LSD receptor affinities

[BilZ0r]

LSD Receptor Affinities

The affinity of LSD for various receptors. The black line represents the lowest affinity LSD could have for that receptors and that effect still being relavant. i.e. Any receptor which has affinities over the bar is not significantly affected by LSD during recreational usage*. I don't know off the top of my head which of those effects are agonisms and which are antagonisms, though I'd be keen for someone to do that dredging.

I put this together to explain LSDs high activity (though could this just be because it is resistant to metabolism? Anyone?) I doubt 5-HT6 has much to do with it, because it seems to be localized heavily in the basal ganglia. 5-HT5 is a possibility thought...


*This conclusion is made from the belief that LSD doesn't reach much above 20nM in the plasma in recreational use, and does not distribute specifically to the brain.


Data from:
PDSP
AGHAJANIAN, G.K. & BING, O.H. (1964). Persistence of Lysergic Acid Diethylamide in the Plasma of Human Subjects. Clin Pharmacol Ther, 10, 611-4.
HAWKS, R.L. & CHIANG, C.N. (1986). Urine Testing for Drugs of Abuse. Rockville, MD: Department of Health and Human Services.

 

[Dr. Beat]

I read on PubMed a few months ago that there are plenty of 5HT 6 receptors in the cortex and when seratonin hits them they reduce glutamate release in the cortex. IT was also saying that a 5ht6 antagonist would increase cognitive ability or something like that.

 

[BilZ0r]

^ Receptor yes, but mRNA, not really.

Ann N Y Acad Sci. 1998 Dec 15;861:91-6.
The putative 5-ht6 receptor: localization and function.
Sleight AJ, Boess FG, Bos M, Bourson A.
In situ hybridization studies and Northern blots indicate that the density of 5-ht6 receptor mRNA is highest in olfactory tubercle, followed by striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. 1,2,4 Lower levels are seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in layers 2,3,4 and 6 of the cortex. 4 5-ht6 mRNA is present in 5-HT projection fields but not in the 5-HT neurons of the raphe nucleus and lesioning of 5-HT neurons by injection of 5,7-dihydroxytryptamine had no effect on the levels of 5-ht6 mRNA. 5

And although the human evidence isn't exactly, regerous, the mRNA in the whole brain homogenate is pretty weak, but massive in the caudate, and low again in the hippocampus and amygdala... things that look bad for cortical expression.

Meanwhile, this reference to glutamate.. I'd be really keen to see that

 

[Dr. Beat]

i am in SE asia right now, but when i get home in a few weeks, i will find it and post it, cause i printed it out a few months ago. It was about a new (and the only) selective 5HT 6 antaganist they just made and they theraputic benifits it could have.

 

[sexyanon2]

A little off topic question:

We have receptor A. Receptor A receives chemical a. Like 5HT2a receives serotonin. Now, if A receives b, A still "fires off", like the 5HT2a "fires off." (When serotonin receptor receives serotonin, a signal is fired off).

Now, if a diff. chemical is received, what's the difference? I believe that with medication, that if an SSRI produces side effects, the SSRI did not get sucked into the SR completely because of molecular structural differences.

But with LSD, what happens? Do we have any other examples of this occuring? Obviously it would have to be something very recent with medicine, but is there something that produces effects? The SSRI just means: less serotonin reuptake. The SR doesn't send off another signal.

Also, have they compared receptor activity in LSD-induced-highs and OOB or any mystical/transcendental experiences? What does each receptor (the ones that LSD has affinity for) do normally?

 

[BilZ0r]

I just want to clear up any ambiguities here.

When a receptor recieves an agonist, i.e. a chemical which activates that receptor, the receptor will in someway, transduce the signal, but that does not mean that the neuron that the receptor is on, will fire.

Of course, there are chemicals which will bind to a receptor, and not activate it. These are antagonists, they stop agonists from activating the receptor.

But with LSD, what happens? Do we have any other examples of this occuring? Obviously it would have to be something very recent with medicine, but is there something that produces effects? The SSRI just means: less serotonin reuptake. The SR doesn't send off another signal.

I don't understand. What happens in regards to what? Do we have any examples of what? What effects? When you say SR what are you talking about? Serotonin receptors, or serotonin reuptake transporters?

 

[scarmani]

D2 Agonism Plays Role In LSD Effects?

Here is a recent journal article that would suggest D2 receptor stimulation plays a significant role in LSD's discriminative stimulus. It is interesting to compare these results with the chart above, which would suggest that the dopaminergic activities of LSD are not potent enough to play a large part in LSD's effects.


Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis.
Danuta Marona-Lewicka, Ronald A. Thisted, David E. Nichols
Psychopharmacology (Berl). 180(3), 427-435 (2005)

http://www.streamload.com/scarmani/...in_the_rat_and_implications_for_psychosis.pdf


Abstract:

RATIONALE: The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity.

OBJECTIVES: We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.

METHODS: Twenty-five male Sprague-Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task.

RESULTS: LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane.

CONCLUSION: The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D2 dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.


Also in the following chapter, Nichols gives the D2 receptor affinity of LSD as 6.4 nM (IC50 in rat striatum for D2-like):

http://www.heffter.org/review/Review2/chap6.pdf

 

[fungus44]

RESULTS: LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane.

Would this explain the central dynamic of a full blown acid trip? My own experience is an early period of anxiety, very uncomfortable and very thoughtful, followed by plateaux, peaks, and a handsome comedown full of grace and joy. I've found a similar structure to 2ct2 trips.

I'm also someone not generally keen on 5HT.

 

[BilZ0r]

^ What do you mean you're not keen on 5-HT?

Anyway, drug discrimination isn't useful for much... certainly like that it's not. 5-MeO-DMT can be made to generalize 100% to 5-HT1A agonists if you do it right, but that doesn't mean that hallucinations have anything to do with 5-HT1A agonism.

 

[scarmani]

5-HT5, 5-HT6, 5-HT7

Here is an article that has an interesting discussion about 5-HT5 receptors; suggesting perhaps that 5-HT5 contributes to LSD's unique effects as BilZ0r suggested?


In The Search For Selective Ligands Of 5-HT5, 5-HT6 and 5-HT7 Serotonin Receptors.
Anna Wesolowska
Polish J. Pharmacol., 54, 327-341 (2002)

http://www.if-pan.krakow.pl/pjp/pdf/2002/4_327.pdf

"The physiological function of 5-HT5a receptors is still unclear. On the basis of their localization it is
proposed that 5-HT5a receptors may be involved in multiple functions of forebrain 5-HT, such as regulation
of affective states, cognition, anxiety (and related behaviors), sensory perception and neuroendocrine functions."


and

5-HT5 receptors.
Nelson D.L.
Curr Drug Targets CNS Neurol Disord., 3(1), 53-58 (2004)

http://www.ingentaconnect.com/content/ben/cdtcnsnd/2004/00000003/00000001/art00006

"The 5-HT5 receptor family consists of two members designated as 5-HT5A and5-HT5B. To date the 5-HT5A receptor has been identified in the mouse, rat, and human.The 5-HT5B receptor also is expressed in the mouse and rat, but not in the human wherethe coding sequence is interrupted by stop codons. Both receptors are essentiallylimited in distribution to the central nervous system (CNS), although the 5-HT5A receptor has also been found on neurons and neuronal-like cells of the carotid body.Within the CNS the 5-HT5A receptor shows a relatively broad distribution, while the5-HT5B receptor has a very restricted distribution. The 5-HT5A receptor has beendemonstrated to couple to G proteins, and the primary coupling appears to be throughGi / o to inhibit adenylyl cyclase activity. The 5-HT5 receptors have not been extensivelycharacterized pharmacologically. Both receptors show their highest affinity for LSD, which appears to act as apartial agonist at the 5-HT5A receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine) alsohas high affinity and has greater potency and affinity at the 5-HT5A receptor than does 5-HT itself. Both[125I]LSD and [3H]5-CT have been used as radioligands to study the receptors in vitro. Nothing is known aboutthe role of the 5-HT5B receptor in vivo. A mouse line has been developed where the 5-HT5A receptor has beenknocked out and these animals have been shown to have a diminished response to LSD-induced increases inlocomotion. The 5-HT5 receptors remain as two of the least studied and understood of the 5-HT receptor subtypes."

 

[scarmani]

5-HT1a agonism plays role in LSD effects

5-MeO-DMT can be made to generalize 100% to 5-HT1A agonists if you do it right, but that doesn't mean that hallucinations have anything to do with 5-HT1A agonism.

It is an interesting question whether 5-HT1A agonism plays an important role in the psychedelic effects of many tryptamines like 5-MeO-DMT. For example here is an article that suggests 5-HT1A agonism plays a significant role in LSD's discriminative stimulus. I wonder if anyone has reported that buspirone (Buspar) or other 5-HT1A receptor agonists potentiate or modulate the effects of psychedelics in humans?


The 5-HT1A receptor and the stimulus effects of LSD in the rat.
C. J. Reissig, J. R. Eckler, R. A. Rabin, J. C. Winter
Psychopharmacology., Online First

PDF


"Rationale: It has been suggested that the 5- HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD).

Objective: The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD.

Methods: Twelve male Fischer 344 rats were trained in a two-lever, fixedratio (FR) 10, and food-reinforced task with LSD (0.1 mg/ kg, i.p.; 15-min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT1A agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT1A ligands were also tested in the presence of the selective 5-HT1A receptor antagonist, WAY-100,635 (0.3 mg/kg, s.c.; 30-min pretreatment).

Results: In combination tests, stimulus control by LSD was increased by all 5-HT1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT1A receptor was abolished by administration of WAY-100,635.

Conclusion: These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT1A receptor has a significant modulatory role in the stimulus effects of LSD."


EDIT: I am having trouble entering long URLs, a "<br />" is being interpolated if the URL is too long. Is there any way I can post long URL adresses without them being rendered invalid? (Else, links I posted to the PDF files will work if the <br />'s which have been inserted are removed.)

 

[BilZ0r]

5-HT1A agonists reduce psychedelic potency.. well thats what I think, which is backed up by this Though some people argue about interpretation because of pinodolols lack of specificity.

It makes sense to me as 5-HT1A agonism leads to a loss of excitation in neurons.

Use thinyurl to make your URLs managable.

 

[moracca]

Can someone please enlighten me as to the relative affinity to 5-HT2A for both LSD and 4-HO-DiPT? It seems to me as though 4-ho-dipt is, structurally, more similar to serotonin, and would therefore bind to its receptors better than LSD. Any insights?

 

[C6H6]

5-HT1A agonists reduce psychedelic potency.. well thats what I think

The jury on this is still out IMO. 5-MeO-DMT for example has much higher affinity for 5-HT1A (11 nM) than for 5-HT2 (130 nM) receptors, but is amongst the most potent tryptamines and psychedelics. LSD (5-HT1A 1.1 nM; 5-HT2A 3.5 nM) also seems to contradict your hypothesis. Some say that pindolol isn't a 5-HT1A antagonist, but a (partial) agonist.

 

[BilZ0r]

That's what I specificied, that's what I think. It gets very hard to compare potencies because you have pharmacokinetic problems. All I know is that the Glennon esque correlation gets fucked if you try and work in 5-HT1A potencies. But of course, that isn't perfect because its DOM generalization, which has no 5-HT1A effects.

 

[fungus44]

I'm also someone not generally keen on 5HT.

I don't much like serotonin. I hate the SSRIs -- worst trips of my life. The good vibes it is supposed to give generally don't do much for me. I do like MDMA once in a blue moon, but generally enjoy 5HT antagonist antihistamines. Chacun son gout.

Edited to add: I do seem to have an unusual sensitivity to serotonin altering drugs. Too much acid as a kid? Generally weird nervous system? I do like melatonin, DMT, and LSD so...