before, but didnt remember the details I guess

 

 

[VERITAS INCORRUPTUS]

Found this

 

http://www.ncbi.nlm....pubmed/24641310

 

Pharmacology and anti-addiction effects of the novel kappa opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. BACKGROUND AND PURPOSE:

Acute activation of kappa opioid receptors (KOPr) results in anti-cocaine like effects, but adverse effects such as dysphoria, aversion, sedation and depression limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogs have been shown to have potent KOPr agonist activity and may induce a unique response with similar anti-cocaine addiction effects as the classic KOPr agonists but with a different side effect profile.

EXPERIMENTAL APPROACH:

We evaluated the duration of effects of Mesyl Sal B in vivo utilising anti-nociception assays and screened cocaine-prime induced cocaine-seeking behavior in self-administering rats to predict anti-addiction effects. Utilising cellular transporter uptake assays and in vitro voltammetry we investigate the ability of Mesyl Sal B to modulate dopamine transporter (DAT) function and investigate transporter trafficking and kinase signaling pathways modulated by KOPr agonists.

KEY RESULTS:

Mesyl Sal B has a longer duration of action than SalA, has anti-addiction properties and increased DAT function in vitro in a KOPr receptor dependent and PTX sensitive manner. These effects on DAT function require ERK1/2 activation. We identify differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering DAT cell-surface expression.

CONCLUSIONS AND IMPLICATIONS:

These findings show that SalA analogues, such as Mesyl Sal B have potential for development as anti-cocaine agents. Further tests are warranted to explain the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOPr ligands produce both anti-addiction and adverse side effects.

 

 

Really fascinating research this. Explains some of the positive long term effects I've had using low dose salvia extract.

 

 

Beta arrestins appears to create the adverse effects as seen with Salvinorin A and likely other cogeners.  The downfall with their use in any rational application is this factor.  Though low dosing of such agonists may avoid the adverse effects (not significantly induce the arrestins cascade) and promote an improvement in kappa tone to promote an antidepressant effect in a similar manner to an antagonist at the KOR.  This cogener in the study would be perceived to have greater therapeutic potential due to its longer duration of action  (and perhaps some oral bioavailability).

Edited by VERITAS INCORRUPTUS, 08 April 2014 - 03:22 PM.

[Strangelove]

Generating interest for a Kor antagonist group buy.

 

http://www.longecity...p-buy/?p=731745