Alpha 1 antagonism, coupled with Alpha 2 antagonsim

[JohnBoy2000]

It still doesn't clarify however - the comparative potency of mianserin vs mirtazapine on noradrenaline.

The fact is - its main mode of action, alpha2 blockade, is actually stronger with mirtazapine (31.5 vs 20 nM).
But then of course mianserin has NET binding and 5HT2 blockade that mirtazapine doesn't.

 

[JohnBoy2000]

5HT1A antagonism - what's it responsible for?

It will be significantly less with mianserin.

Does it implicate NA or DA in any respects?

 

[Cotcha Yankinov]

5-HT1A can be expressed at the axon-hillock where they prevent the lateral spread of signal transduction, they can act as autoreceptors that shut off serotonin efflux. The important thing to remember is that specific cell types (serotonin cells that are known for releasing serotonin at their axon terminal, same for dopamine) must be able to communicate with other neurons by virtue of having serotonin receptors on other cell types, so of course NE implicates serotonin and serotonin implicates NE.

Post synaptically they are known for mediating oxytocin release, and playing a key role in antidepressant response.

The hippocampus has no dopamine but serotonin receptors can mediate dopamine release in other areas. See for example MDMA, all of its dopamine release is mediated through serotonin.

 

[Limpet_Chicken]

Seeing what seem like HUGE doses of mirtazepine suggested earlier up in the thread. Must be abnormally sensitive to it because 3.75mg was absolutely rotten, and not immediately connecting the two, 7.5mg was nothing short of traumatic. Was years ago now and the thought still makes my insides squirm.

 

[Cotcha Yankinov]

Do you have bad reactions to antihistamines or good reactions a2 agonists (clonidine, can't remember the similar a2 agonist used in UK for opioid withdrawal).

 

[Limpet_Chicken]

No problem with CNS penetrant antihistamines generally speaking, at least, not in the respect of the horrendous akathisia mirtazepine caused.

The one your thinking of is lofexidine, and I've never taken it. And yes, I feel far more human on clonidine and tizanidine, I'm rx'd both, the former to prevent all that overloading sensory crap, the other because of a fucked up operation on my knee that left me with some nerve damage thats resulted in permanent clenching of the calf muscle and sometimes foot. Works pretty well as a sleeping oill too if plugged.

To say the very least, I'm far better on it (them) than off

 

[serotonin2A]

Hmmm if 80 nm is active at net and 5nm for strattera is active net is mianserin dose in the hundred of mg ?

It isn't necessarily very useful to compare affinity values across different drugs because PK properties are drug-dependent. The main reason to evaluate the binding affinity is to determine the selectivity of a given drug for the receptors that it acts on.

For some drugs, a Ki of 70 nM would be therapeutically relevant, but for other drugs it would mean that no interaction would occur.

Lets take the example of a Ki of 5 nM for NET, which you are assuming is significant. Now apply that value to a high affinity full agonist at the mu opioid receptor that has Ki 1 pM affinity. Under normal conditions (ie, assuming there isn't dramatic tolerance for opioid effects), no one who ingests that drug is going to have brain levels that are even two orders of magnitude lower than 5 nM (ie, 50 pM) because they would be dead by that point...