Alpha 2 adrenergic receptor blockade - saturation??

[JohnBoy2000]

As far as the pharmaco-profile of lamotrigine goes - so, supposedly acting primarily as a sodium channel blocker, cell membrane stabilization?
Supposedly assists with depressive phases of bi-polar.
Downregulates glutamate release - which would insinuate, sedation, calming?
And in some cases, can give rise to chronic cognitive impairment.

In contrast to the profile of a noradrenergic agent, which would typically be considered activating, a cognitive enhancer.

I am keen to understand the mechanisms of all classes of drugs, simply to alleviate the impetus to basically, try all of them.

But basically, being indicated for convulsion disorders, bipolar etc - based on class alone, it would make me reluctant to go there; not to say that I don't value the suggestion.

But, I'd like to keep my pharmacological intake to, preferably, the least possible amount.
That being said - I had written if off as another typical convulsion agent like depakote in relation to mechanism - which doesn't seem to be the case so - something to bear in mind for future.


I got some magnesium supplements today, cause apparently it acts as a weak NMDA blocker, and some people find it assists with depressive symptoms and low energy.

 

[Cotcha Yankinov]

Sodium channel antagonists can cause a wide range of responses, this seems to be due to the the fact that sodium channels are expressed on such a variety of cells. So as an example, sodium channel antagonists can lead to seizures in overdose because GABA interneurons express sodium channels, and thus a sodium channel antagonist can inhibit GABA and other inhibitory interneurons.

Lamotrigine tends to decrease glutamate release, which could lead to decreased activation of NMDA receptors which normally activate inhibitory interneurons - this could lead to downstream monoamine release and alterations in neural oscillations.

The point is to view the brain as a system, and watch out for tunnel visioning on something like "activation of sodium channels increase neuronal excitability so blocking them must be sedating", or "GABA = sedating". As an example, activation of GABA interneurons in the BNST of the amygdala leads to wakefulness and insomnia.

It's hard to judge whether a medication like lamotrigine will lead to a net decrease or increase in energy at a certain timeframe of the day or in a certain environment because everybody is different. Thus we may only theorize so much. But I think that it is a mood stabilizer that can be effective for depression says a lot.

We can theorize all day about what effect it might have on cell firing in the locus coeruleus by acting directly in the locus coeruleus but it will also be affecting other nuclei and circuitry that control the locus coeruleus, so the net NE cell activity induced by lamotrigine can't be considered by just its direct actions on the locus coeruleus.


The other thing to consider is that different cell firing patterns signal different things, so microdoalysis studies may show the percentage increase of NTs but phasic release can cause a different response than tonic release. Cellular responses are complicated, and different neurotransmitters seem to work in concert to produce responses.

On top of that, lamotrigine is not simply a sodium channel antagonist, and there are categorically different effects that some of these "wonder drugs" have. See for example HDAC inhibition.

 

[JohnBoy2000]

I switched out remeron for mianserin again last night - cause I felt perhaps, with reboxetine, being such a potent NRI, in combination - that it was perhaps inciting very strong alpha 1 adrenoceptor activation, causing large 5HT release via the alpha2 blockade of remeron.
5HT in my case, induces fatigue - as I feel I have a perfectly functioning 5HT system.

So, mianserin, with an alpha 1 blockade, shown via microdialysis to have a null effect on 5ht enhancement - the exaggerated NRI mechanism would not incite this 5ht release - and would therefore not incite the negative symptoms I associate with remeron.

And last night - I slept - the best, I have, since I started reboxetine 2 months ago.
And I feel nice and fresh this morning.

So - keeping my fingers crossed that's sustainable.

60 mg mianserin.
4 mg reboxetine.

 

[JohnBoy2000]

Continuing the blog entry here:

Third night back on Mianserin.

It seems that, after two weeks off, I will have to go through the entire adaption phase again.

What I am watching out for here, is activation with the night time dose of Mianserin.

That's a clear indication that NA levels are too high.
So - keeping reboxetine at the starter dose of 4mg, as I know that, with a potent alpha 2 blocker in place, even a small NRI addition or variation, will yield much magnified changes to NA levels.

So long as I don't get activation at night - as that means, I'll wake up super early, in addition to exacerbating symptoms during the day.

 

[JohnBoy2000]

Maintaining Mianserin at 60 mg - my max tolerated dose, and reducing reboxetine all the way down to, half the starter dose - at two mg's.

Given the results of that microdialysis study - even two mg's in combination with a potent alpha 2 blocker, should increase NE levels by up to 3 figures.
That's my assumption cause, even on 4 mg rebox, I'm getting activation on night time Mianserin where I never did with Mianserin in monotherapy or with desipramine.

The difference between Mianseran and Remeron was so profound, that I'm thinking, if I had been on Venlafaxine with Mianserin, as oppose to the traditional CRF with remeron - my response could potentially have been far improved.

 

[NNorim]

I found a PET occupancy study for you, for whatever it's worth https://www.ncbi.nlm.nih.gov/m/pubmed/17653532/

The issue with using a non-specific ligand like mirtazapine to test against radiolabeled mirtazapine is that we don't know whether it's occupying a2 vs. 5-HT2C vs. histamine, so I couldn't find anything specific to a2 occupation (assuming there is a ligand selective for a2?)

RE: mirtazapine preferentially binding to pre synaptic autoreceptors - many of these receptors that are both pre and post synaptically expressed like 5-HT1A may appear to be predominantly presynaptic, but there seem to be situations where different receptor populations are in the low affinity state (not coupled to G-proteins) vs. high affinity state, which will give rise to preferential binding pre vs. post synaptically

This could create another situation where binding occupancy doesn't = physiological response, and decoupling of post synaptic e.g. 5-HT1A receptors can be a problem in MDD apparently. Another example here is pindolol which "preferentially" blocks 5-HT1A autoreceptors (somatodendritic)

The other thing to consider is that the post synaptic a2 may be positioned to create a much stronger response or categorically different response when activated or blocked, so we may not be able to go off of pure concentration of NTs here if we're talking about post synaptic a2 in the cortex.

Did you study medicine or pharmacology?
You seem to know a great deal about that stuff...

 

[JohnBoy2000]

Bizarre.

When I take 4mg reboxetine with 45 mg mianserin - I can't get out the bed.

When I take 8 mg rebox with 45 etc - I feel, wonderful, for a couple days, that can't sleep worth a damn and go into decline.

So - now, I'm taking - 6mg, and hoping for the best.

I'm surprised the dosing has to be so exact.

Though, perhaps it must be considered that, due to the addition of alpha 2 mediated NRI enhancement - even 2 mg reboxetine, could implicate noradrenaline levels that significantly/profoundly...?

 

[JohnBoy2000]

Like with Venlafaxine - the difference between 150 mg and 225 mg - was night and day.

Though it can be dosed all the way to 375 mg - 225 was the only suitable dose for me.