Nddi

[GrymReefer]

NDDI (norepinephrine-dopamine disinhibitor) basically modulates the extent at which dopamine and norepinephrine can effectively continue "downstream."

I'm sorry if this is a stupid question, but what are they referring to when they inhibit the downstream flow? Are they referring to the secondary activities they regulate after the original release from the brain?

I'm having a difficult time establishing a sound understanding and is this inhibition comparable to a full antagonist or a suicide-inhibitor?

Thanks in advance and sorry if this is a stupid question. I'm just having a gnarly brainfart or something.

 

[sekio]

From how I understand it NDDIs are drugs that don't necessarily increase dopamine release directly, but rather "limit the limiters" and instead helps control how much localized inhibition caused by e.g. autoreceptor agonism will effect the bigger picture.

Are they referring to the secondary activities they regulate after the original release from the brain?

I think so, yes.

 

[serotonin2A]

It's not inhibition, it's disinhibition.

5-HT2C receptors inhibit the firing of dopaminergic neurons, so blocking 5-HT2C increases dopaminergic activity by disinhibiting (exciting) dopaminergic neurons. The end result is that cells in the ventral tegmental area fire more often, and therefore net dopamine release increases.

There are other ways to increase the firing of dopaminergic neurons, such as activating 5-HT1A receptors. Some 5-HT1A agonists have also been classified as NDDIs.

The ligands in the NDDI class don't work by altering the sensitivity of terminal autoreceptors.

 

[GrymReefer]

Oh I read it wrong. Thanks for pointing that our Serotonin2A.

So 5-HT2C from what I have researched is a receptor that mediates the activity of cAMP pathway in regards to cell signaling. So the "disinhibition" is involved with mitigating the regulatory activity from 5-HT2C on dopaminergic pathways and increasing the rate of secretion. Now does this interact with the regulatory activities involved with serotonergic pathways? (I'm assuming there is a homeostatic mechanism involved, but would it be a positive or negative feedback loop?)

Does the subsequent increase in dopamine concentration lead to receptor upregulation or would the NDDI produce a toxic environment from the dopamine concentration and cause destruction to the serotonin axons and eventual receptor internalization via receptor-mediated endocytosis?

Also, NDDI activity and dopamine reuptake is irrelevant correct? This is basically an alteration to the allosteric regulation of some key neurons.

This could be relevant, but I'm doing a speech on the nature of Addyi and its theoretical plausability in successfully treating female hyposexual desire disorder. From what I have gathered so far in reference to its pharmacology and proposed means of pharmacokinetics is that it doesn't seem a 100% convincing. The mostly male case study for FDA review also doesn't help provide any validity to it's medically established use. (How does disinhibiting the regulatory mechanics of dopamine secretion lead to a increased state of sexual desire? Oestrogenic/androgenic related sex hormones are responsible for the most part and they are regulated by the mechanics of SHBG mostly with small input from albumin and transcortin glycoproteins.)

I appreciate any thorough explanations as I am trying to get my first entry-level degree in the subject of metabolic biochemistry. I'm assuming pharmacology/pharmacokinetics will be a great asset to the knowledge as well.

EDIT: Disinhibition can be paradoxical or is this exclusively relevant to the pharmacokinetics of benzos and their interaction with GABA expressions?

Also correct me if I'm wrong, but disinhibition of norepinephrine theoretically leads to increase firing of that neurotransmitter. That would cause an increase in the partial agonist activity on the TAAR1 protein. From what I understand TAAR1 encodes regulatory actions involved with dopamine, norepinephrine, and serotonin neurotransmissions. So it is not only actively antagonizing the the inhibitory functions on dopaminergic activity from 5-HT2C, but also is increasing its own exacerbation of the neuron excitement by potentiating the agonist affinity allowing a greater degree of norepinephrine firing. However I start to get lost in its down stream modulations, from what I read is that it inhibits the postsynaptic firing rate of dopamine receptors. So this activity allows the presynaptic neuron transmission from the neuron releasing its neurotransmitter at a increased rate, but antagonizes the neurotransmitter from inducing further transmissions beyond its current bound receptor location?

It almost appears to me that it expresses activity that could be comparable to a selective dopamine-norepinephrine receptor modulator.

 

[dopamimetic]

How does disinhibiting the regulatory mechanics of dopamine secretion lead to a increased state of sexual desire?

I guess it works rather the other way round. People (including women) with low dopamine levels tend to be shy, anxious, introverted, etc. Increasing dopamine in them leads to more sociality, feeling better etc ... Would be interesting to compare flibanserin with a straight DRI like methylphenidate or better isopropylphenidate.

(Independently confirmed by two good friends, methoxetamine seems to have real aphrodisiac qualities to some women. Not by directly increasing desire, but by creating feelings of love, trust, empathy etc. what I attribute to its serotonergic action combined with the other effects. A girl admitted that she had a hard time to fight her feelings and desires after a trippy night- as friends, not lovers. This was not exactly good for our friendship, even though it was all in her mind..)

 

[GrymReefer]

So these established uses for treatment of sexual desire dysfunction is working to produce the need to have the "love-like" affection and interactions rather than what Viagra does for men in producing a temporary erection that can stand the test of time.

Exciting key parts of the reward system pathway?

Maybe its just me, but is the pharmacokinetics of NDDI's more complex and intricate than what is usually labeled as an anti-depressant? I know flibanserin was originally designed with psychological treatment in mind.

Dopamine doesn't have a whole lot to due with sexual desire. Maybe promotes sexual promiscuity by promoting an increase in one's desire to seek out rewarding activity (whether its positive or negative is subjective to the individual)

 

[serotonin2A]

Dopamine doesn't have a whole lot to due with sexual desire.




[/I]

You've got that wrong. Dopamine is thought to be one of the main driving forces underlyind the desire to have sex. There are probably other chemicals involved, but dopamine is definitely very important. Hence why people taking L-DOPA sometimes become hypersexual and sexually promiscuous.

 

[dopamimetic]

Yeah, but this

Maybe promotes sexual promiscuity by promoting an increase in one's desire to seek out rewarding activity (whether its positive or negative is subjective to the individual)

is very true.

Personally speaking, with low dopamine levels even normal socialization becomes a huge effort and anything related to sex or intimacy seems just out of question. I'd guess this is not much different between men and women. But elevated dopamine does not necessarily mean hypersexuality, I know it's a possible side effect of dopamine agonists and levodopa (and stimulants / speed for the non-ADHD folks) but at least for me it'd require a HUGE surge of dopamine (beyond that threshold of becoming uncomfortable) and plain mania to possibly 'overdrive' and do things I normally wouldn't.

The little sister of this is probably common to quite a few ADHD people. Feeling 'guilty' or 'wrong' about previous (extrovert-ish) socialization and thoughs/ideas when that 'rebound' sets in. This is somewhat disturbing and annoying, but it's the price I have to pay. With co-administered memantine this is much less pronounced, but still occasionally present.

 

[GrymReefer]

Now you say you require a huge surge.. I'm assuming if the causation of the surge is from dopamine agonists then there is the potential for serotonin axon destruction from dopaminergic-induced neurotoxicity?

The "rebound" feeling is what? The residual effects related to neuron overexcitability and the subsequent downregulatory expression of the dopaminergic receptors? Would the down regulation be to the postsynaptic areas of associated neurotransmittor's activity?

I feel like serotonin is the least likely contributor to the whole picture. Norepinephrine isn't as complex as dopamine's pharmacology. I don't really know where I'm going with this anymore. I was just really hoping to fully comprehend how Addyi was agreed upon as a viable compound to use for the proposed treatment.

 

[dopamimetic]

The "rebound" feeling is what? The residual effects related to neuron overexcitability and the subsequent downregulatory expression of the dopaminergic receptors? Would the down regulation be to the postsynaptic areas of associated neurotransmittor's activity?

Don't really know what's causing that - the "crash" or "off" one experiences more or less pronounced when the main effects of e.g. methylphenidate wear off and the plasma levels of the drug fall beyond a certain threshold. This is partly caused by norepinephrine; more dopamine-selective drugs tend to have less comedown (for me) and clonidine does a good job to alleviate this. I suspect the partial metabolism of dopamine into (nor)epinephrine contributes too, as high DA levels tend to limit NE activity. Mucuna pruriens or -low- dosed levodopa helps too.

As said previously, memantine kills maybe 50+% of the rebound and a good part of tolerance development as a whole (most probably by protecting the neurons from overexcitation, and its low-affinity D2 agonism takes a part of the receptors over). It's not sure at all, but I have good hope that the memantine does not only help with psychical symptoms but actually offers some protection.

Now you say you require a huge surge..

At least far above any 'normalization' done by therapeutic MPH doses. Coke is a different beast, becoming uncomfortable, cold and egocentric when a certain concentration is reached. Manic. Or meth maybe, I never tried that.

I feel like serotonin is the least likely contributor to the whole picture.

Serotonin alone has little effect, as seen by acute SSRI administration (or things like MDAI to some extent). But in the right combination - think of MDMA. Methoxetamine is somewhat unique by being an SSRI and NMDA antagonist (possibly sigma agonist?) - okay, DXM does that too, but it fucks you up much more and the noradrenergic part is disturbing.

So, viewed from the other side, I'd suggest that norepinephrine might be contra-sexual. In men it just makes the whole thing impossible, but there is a psychic part too.

 

[GrymReefer]

Thanks for helping me try to better understand the pharmacokinetics. I'm in over my head trying to learn this one at this moment in time.

 

[serotonin2A]

Thanks for helping me try to better understand the pharmacokinetics. I'm in over my head trying to learn this one at this moment in time.

What you are discussing is pharmacodynamics, not pharmacokinetics.

Dopamimetic, you can't really use your subjective experiences as a way to gain insight into how neural circuits function. The situation of endogenous dopamine acting in a discrete neural pathway is completely different then what happens when you take an indirect dopamine agonist. Endogenous dopaminergic activity involves tonic and phasic types of activity that have very different functions, and release is regulated regionally. The action of taking a dopamine agonist, either direct or indirect, does not really mimic how endogenous dopamine functions. Another issue is that high levels of dopamine receptor activation may actually suppress responses that would normally occur with endogenous dopamine, because high levels of receptor activation throughout the brain may induce processes like receptor internalization or activation of inhibitory regulatory mechanisms (e.g., DA receptor activation in one brain region may promote sexual desire, but activation in another brain region may suppress sexual behavior through a different mechanism).

So the reason why NDDIs seem to be useful in this situation is that they activate the dopaminergic system in a physiological manner, whereas direct or indirect agonists do not.

 

[GrymReefer]

What you are discussing is pharmacodynamics, not pharmacokinetics.

Dopamimetic, you can't really use your subjective experiences as a way to gain insight into how neural circuits function. The situation of endogenous dopamine acting in a discrete neural pathway is completely different then what happens when you take an indirect dopamine agonist. Endogenous dopaminergic activity involves tonic and phasic types of activity that have very different functions, and release is regulated regionally. The action of taking a dopamine agonist, either direct or indirect, does not really mimic how endogenous dopamine functions. Another issue is that high levels of dopamine receptor activation may actually suppress responses that would normally occur with endogenous dopamine, because high levels of receptor activation throught the brain may induce processes like receptor internalization or activation of inhibitory regulatory mechanisms (e.g., DA receptor activation in one brain region may promote sexual desire, but activation in another brain region may suppress sexual behavior through a different mechanism).

So the reason why NDDIs seem to be useful in this situation is that they activate the dopaminergic system in a physiological manner, whereas direct or indirect agonists do not.

Thank you thank you for correcting me. I always confuse those two. So pharmacodynamics is what the drug does to the body, and kinetics is what the body does to the drug?

Thank you for the in depth explanation.

 

[Hiltoniano]

(Independently confirmed by two good friends, methoxetamine seems to have real aphrodisiac qualities to some women. Not by directly increasing desire, but by creating feelings of love, trust, empathy etc. what I attribute to its serotonergic action combined with the other effects. A girl admitted that she had a hard time to fight her feelings and desires after a trippy night- as friends, not lovers. This was not exactly good for our friendship, even though it was all in her mind..)

Just wanted to add, a close (ex-close) friend of mine who is male, he had a girl who didn't do many exotic/designer drugs but he introduced methoxetamine to her and they regularly would dose and then have a whole lotta sex. He was quite graphic in how it enhanced her sexual desires and her willingness to try new sex methods and kinky shit. Said she even got to where she wouldn't fuck him unless she dosed mxe first. Weird. But it sounds fun. I have made love on 3-MeO-PCP and that was... Interesting. Very mentally detached feeling but still fun and pleasurable. Just some food for thought :D

 

[Hiltoniano]

Thank you thank you for correcting me. I always confuse those two. So pharmacodynamics is what the drug does to the body, and kinetics is what the body does to the drug?

Thank you for the in depth explanation.

Your interpretation is a tad too 'general' for my tastes. ( The definitions you posted are the most simplified and basic ones, straight from Wikipedia) to really understand the difference, it's more important to get key details of what each is explaining. So, a slightly more in depth definition for the difference is :

Pharmacodynamics involves a drugs receptor binding (including receptor sensitivity), postreceptor effects( which should include levels of up/down regulation at Ligand binding sites) , downstream effects from receptor agonism/antagonism ,and the drugs influence in chemical interactions( which includes interactions between the compound and its general site of action in the body)

Pharmacokinetics is related to the movement of drug into, through, and out of the body; the time course of its absorption, bioavailability , distribution to body tissue, metabolism , and excretion.

Just some more clarification. Seems like the above guy explained as well or better than i did haha.
( to mods, sorry for double post, I didn't realize I was gonna make two replays until I already had the second written out. Merge if needed , whoopsies)

 

[GrymReefer]

Thanks for the input from everyone. I did a current event thing in class about the approval of Addyi, but in my own mind I couldn't identify the details that helped increase its potential for approval. Thought a little explanation of what an NDDI does, but in the end I'm even more lost as to how this eventually increases the overall sexual desire in HSDD. It might be too advance for my current position.

 

[dopamimetic]

Just thought this might be better suited for NSPD here than where I've originally posted (drugs in the media, as a reply):

Flibanserin, a drug for women with hypoactive sexual desire disorder. Didn't even know that a term like this exists until recently, let alone thinking of it as a diagnosis!

But I'd certainly like to try this drug out. 5-HT1a full agonist, 5-HT2a antagonist (okay, this part we wouldn't need for now, a partial agonist or something could promise more fun, but 5-HT2a antagonism is associated with anxiolysis, calming effects etc, then again, 5-HT2a agonism causes an increase in oxytocin.. so no cuddling? ) and dopamine-norepinephrine disinhibitor ... might make a decent mood-lifting agent or social lubricant? These things aren't exactly pro-sexual first hands for me, but this seems to be hard to crack for me anyways and there could be definite potential. Bad mood, anxiety and all that are show stoppers for sure.

Were there any trials done with males by the way? (It won't act like viagra, I'm not thinking of something like that either.)