Do endogenous ligands cause tolerance?

[Limpet_Chicken]

A question popped into my head posting in the big and dandy amanita thread in PD, someone posted a link describing someone's extended and extensive use of low-dose A.Muscaria as a tonic and to beat back the winter blues, and mentioned it caused no tolerance, or withdrawal, fiending after long term use.

My curiosity was, as muscimol is a potent agonist at the GABA binding site on GABAa, could it be mimicking GABA sufficiently as to act enough like it not to cause a tolerance, do endogenous agonist ligands cause downregulation or desensitisation? it would make sense for the native agonist for a receptor to cause little functional tolerance, homeostasis-wise, I know its a plastic process and forever in flux, but do endogenous ligands that pass the BBB cause tolerance by any means usually cause a tolerance if administered in quantities that would be released in normal neurotransmission?

Not that there are that many, most seem to be blocked by the BBB and exert only peripheral effects, GABA, some large peptides, serotonin, oxytocin, most seem to be unable to get in there if taken from the outside, which is likely again a good thing, from the bodys point of view.

 

[Temeraroius]

Really interesting but I frankly have no idea.

 

[The Monkey Mantra]

Yes, they do. An agonist is an agonist is an agonist. While the high-affinity endogenous opioid ligands may have a different time-frame for tolerance and dependance due to the high level of receptor endocytosis they seem to stimulate, there's cross-tolerance and cross-dependence between beta-endorphin and morphine.

Tolerance as a homeostatic mechanism was put into place not only to protect our brains from external drugs but to help regulate *all* signalling.

Here's a ref:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=431379

 

[Limpet_Chicken]

Thanks, about to read that now.

Interesting that met-enkephalin didn't produce attenuation of withdrawal symptoms, at least in the rat model, that would imply at least that an incomplete cross tolerance CAN be produced by some agonists.

Makes me wonder how things like herkinorin tie in, that stuff seems to suggest that its possible to have a ligand that produces no tolerance, at least theoretically (although arrestins aren't probably the sole medium through which tolerance is produced)

Anecdotally, low dose regular use of Amanita Muscaria doesn't seem to produce tolerance, and I have never read a report of addiction or withdrawals, indeed some detailed reports specifically state there was no withdrawal, and everything to me, suggests that withdrawal from a high affinity, high efficacy GABAa agonist ligand would be absolutely hellish, if not even acutely dangerous.

ya know, thats one of the things I love about science in general, with every question answered, it throws up another load of things that need answering.

 

[The Monkey Mantra]

You're correct in noting that beta-arrestin recruitment is just one of MANY tolerance mechanisms. Just because you don't have that going on doesn't mean you don't have phosphorylation, for example. Problem is, a lot of studies on beta-arrestin knockout mice show they don't get tolerant, but they don't show for *how long* this effect lasts. I, for one, just don't believe it lasts forever.