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Serotonin, 5-HT receptors, brain chemistry +++

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Sitting here in front of my screen and drinking coffee in the middle of the night (oh well it's morning now) to try to tame the beast, I was simply searching for an image of the hypothalamus, when Google directed me to this Web site. I spent many hours exploring it with fascination. It has shed light on many aspects of the brain which were still a total mystery to me.

It is not intended at neophytes like us, so large parts of it get much beyond my capacity of total comprehension, but I think it's helping me connecting dots and creating a clearer picture of all that could relate to the brain and its chemical actions, and maybe a better understanding of cluster headaches.

Serotonin sure is a key issue, and I now understand much more why.

Parts are in Italian, but large chunks are in English (with maybe an Italian accent, not sure for English is not my first language either... some sentences seemed twisted a bit). No doubt for me though that these people know what they are talking about.

This web application is a discussion tool between teachers and students at Medicine and Chirurgy department at the Turin University, but its structure can be usefull for Continuum Interactive Training.

So I'm pasting some links that have attracted my attention, but one can navigate through the site and find more, plus links to external sites of much interest, and many many images helping to see how the brain works.

Maybe it offers nothing new to some of you, but it sure helps me getting a clearer picture of how these chemicals rule us. For one thing, I learned that even sexual orientation could be only a matter of brain chemicals :o but there is also a detailed explanation of the chemical actions involved in kissing... so, from the simplest thing as hunger and sleep to the most unexpected, discover serotonin, dopamine and their actions... nuf said. Just read.  :P (also attaching one of the images that fascinated me)








sexual orientation


vitamin D





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Reading and thinking aloud   ;):P This is complex but... what I learn from these readings is: 1- photosensitive ganglion cells were (re)discovered in 1991 and proved to be a 3rd path for light to enter the brain and control circadian rythms; 2- these ganglion-cells play a major role in controlling circadian rythms; 3- they also control pupil dilatation (a CH symptom); 4- they contribute to suppression of melatonin; 5- Melanopsin is a photopigment found in the photosensitive ganglion cells; Melanopsin "is an opsin, a retinylidene protein variety of G-protein-coupled receptor. Melanopsin is most sensitive to blue light.[1] A melanopsin based receptor has been linked to the association between light sensitivity and migraine pain."; 6- LSD "affects a large number of the G protein coupled receptors"

I think this sheds a little more light on how circardian rythms are linked to clusters (correction: oh no, it doesn't actually, but we all know that for sure, don't we?), and how LSD (and surely psilo and others) is linked to circardian rythms...

I also discover that LSD doesn't flood the brain with serotonin like I thought it did, au contraire, it cuts off serotonin sources to the telencephalon (cerebrum), which "is the one of the most important parts of the brain, it controls emotion, hearing, vision, personality and many more things."



In 1991 Russell G. Foster and colleagues, including Ignacio Provencio, discovered a non-rod, non-cone photoreceptor in the eyes of mice. It was shown to mediate circadian rhythms, i.e. the body's 24-hour biological clock.[6] Foster was elected a fellow of the Royal Society in 2008.[7] These novel cells express the photopigment melanopsin, which was first identified by Provencio and colleagues.[8]


Compared to the rods and cones, the ipRGC respond more sluggishly and signal the presence of light over the long term.[3] They represent a small subset (~1-3%) of the retinal ganglion cells. Their functional roles are non-image-forming and fundamentally different from those of pattern vision; they provide a stable representation of ambient light intensity. They have at least three primary functions.

    They play a major role in synchronizing circadian rhythms to the 24-hour light/dark cycle, providing primarily length-of-day and length-of night information. They send light information via the retinohypothalamic tract directly to the circadian pacemaker of the brain, the suprachiasmatic nucleus of the hypothalamus. The physiological properties of these ganglion cells match known properties of the daily light entrainment (synchronization) mechanism regulating circadian rhythms.

    Photosensitive ganglion cells innervate other brain targets, such as the center of pupillary control, the olivary pretectal nucleus of the midbrain. They contribute to the regulation of pupil size and other behavioral responses to ambient lighting conditions.

    They contribute to photic regulation of, and acute photic suppression of, release of the hormone melatonin from the pineal gland.


(...)a third class of photoreceptor exists in the mammalian eye.[6] In 2000, Provencio determined that melanopsin was expressed only in the inner retina of mammals, including humans,(And inner retina is where and only where  the photosensitive ganglion cells are found)


GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:

(...) Behavioral and mood regulation: receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate


LSD affects a large number of the G protein coupled receptors, including all dopamine receptor subtypes, all adrenoreceptor subtypes as well as many others. LSD binds to most serotonin receptor subtypes except for 5-HT3 and 5-HT4. However, most of these receptors are affected at too low affinity to be activated by the brain concentration of approximate 10-20 nM. Recreational doses of LSD can affect 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5 B and 5-HT6. The hallucinogenic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors as specific 5-HT2A agonist drugs are hallucinogenic and largely 5-HT2A specific antagonists block the hallucinogenic activity of LSD. Exactly how this produces the drugÂ’s effects is unknown, but it is thought that it works by increasing glutamate release and hence excitation in the cortex, specifically in layers IV and V. In the later stages, LSD acts through DARPP-32 - related pathways that are likely the same for multiple drugs including Cocaine, amphetamine, nicotine, caffeine, PCP, ethanol and morphine. A particularly compelling look at the actions of LSD was performed by Barry Jacobs recording from electrodes implanted into cat raphe nuclei. Behaviorally relevant doses of LSD result in a complete blockade of action potential activity in the dorsal raphe, effectively shutting off the principal endogenous source of serotonin to the telencephalon.

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Serotonin, or 5-hydroxytryptamine (5-HT), is a

neurotransmitter found in a variety of organisms from

the worm to vertebrates. This diverse presence

indicates that the serotonergic system is evolutionarily

an ancient one.


While serotonin is nearly ubiquitous within the

brain, the diversity and specificity of serotonin

signaling and function arises from the molecules that

receive the signals in the various target regions. These

target molecules are proteins called receptors.

(...) Hallucinogens all have a high affinity for certain

serotonin receptor subtypes, namely, the 5-HT2A and

5-HT2C receptor subtypes

(...) Other drugs, such as lysergic

acid diethylamide (LSD), bind to a variety of receptors

including the 5-HT2A/2C, 5-HT1A, 5-HT6, 5-HT7,

dopamine D1 and D2 and adrenergic receptors and have

aspects of behavior mediated through these multiple



In addition to inhibiting adenylate cyclase,

activation of the receptor leads to closing of calcium

channels via the Go subunit and opening of potassium

channels via the [ch946][ch947] subunits

The serotonin signaling system is very complex.

5-HT2A/2C receptors alone couple to multiple pathways.

Each pathway in turn can activate multiple second



The almost limitless number of these

signaling possibilities emphasizes the variety and

complexities of behaviors influenced by serotonin



Hallucinogenic drugs interact with the serotonergic

system at many levels, from changing intracellular

signaling pathways to altering neuron firing patterns

to altering gene expression. Due to the complexity of

the serotonin system and its multiple behavioral roles,

it is perhaps not surprising that hallucinogens can elicit

their effects at exquisitely low doses. Given the number

of cognitive processes and behaviors in which

serotonin is involved, these drugs are in a unique

position to be used as tools in understanding the

serotonin system.


"Dopamine (DA) is a factor in the regulation of melanopsin mRNA in ipRGCs. Because DA synthesis and release in the rat retina are under the control of rods and cones, it appears that rods and cones, in conjunction with or possibly with the exclusion of direct circadian or photic input, control transcription of melanopsin"


"Serotonin (5-HT) and 5-HT receptor agonists can modify the response of the mammalian suprachiasmatic nucleus (SCN) to light.


The findings indicate that 5-HT may modulate RHT (retinohypothalamic tract) glutamatergic input to the SCN through 2 or more 5-HT receptors. The likely mechanism of altered RHT glutamatergic input to SCN neurons is an alteration of photic effects on the SCN circadian oscillator. "


Serotonin [5-hydroxytryptamine (5-HT)] is a neuromodulator that mediates a wide range of physiological functions by activating multiple receptors.


we have isolated from a mouse brain library a cDNA encoding a new serotonin receptor. Amino acid sequence comparisons revealed that this receptor was a close relative of the previously identified 5-HT5 receptor but was distant from all other 5-HT receptor subtypes; we therefore named it 5-HT5B. When expressed in COS-7 cells, the 5-HT5B receptor displayed a high affinity for the serotonergic radioligand 125I-lysergic acid diethylamide. Its pharmacological profile was distinct from that of all classic 5-HT receptor subtypes. However, the high affinity of the 5-HT5B receptor for 5-carboxamidotryptamine and its low affinity for sumatriptan indicated that it might correspond to recently described 5-HT1D-like binding sites that were labeled with [3H]5-carboxamidotryptamine and insensitive to sumatriptan.


"Most of the tested drugs showed no bias. However, ergotamine, LSD and some of their relatives turned out to be clearly biased in favor of [ch946]-arrestin signaling at the 5-HT2B receptor. Comparison of the ergotamine-bound 5-HT2B structure with the ergotamine-bound 5-HT1B structure revealed the likely reason.  “We could see that when ergotamine is bound to the 5-HT2B receptor it stabilizes the receptor structure in a conformation that interferes with G protein signaling,” said Wacker."

(...) . “These structural data are teaching us to ask better questions about receptor biology,” said Stevens.

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Posting these, I hope I'm helping comprehension of what could be related to clusters... I think it is... circardian rythms, serotonin, dopamine...

Since LSD (and similar acting psilo) has an action on clusters, and that these drugs act on the serotonin (5-HT) and dopamine...

it helps my comprehension... just tought I'd share  :)

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Hi ,, I love this topic.   so alot of CHR's are one sided .. what if they have an over abundance or lack of ganglion cells in the one eye. The Ganglion cells contain melanopsin. When light activates the melanopsin the cells discharge nerve impulses.  these impulses are sent to both the SCN (Suprachiasmatic nucleus) cells in they hypothalmus which causes the pineal to secret melatonin, and to the OPN (Olivary pretectal nucleaus) which controls the pupil of the eye. 

There is some reference to light depravation testing. has anyone tried to cover the affected eye and not allow it to have any light input during the "cluster phase"  ie.  equinox, solstice when the earth is tilting and light is changing..

is there any kind of testing for ganglion cells or melanopsin in the eye ?

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so to add ,,

Melatonin is secreted into the blood by the pineal gland in the brain. Known as the "hormone of darkness," it is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.[23] It may also be produced by a variety of peripheral cells such as bone marrow cells,[24][25] lymphocytes, and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood, but it does not seem to be regulated by the photoperiod.

which might  explain why after falling asleep the headache begins ? 

when I had gall bladder attacks my digestive tract would send a signal to my gall bladder to spit out bile to digest a particularly greesy meal.  stones would block the pathway of the bile.. my intestines would never get the bile and so they would say HEY GALL BLADDER I SAID I NEED SOME BILE,, so in response my gall bladder would squeeze extra super hard to try to squeeze some out causing excrutiating pain.

what if there isnt enough melatonin being released due to a ganglion cell/melanopsin mal function in one eye so the brain (?) over stimulates the optic nerve that the ganglion cells would normally stimulate causing pain ?

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5-HT Receptor Data

Receptor Subtype      Transduction Mechanism      Localization      Function      Specific Agonists      Specific Antagonists

Better to look at the table in the link.

I think, only my opinion, that quite a few of these 5-HT receptors are involved that is why we get such similar but also different results with the type of drugs used for this condition.

Jazz ;)

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Purple interesting, Not to go off on another path but I had a gut feeling so I followed it. I have been looking at the (Hypophseal portal system).Looking at Oxytocin, its structure is very similar to that of vasopressin. When anything hits the HT1A receptors it induced oxytocin stimulation(also found in the retina). It's hard for me to wrap my head around this complex system, but since you like to read thought you may find this interesting. Would like to hear what you think.

Funny thing is my Dr was going to give me CLOMID, it is a hormone to help women get pregnant, he says it resets everything. I didn't have to use it thankfully, but you will see the connection between the two if you read up on it.

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vasopressin..........     ive used the stuff before in a nasal spray..   i was using it off label for memory boosting nootropic affects..  it was quite interesting but i was mixing it with other nootropics so im not quite sure which one was working..        i was becoming a smart ass and no one liked it so i stopped lol (kidding)   actually minus the side affects of facial edema the stuff works wonders on memory if you have 150$ to blow each week.. there has been reports that more then occasional use will shut down your normal bodys ability to make the stuff and you become reliant on synthetic stuff which could be playing with fire ..            its usually used for studying, and laying down things really needed to remember ... beyond that be careful... know your own body.. and when to stop if adverse things start happening...    Steve  ;) 

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Holy cow, thanks for posting. Great stuff.

Regardless of the name or why or how it is happening, we need to address the real problem: Why is this stuff the ONLY great prophylactic for cluster headaches?

And also: Can we achieve the same therapeutic effect by some other means?

BOL-148 seems to hold promise, but to me, the big hurdle is that none of the research investigates long term changes in the body, which could help us identify another drug target. It would save us the trouble of going through such an ordeal to relieve our pain.

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