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Chemically Induced - What's your favorite neurotransmitter/modulator? Why?


abourdon
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As a chemistry graduate student, I feel that I may be the needle in a haystack at SfN. I study the global metabolomics of brain chemistry. Currently, I have detected over 100 compounds from homogenized tissue and ~60 compounds from dialysate. Since my research isn’t focused on studying a single metabolite, I wanted to hear from the SfN community about their favorite neurotransmitter/modulator and why? Please include specifics about the molecules function within the brain, and to what region of the brain. Look forward to your responses.

-The Alchemist

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My favorite neurotransmitter is dopamine because there are so many neurological and neuropsychiatric disorders implicated in dopamine dysfunction/dysregulation such as Parkinson’s disease and ADHD. Dopamine plays a role in reward-motivated behavior, such as learning, and motor control in distinct dopamine pathways such as the tubersinfundibular pathway, nigrostriatal pathway, mesolimbic pathway, and mesocortical pathway of the brain.

Thank you Alchemist for starting this thread!

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  • 3 months later...

One of my favorite neurotransmitters is serotonin. I was introduced to serotonin in 1975 as it became an integral part of my PhD. I had the privilege to establish the serotonin regulation of noradraline in the locus coeruleus. We also established the contribution of the serotonin input from various raphe nuclei to the locus coeruleus. Serontonin certainly plays a significant role in maintaining our well-being as it is related to sleep, mood, appetite and social behavior.
Another of my all time favorites is dopamine.The account written about dopamine by Pizbicki reflects my sentiments as well. I would like to add as a personal note that dopamine is dear to my heart because we were able to establish a potential therapy for Parkinson’s disease by micro-encapsulating it in biodegradable polymers.

Good topic thanks for introducing it. I have other favorites but I will leave them for another time

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Charise White

I like serotonin and dopamine, too, but my current work has drawn my attention to the plethora of neuropeptides. I really want to know more about them. I think of the major neurotransmitters like serotonin and dopamine as a yelled conversation between neurons and the neuropeptides as the whispered, secret messages. Among the neurotransmitters, cholecystokinin currently is my favorite. Btw, is it acceptable to refer to a neuropeptide as a neurotransmitter?

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I remember quite well when life was simple: there were 5 putative neurotransmitters. Then peptide mania hit in the 80s!!! As far as assigning a neurotransmitter role to the plethora of neuropeptides there are certainly those who do. However have all the neuropeptides been tested to meet the requirements of a neurotransmitter? I don’t know the answer.
I always thought it was fascinating that neurotransmitters coexist with specific neuropeptides.
Look at the indirect and direct pathway in the basal ganglia of instance. Cholecystokinin is certainly important especially since it coexists with dopamine.

Great topic

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Charise White

What are the requirements for a neurotransmitter?

It is a bit astounding that the roles of most neuropeptides are mysteries still.

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In Principles of Neuroscience, Kandel, Schwartz and Jessell defined a neurotransmitter as a “substance that is released at a synapse of by one neuron and that affects another cell, either neuron or effector organ, in a specific manner…”

Put more simply, a neurotransmitter is a chemical that supports the transmission of information between cells (including neurons and glia).

4 Criteria:

  1. Must be synthesized (or stored within a releasing cell. Neurotransmitters can be synthesized in the axon terminal, in the cell body (soma), it can be repackaged after uptake and can be made both pre/postsynaptically on demand.

  2. Must have target sites for endogenous transmitter. In other words, it must have receptors for a naturally occurring transmitter.

  3. The endogenous and the exogenous transmitter must elicit the same response.

  4. Presence of a deactivation mechanism.

This is what I learned many years ago.

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Greetings, and thanks for this thread!

I just thought I would give a mention to the receptor type(s) that I have a lot of interest in: the glutamate receptors. A few reasons for my interest are:

  • Glutamate receptors comprise more than 80% of all brain receptors in humans! (Because they are the primary transmitter for excitatory pyramidal cells in cortex, and cortex is so large in humans).

  • Fast (20 msec or less) excitatory transmission in the brain is due almost entirely to glutamate receptors.

  • Glutamate receptors are the widely presumed site of long-lasting memory storage.

  • Centrally active drugs exist for most types of receptors: many, many for ACh, 5HT, NE, DA. But very few as yet for glutamate (Plenty in progress). There are bound to be intriguing future findings in the offing.

Comments very welcome!

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  • 5 months later...

Okay, these may be some “out-there” questions, but here goes and any speculation is encouraged.
Why do you think glutamate has become the major neurotransmitter?
Why do some different brain regions have different primary neurotransmitters, for example, dopaminergic areas?

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Hi Charise –
The ampa-type glutamate receptor phylogenetically shows up early, in peripheral structures, both motor (e.g., lamprey tail-flick behavior) and sensory structures (primary receptor types in both retina and cochlea). In non-peripheral systems, it has always been interesting to me that the largest parts of the reptilian brain (basal ganglia / striatal complex) were driven by gaba and DA, whereas the pallium is predominantly glutamate, and its offshoot, the neocortex, is what grows allometrically very large in mammals, far outpacing the striatal complex. In the brain, then, glutamate was in some ways the slow starter that eventually far outpaced all the others.

But perhaps most interesting is the central rule of glutamate receptors in everyday fact learning. We can zero in on highly unusual biology by focusing on three key features of fact learning:
i) we can learn new facts very rapidly, e.g., someone’s face or name;
ii) the learned information can be very long lasting (decades, not minutes or hours); and
iii) we can learn huge quantities of these facts.

So: lots of rapid changes, that become permanent. This apparently means that fact-learning flies in the face of homeostatic mechanisms.

Most of biology (certainly including the brain) tries to keep things in balance; if something changes, something else homeostatically pushes back. The brain, for instance, is replete with ion pumps and many other careful mechanisms for maintaining equilibria in neurons. Except when it comes to learning - then rapid, permanent changes are enabled. Exactly what homeostasis prevents. (We can of course forget things we learn, but the question addressed here for the moment is how can we possibly retain lifelong memories in those cases when we do not forget). By attending to these anti-homeostatic characteristics of learning, researchers have zeroed in on glutamate receptors.

Learning makes use of both of the two primary types of glutamate receptors (ampa and nmda) in concert. The NMDA receptor triggers the change, which in itself makes a very interesting set of studies. But perhaps even more interesting than the learning trigger, is the learning expression. Evidence indicates that the AMPA type glutamate receptor is the primary means for expressing the change permanently. Either a change to the number, or location, or configuration, of AMPA glutamate receptors, apparently underlies the permanence of fact learning. To make the changes permanent, there must be a physical change involved:

  • something new built (and not homeostatically dismantled), or
  • something snipped (and not homeostatically repaired).

So: something at the site of these ampa receptors is enabling this form of rapid permanent change – something apparently highly unusual in biology. Ampa receptors are far and away the most populous receptor type in human brains. Not only are they the likely site of synaptic learning, but they also are effecting their changes by means that are anti-homeostatic and thus pretty weird in comparison to normal biological mechanisms. To me, they are deeply intriguing. They’re (still) hiding secrets that we haven’t yet cracked.

I will welcome your thoughts on this!

(PS As to asking “out there” questions - I often find them to be highly useful; perhaps they too often go un-asked. I try to remind myself to ask such questions more often. (I’ve got very few answers, but plenty of speculation. :slight_smile:

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In addition to bigbrain, I’m also glad for the ‘out-there’ questions, so please keep-em coming!

Why has glutamate become the major neurotransmitter?

Glutamate was already an amino acid, and can be made from alpha-ketoglutarate, a TCA cycle intermediate. Perhaps glutamate is most frequently used is because it’s precursor is the most bioavailable? That being said, most neurotransmitters are connected to some part of energy/nucleotide/amino acid metabolism- its just the easiest for me to see a line straight from glucose to glutamate (or similarly acetylcholine, the popular peripheral neurotransmitter).

Another answer might lie in the evolution of neurotransmitter receptors, which is much more complicated but equally necessary for any given neurotransmitter to work. The more I think about it, the more likely it seems that the prevalence of glutamate is strongly tied to the prevalence of AMPARs and NMDARs. The evolution of these receptors and thus the choice of head-honcho neurotransmitter may be somewhat random :(…

Why do different brain regions use different neurotransmitters?

It seems like an easier question to answer, which means it probably isn’t… The brain uses different neurotransmitter systems to transmit differents signals (ie glutamate is mostly excitatory, while GABA is mostly inhibitory). However more than one neurotransmitter is excitatory or inhibitory, so why have more than one excitatory neurotransmitter?

One explanation I can imagine is to maintain signal integrity (if you have a dopamine neuron near a glutamate neuron, leakage of neurotransmitter from one synapse to another will not trigger an aberrant action potential.

Another is that the frequency or duration of a postsynaptic response may be dependent on the kinetics of ligand-gated ion channel opening/closing, which may be different for different neurotransmitter receptors, so in that case, different neurotransmitter/receptor pairs transmit different kinds of signal.

I’m mostly just guessing here, though I’m sure there must be some literature that covers these topics.

What are your thoughts?

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Bigbrain and Dhass,

Thank you for your responses. The subject of the evolution of the brain has been kicking around in the back of my brain for a while. (Well actually, it has been kicking around in the front of my brain, i.e. the frontal cortex, right? :slightly_smiling_face:). It is great to have a place to discuss it.

Again, thank you for your responses. I am processing what you wrote and will respond soon.

Cheers,

cw14

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