Neurotransmitters. The brains natural drugs.

[R2o]

Hey its been a while since I've posted here and I have some interesting questions that maybe someone here has some amount of knowledge on.

As you all know, tolerance to a drug is inevitable and dreaded. I have heard of dxm affecting tolerance to opiates in a good way. But why does tolerance occur in the first place? But on a more interesting note, our neurotransmitters are our brains natural drugs and are constantly touching our receptors. So why do we not gain a tolerance to these endogenous chemicals?

 

[sekio]

Our neurotransmitters aren't really "natural drugs". They're the chemicals our brain uses to transmit messages across a small, wet, non-conducting gap between neurons... so the question is kind of like asking why we don't go deaf when people are talking at a normal volume nearby. Usually the release of neurotransmitters into a synapse is self-limiting, e.g. there are serotonin and adrenergic autoreceptors that, when activated, decrease the amount of neurotransmitter release... kind of a negative feedback loop, so you don't get too much, say, serotonin, flooding the synapse at once.

Tolerance is simply your brain's way of trying to maintain a happy medium of neurotransmitter release. When postsynaptic receptors (say for the sake of example, the mu opioid receptor) are stimulated beyond their baseline activity level the body interprets this as "hmm I am making too much endorphin/enkephalin" and decreases production, as well as internalizes (deactivates) opioid receptors to avoid the signaling being at a high level all the time. This means when you stop taking strong opioids after taking them for a while, your body has adapted to having a higher level of opioid signaling, and hence you get withdrawals because your body now doesn't get enough opioid signaling naturally (because it has decreased production of neurotransmitters & internalized the receptors). So you can take a few days, weeks, months or even years of avoiding drugs before you return to homeostasis.

 

[R2o]

Wow! I think you nailed it sekio and thats great because I couldn't find information anywhere on this topic. Thank you for your enlightening reply. Now only if we could figure out that negative feedback loop mechanism and apply that to prevention of drug tolerance. Is there anyone that can offer a scientific response as to why dextromethorphan or even other NMDA antagonists affect tolerance to opiates?

 

[FrogWarrior]

Nobody knows exactly how and why tolerance occurs, if we knew all the specifics we'd be able to figure out how to prevent it and reverse it entirely. It'll be happy days when we figure that out. The brain does develop tolerance to neurotransmitters. People literally have withdrawals from things like gambling cuz the amount of dopamine released drops so their brains have to increase the number of receptors and sensitivity to get back to homeostasis. Amphetamine doesn't actually bind to dopamine receptors, it seeps into synaptic vescicles and forces dopamine and norepinephrine out of them, in other words it forces dopamine to be released, so the tolerance that builds up, a lot of that is tolerance to increased dopamine levels. There is so much we don't yet know about what drugs actually do. One reason NMDA antagonists prevent tolerance is that they block one of the steps in a neurochemical cascade that the brain uses to "learn", in other words it interferes with one of the mechanisms of neuroplasticity. You can consider them the brains natural drugs, notice the way you often feel high right before you actually take the drug. Neurotransmitters are only part of the puzzle though, theres more to it than that, and theres likely gonna be revolutionary changes in the model of pharmacology when more is discovered.

 

[G1forlife]

Greeting, as a Harm Reductionist I would like to intoduce to you the use of amino acids that have proven to help users kick (DLPA) and L-Tyrozine in conjunction with Vitamin C and Calcium Magnesium...

Check it out the Aminos that feed the brain by giving it what the drugs have depleted......

Peace and Be Pure

 

[thikal]

as well as internalizes (deactivates) opioid receptors to avoid the signaling being at a high level all the time.

Isn't the contrary? Receptors stocked in the postsynaptic neurone next to the synapse (not far) first are externalised (fast tolerance), then messages are sent to the nucleus of the postsynaptic neurone to increase receptor synthesis (long term tolerance)?

Basically, isn't tolerance the same mechanism than LTP (long-term potentiation)? That's my understanding of the mechanism but I may be totally out

 

[Jonneh]

Basically, isn't tolerance the same mechanism than LTP (long-term potentiation)? That's my understanding of the mechanism but I may be totally out

It depends which neurons you're talking about, and how the drug acts. In a simple circuit, with an agonist drug or positive modulator, the process will resemble LTD (not LTP); internalisation of the receptors on which the drug acts. Reverse the situation for antagonists or inverse agonists. At synapses onto other types of neurons (excitatory or inhibitory) you might get the opposite result, if the compensatory homeostasis is far-reaching.

 

[endotropic]

Isn't the contrary? Receptors stocked in the postsynaptic neurone next to the synapse (not far) first are externalised (fast tolerance), then messages are sent to the nucleus of the postsynaptic neurone to increase receptor synthesis (long term tolerance)?

Basically, isn't tolerance the same mechanism than LTP (long-term potentiation)? That's my understanding of the mechanism but I may be totally out

If you add more receptors to the synapse then the same stimulus (drug or neurostransmitter) will produce a bigger response in the postsynaptic neuron. You basically just described one mechanism of sensitization, not tolerance. You're right that LTP works that way, so you can think of LTP as a form of sensitization.

 

[thikal]

OK thanks a lot for the input I learnt at uni LTP for memory formation, and thought that this mechanism may explain tolerance. It was the exact opposite actually, LTD.

 

[dopamimetic]

Think LTP / learning is the cause of cravings and "learned" intensified withdrawals or fears of. Also sensitization likely is. But as has been said, tolerance is another thing and imo regarding the most drugs or receptors, is reversible over time. The other question is, how much of a "short-circuit" to the tolerance state is left behind, e.g. if the time needed until tolerance kicks in gets reduced every tolerance-withdrawal cycle. Do have a strong feeling that this is the case for SSRI type anti depressants (maybe serotonergics generically - opioids/gabaerics maybe too, for some - at least the opioids are not in my case. dopaminergics i am unsure of. nor/adrenaline imo is undoubted the least long-term-tolerance sensitive system...?)