I'd like to explore how it doesn't cause overdose when inhaled., but creates a perceptible (debatable) effect otherwise, especially without tolerance. A ceiling effect somehow.
I wasn't aware that (ionotropic) LGIC's really could lead to the altering of transcription factors. That's for GPCR receptors, wherein it's more than a difference in charge in neuronal communication. Nicotine doesn't mess with metabotropic recptors, I thought. Could be wrong. But secondarily somehow I guess binding to NACRs leads to the release of monoamines and such, which I would like to know how that works. Heteromeric activity, guessing, somehow. Dunno lol.
Very interesting questions I can’t promise great answers, but let me try and address each point to the best of my very limited knowledge.
Firstly, nicotine overdose can occur by any root of ingestion. The thing is, inhalation tends to deliver a large dose very quickly to the brain, satisfying the user almost instantly. inhaling any more after that point will create nausea and dizziness instantly and along with airway irritation these prompt the user to stop before they overdose.
As for the ceiling effect, I assume you’re referring to how nicotine euphoria only ever reaches a certain, perhaps disappointingly low level when compared to most other drugs. there are many possible reasons for this and I would say they all revolve around its action at nicotinic receptors. for example, nicotine has no direct effect on dopamine transport like cocaine or amphetamines. instead, it changes dopamine neuron excitability, Slightly increasing their output in a similar manner to alcohol, benzodiazepines and opioids. however, it’s probably not even as strong as those drugs in this regard. but there’s another more interesting property of nicotine that could contribute to a ceiling effect. this is the rapid desensitisation of all nicotinic receptors, but especially the alpha7 nicotinic receptor. on the surface, this sounds disappointing, but it turns out to be incredibly amazing because that mechanism, specifically alpha7 inhibition stops nicotine from literally destroying your brain cells. actually, nicotine is so good at rapidly desensitising these receptors, that nicotine might provide protection against the neurotoxicity of amphetamine analogs like MDMA.
Finally, in regards to how nicotine produces epigenetic effects, i’ve struggled to find a clear explanation in the literature. I suspect most of it comes through activation of ionotropic nicotinic receptors. as for how they modulate transcription factors, I think that happens because the subsequent influx of ions like calcium activate intracellular enzymes such as PKA, ERK1/2 calpain and CDK5 etc. all of these are capable of targeting, and are themselves the targets of various transcription factors.
