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Receptors

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markosheehan

Bluelighter
Joined
Sep 17, 2016
Messages
238
Im sorry i think this is a noob question but i having trouble finding the answer.
Why do we have receptors for drugs in our body ?
What do these receptors do when we are not taking the drugs? Are they stimulated without taking the drugs ?
I read that when a drug binds to a receptors it transmits a signal. What is this signal?
What happens after to produce the effects? Is it to do with downstream pathways?
I am mainly concerned with the first and second question
 
The receptors are really there for "endogenous" ligands. So as an example, we don't have CB1 receptors for THC, we really have CB1 receptors for endocannabinoids - THC just happens to be a similar molecule so it manages to fit into CB1 as well.

After a molecule binds to a receptor different things can happen depending on whether it's a G-protein coupled receptor or whether it's a ligand gated channel. In the case of CB1, after an agonist binds it sets off the G protein signaling cascade and this will cause some change in the cell.
 
are these endogenous ligands like drugs when they bind receptors? does a signaling cascade happen? do they affect consciousness?
thanks for your reply
 
do you know if wikipedia is the best for learning about this stuff or is there better? i have checked out the page on this for sources but some are too complicated and some do not go into enough detail. also some only cover specific topics. is there a general source
 
The endogenous (or "naturally occurring") ligands are indeed like drugs - endogenous ligands bind to receptors and a non-endogenous ligand like THC is essentially an imitator/impersonator of the endocannabinoids.

So we naturally produce serotonin in our brains that is meant for serotonin receptors but LSD can also bind to serotonin receptors because the molecule is a similar shape. But depending on how exactly the molecules bind to the receptor, they will cause the receptor to signal down through different pathways. They call this a biased ligand or functional selectivity. It's kinda the reason why serotonin binding to 5-HT2A doesn't produce psychedelic effects but LSD etc cetera binding to 2A does.

I like wiki but a neuropharmacology book may help
 
Everyone has given good input so far! There's also a distinction between endogenous small molecules, which are things like neurotransmitters (serotonin, dopamine, etc.), and peptides. A number of receptors which respond to small-molecule drugs bind peptide hormones endogenously which provide a similar effect. A good example of this is endorphins, which are natural neuropeptide hormones which are released to mitigate sensation of pain, and which bind to and activate opiate receptors.

It's also important to realize that two drugs can bind the exact same receptor with the exact same affinity, and actually cause distinct signaling cascades. This can be referred to as biased agonism, or functional selectivity.

Honestly, there's quite a few different ways that receptor activation can cause cellular signal propagation; it really depends on the system you're interested in, and you can usually go as far in depth with it as you want to go.
 
Serotonin is psychedelic though? If only briefly upon iirc intraventricular administration. Am i mistaken?

But the point stands that the particular signal cascades are important, as well as selectivity of a drug for subtypes. Serotonin i assume has much less selectivity for 5-HT receptors than various drugs.

With drugs you can tweak things like duration of effect, absorption, resistance to degradation... the necessary things for a drug to last a while instead of being degraded and recycled rapidly like a lot of the brain's own neurotransmitters.

The signal cascade involves a lot of complicated machinery (sometimes more than others), including changes in the structure of the receptor when it's activated, parts that may become dissociated on the inside of the postsynaptic neuron and act as a further messenger (so messages - like stimulating and inhibiting are sent endlessly in the most complicated relay race).
But also what these messages are involved in is the electric polarization of neurons, which charge up and fire. Neurotransmitters influence this firing and also the other way around. I'm sure Cell or something has created wonderful educational videos, or just Ted-Ed etc... to start you off before diving into neuropharm books :D
 
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^RE: 5-HT not being psychdelic, I think the 2 commonly cited practical examples of that are that SSRIs and SRAs (MDA-esque SRAs aside) aren't psychedelic, and that there are also supposedly 5-HT2A agonists that aren't psychedelic while the psychedelic 5-HT2A ligands have some functional selectivity effects going on, and differences in functional selectivity across all the serotonin receptors gives rise to the differences between DMT - psilocybin - LSD and so forth.
 
AFAICT serotonin is too rapidly destroyed to provide a psychedelic effect. Also its polarity makes it a poor BBB crosser.
 
Yeh I said intraventricular... but was wrong about thinking serotonin is psychedelic, not sure where I got that from.

The reason is apparently different: serotonin does not promote 5-HT2A - mGlu2 interaction / inhibitory effect on mGlu2 while psychedelics do. I thought the particular effects of psychedelics had to do with downstream pathway difference (IP3 vs ...), so am I right to assume this is both correct and the mGlu2 interaction makes that difference to downstream pathways?

Anyway sorry if off-topic.

Markosheehan, not 100% sure but I think in this thread there are now and then sources mentioned for studying these matters: http://www.bluelight.org/vb/threads...mistry-Pharmacology-Odds-N-Ends-Thread-Part-3 and maybe then also the previous versions of the thread, but guys correct me if i'm wrong.
 
So, the thing is, most drugs are DRI's, meaning they inhibit the reuptake of dopamine by blocking the reuptake transporter. Some also inhibit MAO/COMT and release all the vesicular dopamine. This floods the synapse with so much dopamine that over time, the postsynaptic neuron ends up degrading their receptors so that it requires more drug to elicit the same effect. This is what people refer to as tolerance. Now, when you stop taking the drug, the body tries to restore homeostasis by upregulating the receptors and this is what is known as withdrawal. It is the shitty feeling that you get when you stop taking a drug because your body is trying to go back to normal.
 
thanks for all your replies
how come 2 bromo lsd is not active something to do with biased agonism yes? is it not active in the same way serotonin is not active?
how do signaling cascades eventually cause changes in consciousness ?
i need to read all your replies in depth. i only skimmed through them.
 
"It was found to bind to many of the same receptor targets as LSD, but acting as a neutral antagonist rather than an agonist."

Biased agonism is about selectivity for pathways activated through agonism, but 2-bromo-LSD is not an agonist so no proper activation of the relevant receptor to begin with. I guess it still does have some activity at one serotonin receptor subtype or another, otherwise I don't get why it retains vasoactive effects useful for migraine treatment.

Receptors like 5-HT2A are found abundantly in the neocortex, the higher brain involved with conscious reflection and awareness and they appear to be important for those functions. I don't think it's really known how or why these particular signaling pathways downstream from 2A activation cause such profound changes in consciousness.
If I had to venture a guess I'd say that there are feedback mechanisms involved which in the right mode could cause things like
- catalysis / potentiation of signals,
- feedback in loops which in sensory systems like the visual cortex could produce fractal patterning among other things
- inhibition of boundaries between normally rather separate faculties (the melding together can cause synaesthesia for example)
- perhaps other forms of chain reaction which could alter thought patterns and combined with the inhibited boundaries allow abnormal associations to be made, much more freely..

Don't know how many steps would be involved in the signal cascade, but I think the best explanation involves such chain reactions - possibly there are key parts in the brain acting like a switchboard / filter, in connection with and in some control of many other functions - it may take relatively small amounts of material acting there to cause profound changes, like a 'single point of failure'. Well, if you'd call that failure.. ;)
 
deadendgame said:
So, the thing is, most drugs are DRI's, meaning they inhibit the reuptake of dopamine by blocking the reuptake transporter. Some also inhibit MAO/COMT and release all the vesicular dopamine. This floods the synapse with so much dopamine that over time, the postsynaptic neuron ends up degrading their receptors so that it requires more drug to elicit the same effect. This is what people refer to as tolerance. Now, when you stop taking the drug, the body tries to restore homeostasis by upregulating the receptors and this is what is known as withdrawal. It is the shitty feeling that you get when you stop taking a drug because your body is trying to go back to normal.
Click to expand...

Some drugs are DRI's, not most.
 
Cotcha Yankinov said:
The endogenous (or "naturally occurring") ligands are indeed like drugs - endogenous ligands bind to receptors and a non-endogenous ligand like THC is essentially an imitator/impersonator of the endocannabinoids.

So we naturally produce serotonin in our brains that is meant for serotonin receptors but LSD can also bind to serotonin receptors because the molecule is a similar shape. But depending on how exactly the molecules bind to the receptor, they will cause the receptor to signal down through different pathways. They call this a biased ligand or functional selectivity. It's kinda the reason why serotonin binding to 5-HT2A doesn't produce psychedelic effects but LSD etc cetera binding to 2A does.

I like wiki but a neuropharmacology book may help
Click to expand...


Agreed. You know your shit and you are very well informed.
 
The entirety of your conscious mind is the result of incredibly complicated chemistry. A lot of that involves trafficking of endogenous receptor ligands and how that influences nervous signals.

The whole receptor signaling thing is a product of evolution. Many psychoactive drugs are derived from natural compounds that organisms evolved in conjunction with the receptors they target. Often, exogenous ligands are actually a defense mechanism against predators.
 
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