Pharmacology - That's How The Light Gets In: The 5-HT Receptor--LSD connection

[Songcycle67]

I did a search for a topic specifically detailing the relationship between LSD (specifically) and the 5-HT receptors but could only find vague articles. If I've mistakenly overlooked a similar thread please delete this one.

I'm posting this thread because there have been a lot of questions regarding tolerance and receptor sites recently and hopefully this will help to pool all that info. Additionally I believe that general information on this subject could help to answer a plethora of other questions. Please post, in as simple terms as possible, any information detailing how the 5-HT receptors respond to the presence of LSD in the brain.

I know there are plenty of SWIMmers out there who are more familiar with neuroscience than I and could help to shed light on this oft misunderstood/neglected subject, so I'll leave it to you all. Articles and excerpts from noted figures on this subject would be greatly appreciated. I also realize that there is a relatively small amount of data available on this subject, but hopefully through discussion we can refine the data that is available.

I suppose the best place to begin would be: very generally, what is the function of the 5-HT's and what is the going logic as to how LSD binding to these receptors engenders the psychedelic experience?


Edit: edited for clarification. Can some modest moderator please update the thread title to reflect this change? It should read "5-HT--LSD connection" instead of "5-HTP--LSD connection." Thanks shampoo.

[Shampoo]

Originally Posted by songcycle67

Please post, in as simple terms as possible, any information detailing how the 5-HTP receptors respond to the presence of LSD in the brain.

Is this a thread about 5-HT (Serotonin) receptors? or about 5-HTP (5-Hydroxytryptophan), a serotonin precursor? There is no receptor for 5-HTP in the brain, but there is a wide variety of receptors for 5-HT, at many of which LSD has action.

[Songcycle67]

Ah, I wasn't aware that 5-HTP was a serotonin precursor, I thought it was generally used to describe the receptor sites to which LSD binds. As I said in my original thread, my knowledge in neuroscience is extremely limited. I suppose I was referring to the 5-HT binding sites primarily, but information on 5-HTP as it relates to LSD and the LSD experience would be good as well. Can you help shed some light, Shampoo? The original post has been edited to clarify.

[Shampoo]

LSD and other tryptamine/phenethylamine psychedelics are postulated to work primarily by acting as agonists at the 5-HT-2a receptor. The 5-HT-2a receptor, a subtype of serotonin (5-HT) receptors is located throughout the prefrontal and somatosensory cortices, as well as the parietal lobe. They also, perhaps most importantly, have a significant presence in layer V pyramidal cells in the cortex that have been proposed to mediate activities that underlie many cognitive processes, including conscious awareness.

The 5-HT2a receptor is a g-protein coupled, metabotropic receptor. This means that unlike ionotrpic receptors, which open or close to change the flow of ions directly from stimulation by a neurotransmitter, they activate messenger proteins which act farther down the line, eventually activated protein kinase C, which in turns increases Ca++ release, which is a necessary component of further neurotransmitter release. Its actions are primarily excitatory, meaning that it increases the probability of neurons firing action potentials (sending signals). It has action outside of the brain as well, in muscular contraction and vascular dilation, but these activities hold far less importance regarding the action of LSD and other psychedelics. Though the receptor is generally excitatory, it shows some inhibitory action at the visual and orbitofrontal cortices, the former of which may explain its effects on vision (though I happen to believe that occurs elsewhere, that’s a topic for another discussion I suppose) and the later of which has been implicated in the neural activity of decision making.

Studies examining the co-administration of LSD and other tryptamine/phenethylamine psychedelics with 5-HT2 antagonists have shown that the discriminative stimulus effects of the agonists are effectively blocked by antagonists. This gives credence to Glennon’s original proposal that these psychedelics elicit their effects through the 5-HT2 subtypes of serotonin receptors. This search was further narrowed by blocking only the 5-HT2A receptor, and not other 5-HT2 subtypes targeted by the psychedelics (particularly 5-HT2C). This antagonism of 5-HT2A also showed efficient blocking of the effects of LSD and other psychedelics, even when the compounds were still allowed to act as agonists at the other 5-HT2 subtypes. 5-HT2C antagonists have been shown to have no effect on the action of LSD and other psychedelics. Further evidence still, conducted by Strassman et al. on the activity of DMT at 5-HT2 receptors, provided support for the 5-HT2a receptor as the primary site of action for hallucinogenic tryptamines. Downregulation of the 5-HT2c receptor showed no decrease in subjective effects of the psychedelic, while downregulation of the 5-HT2a showed a marked diminishing effect. Though most of this evidence comes from rat trials, recent tests using human subjects showed a marked decrease in the subjective effects of hallucinogens following administration of a highly selective 5-HT2a antagonist.

The 5-HT1a receptor has also been shown to play a vital role in the activity of the psychedelic hallucinogens, which has been primarily investigated via 5-MeO-DMT, which like LSD acts as an agonist at both the 5-HT2a and 5-HT1a receptors.

Problems with this theory: the primary problem with the hypothesis that LSD activity is mediated primarily or even solely via the 5-HT2a receptor is that LSD has a much weaker binding affinity for this receptor than other compounds which are 20-30 times less potent, like DOI and DOM, which have a much greater affinity for the 5-HT2a receptor. If the 5-HT2a receptor is the primary site of activity for psychedelics, then shouldn’t compounds with greater binding affinities be more active? The most common explanation for this is that the 5-HT2a receptor is coupled to a yet undefined or undiscovered pathway. It is also possible that LSD’s effects elsewhere have a modulatory effect on the 5-HT system, or even particularly on the 5-HT2a receptor.

Additionally, in vitro studies show different effects than those in vivo, which more than likely has to do with the fact that the receptor is metabotropic and not ionotropic. While in vivo studies show that administration of an agonist results in a marked increase of 5-HT in the synaptic cleft, in vitro studies show the opposite, which led many researchers to originally call LSD a 5-HT antagonist that reduced the release of 5-HT. This is further complicated by the fact that LSD also acts as an agonist of the 5-HT1a receptor, which is a somatodendritic autorceeptor, which in simple functional acts in an opposite manner of the other 5-HT subtypes. Autoreceptors inhibit neurotransmitter release, and thus an agonist of the 5-HT1a receptor will inhibit the release of 5-HT. This effect is more than counteracted by the agnonism of excitatory postsynaptic receptors, though it has confused many a researched in investigating the effects of LSD.

Questions? I wasnt really sure where to begin or what to focus on, so I just kind of picked and choosed what I thought might be relevant information. There is a whole lot of information here, alot of which may be complex or riddled with jargon for some people. Please let me know what you would like to be most clarified, the actions of LSD at the 5-HT receptors biologically? or the activities of 5-HT receptors in mediating behavioral and cognitive processes? I am happy to simplify or clarify anything above, as well as expand.

Reputation Comments on this post:

	wonderful, thorough information!
	there should be a forum dedicated to neuropharm
	awesome post

[Songcycle67]

It seems pretty straight forward to me and it definitely answered a lot of the questions that I was looking for. Excellently thorough. Could you or anyone else give any more information as to how LSD binding to these sites illicits things such as synaesthesia, visuals, euphoria, etc? For example how do the effects of normal compounds like serotonin differ from LSD in their action when they go through the 5-HT's? Do they just overexcite the neurons? Is the inebriation due to the brain being "scrambled" basically or is it something more elegant?


Also, as a sidenote are there any notable differences between the action of LSD once it enters the 5-HT's and mescaline or mushrooms?