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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 8 of 8. This is the beginning of the thread.
Posted by linkadge on December 25, 2011, at 19:54:22
ok, so I think I'm on to something here.
Lithium has been postulated to interact with the 5-ht1b serotonin autoreceptors. In doing some reading, this effect may be due to the interaction of lithium with gsk-3b.
http://www.ncbi.nlm.nih.gov/pubmed/21372171
According to the website above, gsk-3b inhibitors work to desensitize the serotonin 1b autoreceptor. This effect would enhance the activity of serotonin via reuptake inhibition.
Normally, the 5-ht1b autoreceptors inhibit serotonin release in limbic brain regions. Combining an SSRI with lithium (or another gsk-3b inhibitor like omega-3) would theoretically reduce the activity of the 5-ht1b autoreceptors and thus enhance antidepressant action.
Linkadge
Posted by SLS on December 26, 2011, at 8:53:05
In reply to lithium 5-ht1b + gsk-3b, posted by linkadge on December 25, 2011, at 19:54:22
> ok, so I think I'm on to something here.
>
> Lithium has been postulated to interact with the 5-ht1b serotonin autoreceptors. In doing some reading, this effect may be due to the interaction of lithium with gsk-3b.
>
> http://www.ncbi.nlm.nih.gov/pubmed/21372171
>
> According to the website above, gsk-3b inhibitors work to desensitize the serotonin 1b autoreceptor. This effect would enhance the activity of serotonin via reuptake inhibition.Did you mean to say via negative feedback? If not, then I am confused.
> Normally, the 5-ht1b autoreceptors inhibit serotonin release in limbic brain regions. Combining an SSRI with lithium (or another gsk-3b inhibitor like omega-3) would theoretically reduce the activity of the 5-ht1b autoreceptors and thus enhance antidepressant action.
I guess that this elucidates the mechanism by which lithium promotes serotonin release; a phenomenon noted for several decades, but formally without explanation.
- Scott
Posted by Phillipa on December 26, 2011, at 9:44:20
In reply to Re: lithium 5-ht1b + gsk-3b, posted by SLS on December 26, 2011, at 8:53:05
How does lithium control and provide relief from mania? And I've seen low doses really provide anxiety relief for alchoholism? Phillipa
Posted by SLS on December 26, 2011, at 11:19:48
In reply to Re: lithium 5-ht1b + gsk-3b, posted by Phillipa on December 26, 2011, at 9:44:20
> How does lithium control and provide relief from mania?
One mechanism proposed is the inhibition of protein kinase C (PKC) and a reduction in the activity of membrane-bound G-protein dopamine and glutamate receptors. Another involves the inhibition of dopamine receptor glycogen synthase kinase-3 (GSK-3) signalling. Note that these explain mania rather than depression.
- Scott
Posted by Phillipa on December 26, 2011, at 18:36:59
In reply to Re: lithium 5-ht1b + gsk-3b, posted by SLS on December 26, 2011, at 11:19:48
Thanks. Phillipa
Posted by linkadge on December 27, 2011, at 20:19:58
In reply to Re: lithium 5-ht1b + gsk-3b, posted by SLS on December 26, 2011, at 8:53:05
There was (is) some question as to whether lithium directly affects the 5-ht1b autoreceptor. Lithium may still directly antagonize the receptor.
For instance, application of lithium acutely causes serotonin release, but the downregulation of gsk-3b might be expected to take more time?
Linkadge
Posted by linkadge on December 27, 2011, at 20:30:14
In reply to Re: lithium 5-ht1b + gsk-3b, posted by SLS on December 26, 2011, at 11:19:48
>Another involves the inhibition of dopamine >receptor glycogen synthase kinase-3 (GSK-3) >signalling. Note that these explain mania rather >than depression.
Gsk-3b inhibitors have *some* antidepressant effects. GSK-3b is increased by dopaminergics (d2 activation) (i.e. psychostimulants) and decreased by serotonergics. In mice lacking trytophoan hydroxylase, gsk-3b is upregulated. The behavioral dysregulation in these mice can be reversed with selective gsk-3b inhibitors.
Schizophrenic symptoms appear to be ameleorated in mice with selective gsk-3b inhibitors.
Also, gsk-3b inhibitors have substantial neurotrophic effects. Selective gsk-3b inhibitors mimic many of the trophic effects of lithium and valproate.
I think I remember reading one study that said fluoxetine was a gsk-3b inhibitor. Oh here it is...It also shows that imipramine, clorgyline and fenfluramine indirectly inhibit gsk-3b.
http://www.nature.com/npp/journal/v29/n8/full/1300439a.html
Anyhow, gks-3b is an interesting target for certain mood disorders because it interacts with circadian genes, as well as the regulation of the 5-ht1b receptor, which is critical in the control of limbic serotonin.
Posted by SLS on December 27, 2011, at 21:02:49
In reply to Re: lithium 5-ht1b + gsk-3b » SLS, posted by linkadge on December 27, 2011, at 20:30:14
Thanks for this, Linkadge. I'll need to reread it a few dozen times in order for it to stick.
- Scott
> Gsk-3b inhibitors have *some* antidepressant effects. GSK-3b is increased by dopaminergics (d2 activation) (i.e. psychostimulants) and decreased by serotonergics. In mice lacking trytophoan hydroxylase, gsk-3b is upregulated. The behavioral dysregulation in these mice can be reversed with selective gsk-3b inhibitors.
>
> Schizophrenic symptoms appear to be ameleorated in mice with selective gsk-3b inhibitors.
>
> Also, gsk-3b inhibitors have substantial neurotrophic effects. Selective gsk-3b inhibitors mimic many of the trophic effects of lithium and valproate.
>
> I think I remember reading one study that said fluoxetine was a gsk-3b inhibitor. Oh here it is...It also shows that imipramine, clorgyline and fenfluramine indirectly inhibit gsk-3b.
>
> http://www.nature.com/npp/journal/v29/n8/full/1300439a.html
>
> Anyhow, gks-3b is an interesting target for certain mood disorders because it interacts with circadian genes, as well as the regulation of the 5-ht1b receptor, which is critical in the control of limbic serotonin.
>
>
>
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