Excess DA and NE in the PFC

[serotonin2A]

I'm not sure I understand your question correctly, but you know that unless there is a covalent bond formed (irreversible binding) the free drug and drug-receptor complex are in dynamic equilibrium, meaning that it attaches and detaches very quickly all the time. The affinity of the antagonist in comparison to the endogenous ligand determines at what concentrations of said drug you can talk about sufficient receptor blockade, so knowing that you can estimate how long it will take for the concentration to fall below a certain "threshold". The drug you're taking isn't an irreversible antagonist, right? Because in that case half-life would have little meaning.

I'm a little confused by your answer to his question. The free drug and drug-receptor complex are only at dynamic equilibrium when the concentration = the Kd. Ligands don't necessarily attach and detach very quickly -- it depends on the on-rate (Kon) and off-rate (Koff) of the particular ligand.

The affinity (Kd) = Koff/Kon. So a ligand can have high affinity if it has a slow disassociation rate, a fast association rate, or both. You can think about it like this: if the ligand and receptor associate faster than they can disassociate, then ligand-receptor complex will start to accumulate relative to the free receptor and the free ligand. Hence the Kd will occur at a lower concentration (ie, higher affinity).

But ultimately the length of time that a ligand stays bound to the receptor varies across ligands. Some ligands like buprenorphine and LSD have very long off-rates and are pseudoirreversible.

 

[Cotcha Yankinov]

Yeah it's just a regular antagonist, my pondering was that if this drug would bind to a receptor for let's say 3 hours then you could take it long before bedtime to start ramping up maximal blockade, but it sounds like taking it early would only be effective for irreversibly binding drugs.. When you say that it attaches and detaches very quickly, do you think we are talking about it staying attached a matter of seconds or something?

 

[serotonin2A]

Yeah it's just a regular antagonist, my pondering was that if this drug would bind to a receptor for let's say 3 hours then you could take it long before bedtime to start ramping up maximal blockade, but it sounds like taking it early would only be effective for irreversibly binding drugs.. When you say that it attaches and detaches very quickly, do you think we are talking about it staying attached a matter of seconds or something?

Suvorexant has a Koff of 0.012/min and a dissociation half-life of 79 minutes. The dissociation is pretty slow.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904256/#!po=42.5234
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[Cotcha Yankinov]

Does a dissociation half-life of 79 minutes mean that the number of actively bound ligands decreases by half every 79 minutes?

 

[belligerent drunk]

I'm a little confused by your answer to his question. The free drug and drug-receptor complex are only at dynamic equilibrium when the concentration = the Kd. Ligands don't necessarily attach and detach very quickly -- it depends on the on-rate (Kon) and off-rate (Koff) of the particular ligand.

The affinity (Kd) = Koff/Kon. So a ligand can have high affinity if it has a slow disassociation rate, a fast association rate, or both. You can think about it like this: if the ligand and receptor associate faster than they can disassociate, then ligand-receptor complex will start to accumulate relative to the free receptor and the free ligand. Hence the Kd will occur at a lower concentration (ie, higher affinity).

But ultimately the length of time that a ligand stays bound to the receptor varies across ligands. Some ligands like buprenorphine and LSD have very long off-rates and are pseudoirreversible.

Generally processes on molecular level are incomparably faster than what we're used to on macro level, is that not the case with receptor binding? Do you mean to say that some ligands bind and stay at the receptor, without dissociating, for minutes or even hours? Also I'm not sure what you mean by them being at dynamic equilibrium only when concentration = Kd.

 

[serotonin2A]

Generally processes on molecular level are incomparably faster than what we're used to on macro level, is that not the case with receptor binding? Do you mean to say that some ligands bind and stay at the receptor, without dissociating, for minutes or even hours?

Dissociation generally occurs on the scale of seconds to hours. For example, the off-rate of buprenorphine is approximately 0.069/min, which means that it takes about 10 min for 50% of bound buprenorphine to dissociate.

http://jpet.aspetjournals.org/content/319/2/682.full.pdf+html

Also I'm not sure what you mean by them being at dynamic equilibrium only when concentration = Kd.

Kd is defined as the concentration where binding (R + L → RL) and unbinding (RL → R + L ) are in dynamic equilibrium (i.e, the association rate = the dissociation rate). This makes sense, because if they weren't in equilibrium then either (RL) or (R + L) would dominate. For example, if [L] > Kd then the equilibrium will shift so that (RL) dominates. That is what causes the occupation level to increase >50% when [L] > Kd. So the system isn't always at dynamic equilibrium.

 

[belligerent drunk]

Kd is defined as the concentration where binding ([RL]) and unbinding ([R]+[L]) are in dynamic equilibrium (i.e, the association rate = the dissociation rate). This makes sense, because if they weren't in equilibrium then either ([RL]) or ([R]+[L]) would predominate. But if the [L] increases below or above Kd then ([RL]) and ([R]+[L]) will not be at steady state and the equilibrium will shift toward one or the other.

Thanks for the insight about receptor binding rates, I wasn't aware that it could be that slow, so my apologies to Cotcha for possibly confusing you.

Yes, that's how dynamic equilibrium works, but your original statement sounds like equilibrium is only achieved at a certain concentration, which is not the way it works. As long as the ratio of [RL]/([R] + [L]) is (almost) equal to Kd, they're in equilibrium.

Also, I apologize in advance in case I unwittingly say something erroneous again, because pharmacology is mostly just my hobby, so I may apply chemical principles that don't really work the same way in biochemical systems.

 

[serotonin2A]

Yes, that's how dynamic equilibrium works, but your original statement sounds like equilibrium is only achieved at a certain concentration, which is not the way it works. As long as the ratio of [RL]/([R] + [L]) is (almost) equal to Kd, they're in equilibrium.

But the ratio of [RL]/([R] + [L]) is often not equivalent to Kd! For example, classical neuroleptics are generally dosed at levels that produce 70% occupation, which means they are dosed so that brain concentration is at least 2.3 x Kd. That shifts the equilibrium toward [RL]. On the other hand, full MOR agonists produce anesthesia at about 10% receptor occupation, so they would be dosed at 0.1 x Kd. That shifts the equilibrium toward ([R] + [L]).

I think we might be talking about two different things -- I'm not talking about steady state/equilibrium. Eventually, if [L] stays constant, binding will reach some steady state/equilibrium. But that isn't the same thing as dynamic equilibrium, which only occurs at Kd.

 

[belligerent drunk]

Sorry, I don't really see how Kd has anything to do with receptor occupation in this context. The ratio may not be equal to Kd if the process is kinetically limited, for example like you described a ligand dissociates more slowly than the free drug is eliminated, in which case the ratio is >Kd. How does receptor occupation influence the equilibrium? Generally there has to be an external energy input in order to shift the system away from equilibrium. Just a completely random illustration: a chemical reaction in which water is formed, which would normally be at an equilibrium with 1:1 reagent: product ratio, but the water is trapped/absorbed on a solid, and that shifts the equilibrium towards products - in this case the "isolated" reagent/product system is "shifted away from equilibrium" with reagent: product ratio (except water) being a lot smaller than K would suggest.

So to my understanding the higher the [L], the higher the [RL] will be if there is no kinetic limitations, so higher receptor occupation, right? Don't see why the ratio should change though. Anyway, what do you mean by comparing drug concentration to Kd if they have different dimensions?

 

[Cotcha Yankinov]

Holding the stimulus in WM isn't akin to a hallucination because it isn't necessarily accompanied by a top-down activation of sensory cortices.

I have an idea that hopefully you can make sense out of! I was thinking that maybe through a mechanism of mirror neurons that some activation of sensory cortices might be possible concerning something that may or may not be considered working memory activating the senses. I'm a lifelong musician with audio hallucinations (voices) as well as horrible musical hallucinations (bane of my sleep-deprived existence) so I'll pick on audio, and hopefully gain some insights on my hallucinations

Apparently piano player's motor regions activate when listening to piano music. If those same piano players "imagine" piano music or happen to have a song stuck in their head, might it produce the same motor region activation? Or might that motor region activation only occur with someone who has genuine musical hallucinations? I don't know if you would consider playing a song/instrument in your head to be working memory however.. I realize that what is important concerning that piano player research is the pairing of the stimulus with the motor cortex, but when the stimulus itself comes from within constantly (hallucinations) might that pairing occur not with the motor cortex but with whatever other neurons are triggered by the imagined music? Or are mirror neurons very related to just motor movements and the process of developing musical hallucinations might be unrelated to mirror neurons?

Now if an audio stimulus can set off a motor cortex response, can a motor response set of an auditory region response? Because if so then an audio stimulus (that might come from within) could stimulate the motor region and the motor region could once again stimulate the audio system in a feedback loop. Any guesses on if playing piano without sound (just motor activity) or imagining playing the piano in your head results in audio region activity?

Is there a difference between a normal song stuck in the head and a musical/audio hallucination in the sense that maybe only with the musical/audio hallucinations do you see a real activation of brain regions that makes it look like the person is really hearing something?

Excuse my craziness.

Also, does a dissociation half life of 79 minutes mean the number of actively bound ligands decreases by half every 79 minutes? It sounds like suvoxerant shouldn't be taken just before bed if that is the case.

 

[serotonin2A]

Sorry, I don't really see how Kd has anything to do with receptor occupation in this context. The ratio may not be equal to Kd if the process is kinetically limited, for example like you described a ligand dissociates more slowly than the free drug is eliminated, in which case the ratio is >Kd. How does receptor occupation influence the equilibrium? Generally there has to be an external energy input in order to shift the system away from equilibrium. Just a completely random illustration: a chemical reaction in which water is formed, which would normally be at an equilibrium with 1:1 reagent: product ratio, but the water is trapped/absorbed on a solid, and that shifts the equilibrium towards products - in this case the "isolated" reagent/product system is "shifted away from equilibrium" with reagent: product ratio (except water) being a lot smaller than K would suggest.

So to my understanding the higher the [L], the higher the [RL] will be if there is no kinetic limitations, so higher receptor occupation, right? Don't see why the ratio should change though. Anyway, what do you mean by comparing drug concentration to Kd if they have different dimensions?

Kd and ligand concentration are both in exactly the same units (concentration in moles/L).

You are looking at what I'm saying backwards. I am not saying occupation determines the equilibrium, rather I am saying the equilibrium between L and RL determines receptor occupation in a very predictable manner.

It is very easy to prove that occupancy is always 50% when [L] = Kd.

Look up the formula for receptor occupancy. Fractional occupancy = [L]/(Kd + [L]). Let's test this by looking at occupancy at Kd. We'll set [L] = Kd = 1 nM. You can plug in any other concentration for both but the math is easy to do when you use 1 nM. So you have: 1/(1+1). That gives you a fractional occupancy of 1/2, or 50% of the receptors. So when [L] = Kd, the occupancy always equals 50%.

The reason why Kd is set = Koff/Kon is because that it is the concentration at which receptor occupation is 50%. That happens because that is the concentration at which Kon and Koff are in dynamic equilibrium.

I'm not sure why you are bringing up the ratio of [L] to [RL]? The ratio is nonlinear. As [L] increases, the equlibrium shifts toward [RL] and you end up with a greater %occupation. But occupation ([RL]) is asymptotic; [L] can increase indefinitely but [RL] is limited by Bmax.

Also, does a dissociation half life of 79 minutes mean the number of actively bound ligands decreases by half every 79 minutes? It sounds like suvoxerant shouldn't be taken just before bed if that is the case.

That is exactly what it means. The long dissociation rate may not be bad in this case. A major problem with many hypnotics is that their duration of action is too short and people wake up too early. So the fact that suvoxerant stays bound for a long period may mean that it won't wear off in the middle of the night. With traditional hypnotics it is bad if they remain bound for too long because that can cause a daytime hangover. But I'm not sure if that would happen with orexin antagonists because technically they don't work by putting you to sleep but rather they stop orexin from waking you up. So that may not translate to daytime sleepiness. What does it feel like when you wake up -- do you feel like you have a sedative hangover?

Sorry that I didn't reply to your other question yet but I promise I will as soon as I have a chance.

 

[Cotcha Yankinov]

Suvoxerant at the highest dose 20mg leaves me with absolutely no after effects in the morning, I am very confused by this drug, like you say it almost seems to help allow sleep rather than induce sleep. It's not horribly effective however and some people anecdotally report zero improvement of sleep. What's interesting is it seems they proved efficacy at 40mg and up I believe while that was not deemed safe so the max dose is 20mg. But I can vouch that it's not very habit forming at all thankfully. Also thought I'd share this with you http://www.ncbi.nlm.nih.gov/pubmed/19779148 - "Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice." So presumably there is no direct connection between excess orexin and amyloid beta but rather excess orexin leads to excess wakefulness which leads to decreased nocturnal clearance of amyloid beta? The orexin antagonist administered mice spent 10% less time awake.

And no worries take your time Sorry I just thought you might not have seen my other ponderings. Sorry to always overload you with questions hahaha.

 

[belligerent drunk]

The reason why Kd is set = Koff/Kon is because that it is the concentration at which receptor occupation is 50%. That happens because that is the concentration at which Kon and Koff are in dynamic equilibrium.

I still don't see what you're trying to say by that. The system is in dynamic equilibrium regardless of concentration unless it is being affected (given energy) externally. How can constants be in dynamic equilibrium anyway?

I'm not sure why you are bringing up the ratio of [L] to [RL]? The ratio is nonlinear. As [L] increases, the equlibrium shifts toward [RL] and you end up with a greater %occupation. But occupation ([RL]) is asymptotic; [L] can increase indefinitely but [RL] is limited by Bmax.

I never said the relationship was linear, I just pointed to the fact that the higher [L], the higher [RL].

Anyway, I now realized that we were talking about slightly different things and I see what you meant all along now.

 

[Cotcha Yankinov]

Thought I would just post this study that seems to lend credence to the idea that "inferred" or internally generated things probably set off mirror neurons http://www.ncbi.nlm.nih.gov/m/pubmed/11498058/ They looked at the mirror neurons of monkeys responding to a visual task but hid the final portion of the task from view, and the mirror neurons still went off. From this we might conclude that they internally generated the last portion of the task but it still set off mirror neurons.