Serotonin - Dopamin - (mu)-Opioid - connections? Please help me to understand

[Cotcha Yankinov]

I would sure love to know at what point biological activity translates into conscious experience.... I think most people would be obsessed with what causes pleasure but I'd be very curious to know how chemical/biological phenomena add up to a conscious experience as a whole. I mean is consciousness the total electrical activity of the brain or something? At what point (10 neurons, 20 neurons, half a neuron) does conscious begin to appear, or is it present to some minute degree in all matter? Sorry for rambling lol.

 

[AlphaMethylPhenyl]

Actually, I think those are very big, important questions. But then we do veer off into philosophy a bit, and even theology. There are certainly those out there who think that everything has a consciousness, and those on the other side of the spectrum who think that only humans are conscious, or that humans delude themselves into believing that they have achieved true consciousness. I think that it's kind of a loaded question that comes down to opinion.

 

[serotonin2A]

And yet it's only when autoreceptors begin to fill up that nor/adrenaline have inhibitory effects, which was presupposed.

That isn't true. As an example:

"...NE elicits a mixed repertoire of excitatory, inhibitory, and biphasic effects on the firing activity and transmitter release of cortical neurons."

http://www.ncbi.nlm.nih.gov/pubmed/26820639

Dopaminergic activity is not generally associated with inhibitory action.

Again, not true. Some DA receptors are inhibitory and some are excitatory.

For example, check out Figure 13 in the following paper. Application of DA inhibits striatal neurons in the indirect pathway via D2R.

http://www.ncbi.nlm.nih.gov/pubmed/3183715

There are many other examples. D2R inhibits adenylate cyclase, which tends to inhibit neurons.

Serotonin has seven subtypes, two of which are inhibitory, if that means anything (it might not, as number of the various subtypes in the brain would determine better, but a five to two is pretty stiff odds).

There are 14 serotonin receptor subtypes in 7 families. All of the subtypes in the 5-HT1 family (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F) are coupled to inhibition of adenylate cyclase and induce neuronal inhibition. The 5-HT5A receptor is also inhibitory.

 

[aced126]

Also thought I'd comment on NMDA antagonists ability to increase dopamine and induce DeltaFosB - it appears that NMDA is providing a lot of input to inhibitory interneurons that inhibit the nucleus accumbens.

Selective DRIs seem very disappointing and even dysphoric to some. Also cocaine is probably a DAT inverse agonist, and methylphenidate is also possibly a DAT inverse agonist.

Ho, regarding the enzyme, are you thinking of COMT or MAO-B?

The enzyme catalysing norepinephrine synthesis from dopamine is dopamine beta hydroxylase, a copper containing oxygenase.

 

[DotChem]

....what point biological activity translates into conscious experience....but I'd be very curious to know how chemical/biological phenomena add up to a conscious experience as a whole. I mean is consciousness the total electrical activity of the brain or something? At what point (10 neurons, 20 neurons, half a neuron) does conscious begin to appear, or is it present to some minute degree in all matter? Sorry for rambling lol.

It seems the claustrum control "consciousness" or rather conscious activity.

Clinical evidence has suggested that the claustrum plays an important role in maintaining consciousness, potentially being usable as an "on-off switch". In 2014 the case of one woman was reported who fell unconscious when her claustrum was electrically stimulated and regained consciousness as soon as the stimulation stopped.^[8][9]

Is it possible to pin it down to few neurons within the claustrum? But what exactly is "consciousness"? Does it include "consciousness" of a sleeping/dreaming brain? or that of a "dead brain" for that matter? ie which part of the dreaming brain is "conscious" of the experience? the same claustrum? How about "dead brain" as in ppl who are thought brain dead but come back to life..the so-called Near-death experience where they report experiencing other "dimensions" "consciousness?

For one kappa activation by agonists such as Salvinorin A are known to make the brain "cross" "switch" from what might be called "waking consciousness" to a different "sleeping dreaming consciousness" or even a "disso consciusness" (smoke Salvia mint or eat iboga roots to experience that! then the concept of "consciousness" will become relative .. meaningless really.. just a State of the Brain a configuration of neurons among lots of others). (@solipsis: you sure its spelled: "saliva" not "salvia"?)

The claustrum is the region of the brain in which the KOR is most densely expressed.^[10][11][12] It has been proposed that this area, based on its structure and connectivity, has "a role in coordinating a set of diverse brain functions", and the claustrum has been elucidated as playing a crucial role in consciousness.^[11][12] As examples, lesions of the claustrum in humans are associated with disruption of consciousness and cognition, and electrical stimulation of the area between the insula and the claustrum has been found to produce an immediate loss of consciousness in humans along with recovery of consciousness upon cessation of the stimulation.^[12][13] On the basis of the preceding knowledge, it has been proposed that inhibition of the claustrum (as well as, "additionally, the deep layers of the cortex, mainly in prefrontal areas") by activation of KORs in these areas is primarily responsible for the profound consciousness-altering/dissociative hallucinogen effects of salvinorin A and other KOR agonists.^[11][12] In addition, it has been stated that "the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen [LSD]", and it has been postulated that inhibition of a brain area that is apparently as fundamentally involved in consciousness and higher cognitive function as the claustrum may explain this.^[11] However, these conclusions are merely tentative, as "[KORs] are not exclusive to the claustrum; there is also a fairly high density of receptors located in the prefrontal cortex, hippocampus, nucleus accumbens and putamen", and "disruptions to other brain regions could also explain the consciousness-altering effects [of salvinorin A]".^[12]

In supplementation of the above, according to Addy et al.:^[10]

Theories suggest the claustrum may act to bind and integrate multisensory information, or else to encode sensory stimuli as salient or nonsalient (Mathur, 2014). One theory suggests the claustrum harmonizes and coordinates activity in various parts of the cortex, leading to the seamless integrated nature of subjective conscious experience (Crick and Koch, 2005; Stiefel et al., 2014). Disrupting claustral activity may lead to conscious experiences of disintegrated or unusually bound sensory information, perhaps including synesthesia. Such theories are in part corroborated by the fact that [salvia divinorum], which functions almost exclusively on the KOR system, can cause consciousness to be decoupled from external sensory input, leading to experiencing other environments and locations, perceiving other “beings” besides those actually in the room, and forgetting oneself and one’s body in the experience.
​

One strange thing about kappa is that brain on SalvinorinA will resonate gamma waves while fully "conscious". Rythmic gamma waves(~40 Hz) back and forth from PFC to the hypothalamus and the cerebelum. Where these waves originated? nobody knows ifaik. These waves are only seen in "advanced" meditators while awake, in deep REM sleep or just before...death! What does kappa activation have to do with that? kappa activation btw also induce dysphoria and aversion the exact opposite of euphoria and pleasure!

https://en.wikipedia.org/wiki/Gamma_wave

The suggested mechanism is that gamma waves relate to neural consciousness via the mechanism for conscious attention:
The proposed answer lies in a wave that, originating in the thalamus, sweeps the brain from front to back, 40 times per second, drawing different neuronal circuits into synch with the precept, and thereby bringing the precept into the attentional foreground. If the thalamus is damaged even a little bit, this wave stops, conscious awarenesses do not form, and the patient slips into profound coma.^[4]
Thus the claim is that when all these neuronal clusters oscillate together during these transient periods of synchronized firing, they help bring up memories and associations from the visual precept to other notions. This brings a distributed matrix of cognitive processes together to generate a coherent, concerted cognitive act, such as perception. This has led to theories that gamma waves are associated with solving the binding problem.^[3]

Sorry for the long quotes but I find that subject pretty fascinating ..

 

[serotonin2A]

One strange thing about kappa is that brain on SalvinorinA will resonate gamma waves while fully "conscious". Rythmic gamma waves(~40 Hz) back and forth from PFC to the hypothalamus and the cerebelum. Where these waves originated? nobody knows ifaik. These waves are only seen in "advanced" meditators while awake, in deep REM sleep or just before...death!

You are making gamma waves way more mysterious than they actually are. Gamma activity in cortex originates from the the interactions of pyramidal neurons and GABAergic interneurons. Those two classes of cells are organized so that when the pyramidal neurons fire they activate neighboring interneurons, which provide feedback inhibition to the pyramidal neuron. The end result is that the pyramidal neurons oscillate at gamma frequencies. Depending on the exact circuit wiring and the distribution of ion channels on the cell surfaces, the neurons "ring" at particular resonant frequencies, just like what happens when you ring a bell.

Networks of neurons communicate by multiplexing activity at different frequencies. That way multiple streams of info can be conveyed over the same circuit simultaneously. You can think of it as being analogous to radio transmission where radio transmitters can send info to specific receivers that are tuned to oscillate at the same frequency.

So rhythmic activity is seen in all brains and in fact is necessary for normal brain function.

 

[AlphaMethylPhenyl]

That isn't true. As an example:

"...NE elicits a mixed repertoire of excitatory, inhibitory, and biphasic effects on the firing activity and transmitter release of cortical neurons."

http://www.ncbi.nlm.nih.gov/pubmed/26820639



Again, not true. Some DA receptors are inhibitory and some are excitatory.

For example, check out Figure 13 in the following paper. Application of DA inhibits striatal neurons in the indirect pathway via D2R.

http://www.ncbi.nlm.nih.gov/pubmed/3183715

There are many other examples. D2R inhibits adenylate cyclase, which tends to inhibit neurons.



There are 14 serotonin receptor subtypes in 7 families. All of the subtypes in the 5-HT1 family (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F) are coupled to inhibition of adenylate cyclase and induce neuronal inhibition. The 5-HT5A receptor is also inhibitory.

Ouch wasted lol. I yeild! Apart from that, now that i think about it, I didn't consider the paradoxical effects that stimulants can elicit, which I guess theoretically has some neurological basis.

I did know the thing about the 5-HT1 subtypes, I just thought, mistakenly so, that 5-HT1 subtypes were all under the name "subtype".

 

[Cotcha Yankinov]

rhythmic activity is seen in all brains and in fact is necessary for normal brain function.

Is dysfunction of rhythmic activity thought to play a role in any mental illness, or can modifying rhythmic activity be therapeutic in any instances (I seem to recall something regarding LSD altering rhythmic activity)?

 

[serotonin2A]

Is dysfunction of rhythmic activity thought to play a role in any mental illness, or can modifying rhythmic activity be therapeutic in any instances (I seem to recall something regarding LSD altering rhythmic activity)?

Yes to both. One view of Parkinson's disease is that the symptoms -- to some extent -- reflect problems transmitting info through the basal ganglia due to impaired rhythmic activity. Basal ganglia stimulation is used as a treatment, but there is work being done to see if the results can be improved using specific stimulation frequencies/patterns.

 

[Cotcha Yankinov]

Are there any particular receptors on these pyramidal neurons that can be used to alter rhythmic activity?

It sounds like these rhythmic oscillations function something like pacemakers, to try to keep a basal level of activity throughout the brain, but are there situations where there is genuine information being carried in the oscillation itself (and the oscillation is not just allowing other neurons to spread their information by being activated by the oscillation)?

 

[DotChem]

You are making gamma waves way more mysterious than they actually are. Gamma activity in cortex originates from the the interactions of pyramidal neurons and GABAergic interneurons....

What I was trying to say is that these oscillations are observed primarily in States of Consciousness that are to say the least mysterious: kappa dissociation, deep meditation, REM sleep or NDE? what you are describing is their effect not their origin? in other words under the control of which part of the brain are they? the Claustrum? if yes then that's where one should go look for "consciousness neurons" if any! that will be the "site of consciousness (or rather consciousnesses.. ) since the topic (or rather a bit off-topic) was about the interface between molecules(neurons) and "consciousness".

The evidence I came across so far all robustly implicate KOPr as the key to "consciousness" or "perception" or "awareness" or just "knowing". The part of the brain that "knows" all sensory experiences! The mystery to me is that KOPr activation induce the same rythmic gamma oscillations observed with advanced meditators, salvia smokers, Iboga eaters or clinically "brain dead" people.. The nature of the waves is not really a mystery: you can generate and measure them. Question is: how activation of KOPr (in the claustrum?) and resulting gamma activity is related to different States of Consciousness?

 

[serotonin2A]

What I was trying to say is that these oscillations are observed primarily in States of Consciousness that are to say the least mysterious: kappa dissociation, deep meditation, REM sleep or NDE?

Gamma activity occurs when the brain is awake, so it is not surprising that gamma activity occurs in ASCs. Gamma activity is necessary for ordinary mental function so it is incorrect to say it is observed primarily in altered states of consciousness.

what you are describing is their effect not their origin? in other words under the control of which part of the brain are they? the Claustrum?

I described both the origin and the function of gamma activity -- gamma activity is generated by the interplay between pyramidal neurons and interneurons in many different cortical regions. There isn't one specific region that controls gamma activity. In fact, if you remove the brain and slice the cortex into sections, then you can potentially detect gamma activity in the individual pieces of cortex.

http://www.nature.com/nrn/journal/v8/n1/full/nrn2044.html

 

[serotonin2A]

Are there any particular receptors on these pyramidal neurons that can be used to alter rhythmic activity?

It sounds like these rhythmic oscillations function something like pacemakers, to try to keep a basal level of activity throughout the brain, but are there situations where there is genuine information being carried in the oscillation itself (and the oscillation is not just allowing other neurons to spread their information by being activated by the oscillation)?

It isn't simply pacemaker activity. The synchronous activity allows the receiving neuron to receive information, but it doesn't convey the information. The information is encoded in the firing of the neurons.

As an example, there is a network of neurons oscillating at gamma frequencies. Because the neurons are oscillating, they cycle through periods of depolarization (UP states) and hyperpolarization (DOWN states). If excitatory input to the network arrives during the down state, it is unlikely to produce a response because most receiving neurons are hyperpolarized and therefore more difficult to excite. On the other hand, if excitatory input arrives during the up state then it is more likely to produce a response because the receiving neurons are already slightly depolarized. So you want the neurons sending info to the network to oscillate at the same frequency as the receiving neurons so that information will be transferred and received during an UP state.

 

[Cotcha Yankinov]

That makes a lot of sense, thank you.

So death/dysfunction of either the inhibitory neurons or pyramidal neurons presumably results in dysfunction of gamma waves - I might be confused on this next part but I am under the impression that benzodiazepines suppress REM sleep. Is this due to them altering the inhibitory interneuron portion of the gamma oscillations?

 

[palmanita]

But what exactly is "consciousness"? Does it include "consciousness" of a sleeping/dreaming brain? or that of a "dead brain" for that matter? ie which part of the dreaming brain is "conscious" of the experience? the same claustrum? How about "dead brain" as in ppl who are thought brain dead but come back to life..the so-called Near-death experience where they report experiencing other "dimensions" "consciousness?

I think of any state as conscious where one either "directly" experiences -waking state, dreaming (even when one thinks of not having actually experienced the dream but just memories of it, there is no clear border at all on to fully lucid dreams, if you've ever experienced such one then you know it's consciousness. They can feel so real and it's possible to consciously decide to wake up, modify the world around you, and so on.. Also nightmares wouldn't wake you up otherwise, [or?]), dissociated state until anesthesia shuts perception including the disso world off, etc.. - abstracted consciousness does not relate to any "world" but to the experience of being conscious (where the theory of fooling oneself into believing of being conscious sets in- then everything could be an illusion.....).

I'm not even sure anymore that the core of consciousness is completely explainable by science. How to control, modulate etc. it yes, but maybe not what defines "life" or where being conscious begin and why (you'll never know for sure at least for now.. animals can't speak and any finding of what mechanism could be be the key, based on which one could scan them etc., might be wrong.)

Sorry for getting into philosophy but it's so interesting

 

[Nagelfar]

So rhythmic activity is seen in all brains and in fact is necessary for normal brain function.

This contingent-rhythm/wave type functioning was the kind discussed in the book "The Holographic Universe" (though they call the brain functional in such a way that it is likened to being a 'hologram', in correspondence to how it saves data with how holographic images are stored; evenly throughout instead of in any one specific area, I'd say, 'graphing' such as rationing may not be as poignant a term as "holonomic" e.g. holo-law/ruled/structured)