Does increased synaptic noradrenaline ENHANCE mirtazapine induced rise in 5HT??

[JohnBoy2000]

Mirtazapine will normally increase 5HT via alpha2 heteroreceptor blockade, disinhibiting 5HT release in the presence of increased synaptic NE.

However, alpha1 adrenergic heteroreceptors, when activated, also incite release of serotonin.

So - with regard to the effects of mirtazapine on 5HT, is it twofold, in the presence of enhanced synaptic NE levels??

Alpha 2 blockade => release
Alpha 1 activation = > release

Is that correct?

I do know the principle that the combination therapy of venlafaxine with mirtazapine, works on - is that rise in NE via effexors NRI property (albeit mild), works synergistically with the "cutting of the NE break cable", in regards to the autoinhibitory alpha2 autoreceptor blockade.
That's relative to NE.

But specifically relative to the rise in 5HT??

If mirtazapine were administered with a pure NRI, would there be a greater release of 5HT specifically, in combination with an NRI via mirtazapine, than with mirtazapine alone or in monotherapy???

 

[NNorim]

I do know the principle that the combination therapy of venlafaxine with mirtazapine, works on - is that rise in NE via effexors NRI property (albeit mild), works synergistically with the "cutting of the NE break cable", in regards to the autoinhibitory alpha2 autoreceptor blockade.
That's relative to NE.

How does Venlafaxine compare to Sertraline?
There is this SSRI + Mirtazapine combo.

 

[JohnBoy2000]

How does Venlafaxine compare to Sertraline?
There is this SSRI + Mirtazapine combo.

I don't think there's any synergy between an SSRI and mirtazapine.

Mirtazapine works specifically via adrenoceptor blockades - which would not be implicated by a rise in synaptic serotonin.

My understanding is, venlafaxine would potentiate the rise is serotonin far more so than an SSRI in combination therapy with mirtazapine.

The precise pharmacology of why that is the case - is pretty much the same question I have as well.

I suspect it's relative to 5HT disinhibition via alpha 2 blockade, plus 5HT release via alpha 1 activation.

But I'm hoping someone better versed in these matters can lend some perspective on that myself.

 

[Cotcha Yankinov]

NE binding can potentiate the cellular response that is produced by 5-HT binding, pathways in common between 5-HT and NE enhance their response over time (pathways like cAMP are both used by 5-HT and NE)

But in the short term, SSRIs can activate 5-HT1A somatodendritic autoreceptors and decrease monoamine output (until autoreceptors desensitize)

See for example

http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1996.66020599.x/abstract

 

[NNorim]

Thanks for your answer

I don't think there's any synergy between an SSRI and mirtazapine.

Mirtazapine works specifically via adrenoceptor blockades - which would not be implicated by a rise in synaptic serotonin.

My understanding is, venlafaxine would potentiate the rise is serotonin far more so than an SSRI in combination therapy with mirtazapine.

The precise pharmacology of why that is the case - is pretty much the same question I have as well.

I suspect it's relative to 5HT disinhibition via alpha 2 blockade, plus 5HT release via alpha 1 activation.

But I'm hoping someone better versed in these matters can lend some perspective on that myself.

Indeed, that would be nice.
I've been thinking about trying that California Rocket Fuel.

 

[JohnBoy2000]

Mirtazapine via alpha 2 adrenoceptor blockade - disinhibits NE and SER release.

Does it then apply that, the disinhibited NE via alpha2 - works to activate the alpha1 heteroreceptors on SER neurons - inciting SER release?

Thus, mirtazapines potency of SER release - about twice as profound as its enhancement of NE??


Because, if that is the case, it would make sense that, with the addition of and NRI, further enhancing synaptic NE, that further alpha 1 activation would be induced, and thus greater potentiation of SER release; adding an NRI to mirtazapine.

There's bound to be academic paper or something on this, no?

 

[JohnBoy2000]

"The noradrenergic activation and the consequent indirect enhancement of serotonergic transmission most probably underlie the marked therapeutic activity of mirtazapine."

http://journals.lww.com/intclinpsychopharm/Abstract/1995/12004/The_effects_of_mirtazapine_on_central.4.aspx

That's the part I would like more specific information on.

It seems to suggest that, mirtazapine incites noradrenaline release - and THIS, in turn, incites 5HT release.

Y/N?


**

Second study, repeating that:

"These effects are explained by noradrenergic enhancement of 5-HT cell firing and blockade of noradrenaline mediated inhibition of hippocampal 5-HT release"

http://onlinelibrary.wiley.com/doi/10.1002/hup.470100805/full


Thus - if NE enhances 5ht firing via mirrtazapine - then adding an NRI to the mix, would almost certainly compound that action - right?

....


RIGHT!!!???


j/k

 

[JohnBoy2000]

https://link.springer.com/article/10.1007/s00213-013-3122-9

"results suggest that enhanced serotonergic transmission resulting from α2 adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors"

Re: previous statement in relation to somatadendritic 5ht1a autoreceptors, inhibiting SER release.

 

[JohnBoy2000]

By pharmacologic - this NE mediated enhancement of SER would not occur without the presence of an alpha 2 adrenoceptor blocker, due to this receptors inhibitory effects on the release of SER.

Which is why, I assume, we don't see a rise in SER with an NRI is administered in monotherapy.

 

[JohnBoy2000]

And this

https://link.springer.com/article/10.1007/s002100000294

"Mirtazapine (Mir) is a novel antidepressant, reported to raise extracellular noradrenaline (NA) through blockade of α2-autoreceptors and serotonin (5-HT) output via (1) indirect activation of facilitatory α1-adrenoceptors on the cell bodies of ascending 5-HT neurones and (2) blockade of presynaptic release-modulating α2-heteroreceptors on 5-HT terminals in the forebrain"


Specifically references alpha 1 activation as the means of 5HT release via mirtazapine.

Thus, again - an NRI will inadvertently enhance 5HT, provided the inhibitory alpha 2 receptor is blocked in its presence.

 

[Cotcha Yankinov]

^I would take care to differentiate between "enhancement of 5-HT transmission" and "enhancement of 5-HT release" as you said the latter but the paper said the former - it could be the case that NRIs sensitize the post-synaptic response to serotonin, as was part of the old TCA theory. Post synaptic 5-HT1A thats critical for antidepressant response are often under-responsive in MDD - antidepressant treatment re-sensitizes 5-HT1A mediated postsynaptic response, although it also upregulates 5-HT1A as well.

There are also different kinds of pre-synaptic signaling, touch-and-go vesicle fusion (kiss and run), phasic vs. tonic release that can signal different things, so who knows how autoreceptor activation is messing with vesicle binding specifically, especially on some of these cells that are releasing more than one transmitter.