Confused about pharmacodynamics of drugs

[Lightning-Nl]

I am having a hard time clarifying this using materials online.

I know that there are chemicals which mimic neurotransmitters and therefore don't actually heighten levels of said neurotransmitter, but rather "enhance it" by mimicking the neurotransmitter. (one such category would be benzodiazepines). And then there are chemicals that exert their MOA by heightening or lowering levels of neurotransmitters. For instance I know that Amphetamine doesn't actually bind to (and therefore doesn't mimic) Dopamine receptors, but heightens it through indirect agonization (reversing transporters).

This is where I get confused. I always thought that when a drug binds to a receptor, it releases its respective neurotransmitter and that's what produces its effects. However, I know that benzodiazepines don't actually heighten GABA but rather make the body believe that massive amounts of GABA are binding to the receptors.

So what's the actual deal here? Was I wrong that when a drug binds to a receptor that it doesn't release that receptors neurotransmitter? But rather just mimics it? Or was I right?

On a side note. Do opiates mimic endogenous peptides? Or does it cause a release of endogenous opiates?

Thanks guys.

 

[endotropic]

I am having a hard time clarifying this using materials online.

I know that there are chemicals which mimic neurotransmitters and therefore don't actually heighten levels of said neurotransmitter, but rather "enhance it" by mimicking the neurotransmitter. (one such category would be benzodiazepines). And then there are chemicals that exert their MOA by heightening or lowering levels of neurotransmitters. For instance I know that Amphetamine doesn't actually bind to (and therefore doesn't mimic) Dopamine receptors, but heightens it through indirect agonization (reversing transporters).

This is where I get confused. I always thought that when a drug binds to a receptor, it releases its respective neurotransmitter and that's what produces its effects. However, I know that benzodiazepines don't actually heighten GABA but rather make the body believe that massive amounts of GABA are binding to the receptors.

So what's the actual deal here? Was I wrong that when a drug binds to a receptor that it doesn't release that receptors neurotransmitter? But rather just mimics it? Or was I right?

On a side note. Do opiates mimic endogenous peptides? Or does it cause a release of endogenous opiates?

Thanks guys.

Receptors themselves don't contain or release neurotransmitters, neurons do. A neuron that releases GABA can have dopamine receptors, GABA receptors, glutamate receptors, whatever receptors. When dopamine binds to a dopamine receptor on a GABA neuron, it changes the amount of GABA released from that neuron, it does not cause dopamine release. Does that clear things up?

Side note: Opiates mimic endogenous peptides.

 

[Lightning-Nl]

Receptors themselves don't contain or release neurotransmitters, neurons do. A neuron that releases GABA can have dopamine receptors, GABA receptors, glutamate receptors, whatever receptors. When dopamine binds to a dopamine receptor on a GABA neuron, it changes the amount of GABA released from that neuron, it does not cause dopamine release. Does that clear things up?

Side note: Opiates mimic endogenous peptides.

I was aware that neurons are what release the neurotransmitters but the rest I had no idea about! I was unaware that neurons can have all receptors on them. That makes me assume that...lets say GABA binds to a Dopamine neuron; I'm assuming that the increase GABA binding will cause the neurons to greatly decrease the outflow of Dopamine, correct?

 

[sekio]

it depends on where the neurons are located and which particular signalling cascades they express. if every neuron in the brain expressed every receptor it would be hard to get any sort of selectivity towards, well, anything.

the term you are thinking of (w.r.t benzodiazepines) is a positive allosteric modulator. benzodiazepines and z-drugs make some subtypes of gaba-a receptors remain in the open conformation for longer - thereby increasing "sensitivity" to GABA. they neither make the body think there is an excess of the neurotransmitter, nor do they activate the receptor directly.
there are also negative modulators of receptors, like some compounds binding e.g. the NMDA receptor.

So what's the actual deal here? Was I wrong that when a drug binds to a receptor that it doesn't release that receptors neurotransmitter? But rather just mimics it?

that's pretty much the long and short of it. generally drugs that are "receptor activators" just bind to the recptor and stabilise it in its active conformation.

in some special cases like e.g. autoreceptors, the receptors are part of a feedback loop and agonising them makes your body think there is elevated levels of neurotransmitter, reducing release as a result. some, but not all, 5ht1a receptors do this, for instance. (the autoreceptor is actually a slightly different expressed genetic sequence than the postsynaptic "normal" receptors and can thus be selected towards, or against.)

there are autoreceptors for a lot of systems. the most common 2 off the top of my head are a2 adrenoreceptor and 5ht1a.

On a side note. Do opiates mimic endogenous peptides?

yes, the "natural" ligands for the mu/delta/kappa receptors are all protiens.

 

[Lightning-Nl]

ah sekio, you just made the mechanism of action of alpha-2-adrenonergic agonist like clonidine, and Guaficine(Inutiv-SP?) so much clearer too me. I never understood the whole auto-receptor thing, and how agonizing alpha-2 "tricks" the brain into thinking there's too much NE. Thankyou alot for that post alot Sekio, I continue to learn alot from your contributions

I concur. Your insight is invaluable Sekio. I'm sure everyone on this forum appreciates your contributions.

 

[sekio]

no problem. i try my best.

 

[endotropic]

in some special cases like e.g. autoreceptors, the receptors are part of a feedback loop and agonising them makes your body think there is elevated levels of neurotransmitter, reducing release as a result. some, but not all, 5ht1a receptors do this, for instance. (the autoreceptor is actually a slightly different expressed genetic sequence than the postsynaptic "normal" receptors and can thus be selected towards, or against.)

As far as I'm aware, there's no difference in the genetic sequence between 5-HT1A auto/heteroreceptors. The only difference between the two pools of receptors is the neuronal type they're located on (auto = 5-HT neuron, hetero = glutamate, GABA, ACh , etc.). How some drugs select between these two pools is a mystery.