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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 9 of 9. This is the beginning of the thread.
Posted by linkadge on February 15, 2009, at 7:15:42
Hi, I am reading that sertraline has high affinity for the sigma receptors, but cannot determine whether this is an agonist or antagonist effect.
Linkadge
Posted by SLS on February 15, 2009, at 7:48:51
In reply to Sertraline + sigma agonist or antagonis?, posted by linkadge on February 15, 2009, at 7:15:42
> Hi, I am reading that sertraline has high affinity for the sigma receptors, but cannot determine whether this is an agonist or antagonist effect.
I can't speak to sertraline, but fluvoxamine is an agonist at sigma-1 receptors. I can't provide the link, but:
1: PLoS ONE. 2008 Jul 2;3(7):e2558.Click here to read Click here to read Links
Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways.
Nishimura T, Ishima T, Iyo M, Hashimoto K.Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have been widely used and are a major therapeutic advance in psychopharmacology. However, their pharmacology is quite heterogeneous. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC 12 cells. However, the precise cellular and molecular mechanisms underlying potentiation by fluvoxamine are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists. METHODS AND FINDINGS: The effects of three SSRIs (fluvoxamine, sertraline, paroxetine) and three sigma-1 receptor agonists (SA4503, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), and dehydroepiandrosterone (DHEA)-sulfate) on NGF-induced neurite outgrowth in PC12 cells were examined. Also examined were the effects of the sigma-1 receptor antagonist NE-100, inositol 1,4,5-triphosphate (IP(3)) receptor antagonist, and specific inhibitors of signaling pathways in the potentiation of NGF-induced neurite outgrowth by selective sigma-1 receptor agonist SA4503. Fluvoxamine (but not sertraline or paroxetine) and the sigma-1 receptor agonists SA4503, PPBP, and DHEA-sulfate significantly potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. The potentiation by fluvoxamine and the three sigma-1 receptor agonists was blocked by co-administration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptors play a role in blocking the enhancement of NGF-induced neurite outgrowth. Moreover, the potentiation by SA4503 was blocked by co-administration of the IP(3) receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-gamma), phosphatidylinositol 3-kinase (PI3K), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways blocked the potentiation of NGF-induced neurite outgrowth by SA4503. CONCLUSION: These findings suggest that stimulation of sigma-1 receptors and subsequent interaction with IP(3) receptors, PLC-gamma, PI3K, p38MAPK, JNK, and the Ras/Raf/MAPK signaling pathways are involved in the mechanisms of action of sigma-1 receptor agonists such as fluvoxamine and SA4503.
PMID: 18596927 [PubMed - indexed for MEDLINE]
Posted by SLS on February 15, 2009, at 7:53:24
In reply to Re: Sertraline + sigma agonist or antagonis? » linkadge, posted by SLS on February 15, 2009, at 7:48:51
You might want to take a look at this. It speaks to something you said a few days ago, and is relevant to sertraline in particular.
- Scott
Posted by SLS on February 15, 2009, at 7:56:17
In reply to Re: Sertraline + sigma agonist or antagonis? » SLS, posted by SLS on February 15, 2009, at 7:53:24
Here you go, Linkadge:
http://en.wikipedia.org/wiki/Sertraline
"Mechanism of action
Sertraline is primarily a serotonin reuptake inhibitor (SRI). Therapeutic doses of sertraline (50200 mg/day) taken by patients for four weeks resulted in 8090% inhibition of serotonin transporter (SERT) in striatum as measured by positron emission tomography. A daily 9 mg dose was sufficient to inhibit 50% of SERT.[148] Sertraline is also a dopamine reuptake inhibitor, with 1% of its SRI potency,[149] and a sigma-1 receptor agonist with 5% of its SRI potency.[150] Sertraline weakly blocks α1-adrenoreceptors with 110% of its SRI potency.[149][151]"
- Scott
Posted by linkadge on February 15, 2009, at 8:37:14
In reply to Re: Sertraline + sigma agonist or antagonis?, posted by SLS on February 15, 2009, at 7:56:17
Thanks,
I read the wikipedia however and although the body of the article suggests that sertraline is an agonist, the referene they provide for this only suggests affinity, it does not mention agonist.
Linkadge
Posted by SLS on February 15, 2009, at 9:16:20
In reply to Re: Sertraline + sigma agonist or antagonis?, posted by linkadge on February 15, 2009, at 8:37:14
> Thanks,
>
> I read the wikipedia however and although the body of the article suggests that sertraline is an agonist, the referene they provide for this only suggests affinity, it does not mention agonist.
>
> Linkadge
Maybe you can look for something that indicates that sertraline increases NGF. That would probably mean that it is acting as an agonist.
- Scott
Posted by SLS on February 15, 2009, at 11:19:54
In reply to Re: Sertraline + sigma agonist or antagonist?, posted by SLS on February 15, 2009, at 9:16:20
According to Stephen Stahl, sertraline has mild antagonist actions at sigma receptors. Furthermore, sertraline does not potentiate NGF induced neurite growth, indicating that it is not an agonist. On the other hand, fluvoxamine is a fairly potent agonist.
- Scott
Posted by desolationrower on February 16, 2009, at 1:47:48
In reply to Re: Sertraline + sigma agonist or antagonist?, posted by SLS on February 15, 2009, at 11:19:54
i'm pretty sure it is an antagonist; i found it the worst of the sris i tried and spent a while looking for its action at the sigma receptors. i didn't record the pmid though.
-d/r
Posted by linkadge on February 16, 2009, at 10:48:19
In reply to Re: Sertraline + sigma agonist or antagonist?, posted by desolationrower on February 16, 2009, at 1:47:48
Interesting. Sertraline gives me a lot less agitation than say fluvoxamine.
Linkadge
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