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Neurotransmitters - A Primer


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Neurotransmitters - A Primer

By Kayt Sukel

The Dana Foundation

 

COMMENT: This article briefly discusses the several types of neurotransmitters/neurohormones (60+ and counting) and highlights the complex interconnectedness of the system.

 

"And while neurotransmitters are too often discussed as having a single role or function, neuroscientists are finding that they are multi-faceted, complex, and interact with one another in a variety of different ways."

 

The brain contains billions and billions of neurons. These cells communicate with one another by releasing small endogenous chemical messengers, called neurotransmitters, into the synapse, where they are then taken up by specific receptors on neighboring cells. There are many types of neurotransmitters in the brain—what they have in common is that they are produced inside a neuron, released into the synapse, and then cause an excitatory or inhibitory effect on receptor cells, helping to propagate or downgrade action potentials.

 

Neurotransmitters are often classified into two types: small-molecule transmitters and neuropeptides. Small-molecule transmitters can be further differentiated into monoamines like dopamine and amino acids like glutamate. The neuropeptide class includes endorphins, insulin, and oxytocin. Typically, small-molecule transmitters are direct actors on neighboring cells. Neuropeptides, on the other hand, are better suited for more subtle modulatory effects.[ii]

 

Originally, neuroscientists believed that each type of neuron released only a single, unique neurotransmitter. This theory, referred to as Dale’s Law or Dale’s Principle after the observations of English neuroscientist Henry Hallett Dale, was first put forward by Australian neurophysiologist and Nobel Laureate John Eccles. Further examination, however, showed that neurons synthesize and release more than one type of neurotransmitter at their terminals. Eccles later revised Dale’s principle to suggest that specific neurons do not release just a single type of neurotransmitter but rather the same set of transmitter types at their synapses.[iii] Today, most neuroscientists posit that most axonal branches of a neuron release the same neurotransmitter(s)—which explains why different neuron types are still referred to as “dopaminergic” or “serotonergic” cells in scientific publications.[iv]

 

To date, scientists have identified more than 60 different neurotransmitters in the human brain—and expect to find more in the future. They are learning that neurotransmitters like acetylcholine, dopamine, glutamate, serotonin, norepinephrine, GABA, and others play important roles in human cognition and behavior. And while neurotransmitters are too often discussed as having a single role or function, neuroscientists are finding that they are multi-faceted, complex, and interact with one another in a variety of different ways. For example, dopamine has long been thought of as the neurotransmitter involved with reward processing. But new research suggests that the release of acetylcholine results in the release of dopamine—and, ultimately, both influence reward processing and learning. [v] ,[vi]

 

Acetylcholine

 

Acetylcholine (Ach) was the first neurotransmitter to be identified. It is a small-molecule neurotransmitter that works primarily at the neuromuscular junction, translating intention into action between the neuron and the muscle fiber. But it has also been linked to cortical neuroplasticity[vii] and attention.[viii]

 

Dopamine

 

Often referred to as the “pleasure chemical,” dopamine (DA) was first linked to issues with decision-making in patients with Parkinson’s disease.[ix] Since then, it has been one of the most extensively studied neurochemicals—mainly because it plays such diverse roles in human behavior and cognition. DA is involved with motivation, decision-making, movement, reward processing, attention, working memory and learning. It also plays an important role in addiction, schizophrenia, Parkinson’s disease, and other neuropsychiatric disorders.[x] ,[xi]

 

Glutamate

 

Glutamate (GLU) is the most excitatory neurotransmitter in the cortex. In fact, too much glutamate results in excitotoxicity—or the death of neurons due to stroke, traumatic brain injury, and Lou Gehrig’s disease. Yet, GLU also plays an important role in learning and memory—long term potentiation (LTP), the molecular process believed to help form memories, occurs in glutamatergic neurons in the hippocampus and cortex.[xii]

 

Serotonin

 

Serotonin (5HT), sometimes called the “calming chemical,” is best known for its mood modulating effects. A lack of 5HT has been linked to depression and related neuropsychiatric disorders.[xiii] But 5HT is farther reaching—and has also been implicated in appetite, sleep, memory, and, most recently, decision making behaviors.[xiv]

 

Norepinephrine

 

Norepinephrine (NE) is both a hormone and a neurotransmitter. It has been linked to mood, arousal, vigilance, memory, and stress. Newer research has focused on its role in both post-traumatic stress disorder (PTSD) and Parkinson’s disease.[xv]

 

gamma-Aminobutyric acid (GABA)

 

If GLU is the most excitatory neurotransmitter, than its inhibitory correlate is GABA. GABA works to inhibit action potentials. And, in doing so, has been linked to seizure and other pathologies. But this neurotransmitter also plays an important role in brain development. New research suggests that changes in GABA polarity, exciting immature neurons, may help lay down important brain circuits in early development.[xvi]

 

Other neurotransmitters

 

Neurochemicals like oxytocin and vasopressin are also classified as neurotransmitters. These small neurochemicals, made and released from the hypothalamus’ paraventricular nucleus, act directly on neurons and have been linked to pair-bond formation, monogamous behaviors, and drug addiction.[xvii] Hormones like estrogen and testosterone can also work as neurotransmitters and influence synaptic activity [Can add link to neuroendocrine primer].

 

Other neurotransmitter types identified include corticotropin-releasing factor (CRF), galanin, enkephalin, dynorphin, and neuropeptide Y. CRH, dynorphin, and neuropeptide Y have been implicated in the brain’s response to stress.[xviii] ,[xix] Galanin, encephalin, and neuropeptide Y are often referred to as “co-transmitters.” Galanin, for example, is released by some cholinergic neurons. Recent work suggests that it may have a neuroprotective effect in Alzheimer’s disease.[xx] Enkephalin, on the other hand, is released with glutamate to signal the desire to eat and process rewards.[xxi]

 

As neuroscientists are learning more about the complexity of neurotransmission, it’s clear that the co-expression of various molecules allows for greater range of flexibility and function. These different neurotransmitter molecules can also be released both pre-synaptically and post-synaptically to modulate neural activity in different ways.

 

Glia release neurotransmitters, too

 

It was also once believed that only neurons released neurotransmitters. New research, however, has now demonstrated, glia, the cells that make up the brain’s “white matter,” also releases neurotransmitters into synapses. In 2004, researchers noted that glial cells release glutamate into synapses in the hippocampus, helping to synchronize neuronal activity. [xxii] Further work has shown that glial cells don’t just release glutamate—astrocytes, a type of glial cell, mediate synaptic plasticity by releasing different neurotransmitter and neuromodulator molecules into the synapse as required.[xxiii] Researchers are working diligently to understand the contributions of these different cell types—and the neurotransmitter molecules they release—to neural activity.[xxiv]

 

Kolb B and Whishaw IQ. An Introduction to Brain and Behavior, Third Edition. (Worth Publishers, 2009).

 

[ii] Freberg L. Discovering Biological Psychology, Second Edition. (Wadsworth Publishing, 2009)

 

[iii] Taupin P. The Hippocampus: Neurotransmission and Plasticity in the Nervous System (Nova Science Publishers 2008)

 

[iv] http://www.d.umn.edu/~jfitzake/Lectures/DMED/NeuralCommunication/Neurotransmission/DalesLaw.html

 

[v] You Z-B, Wang B, Ziztman D and Wise RA. Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: Conditioned and unconditioned contributions to reward and motivation. Journal of Neuroscience, 3 September 2008, 28(36): 9021-9029.

 

[vi] Surmeier DJ and Graybiel AM. A feud that wasn’t: Acetylcholine evokes dopamine release in the striatum. Neuron, 12 July 2012, 75(1): 1-3.

 

[vii] Suppa A and Papazachariadis O. Unvraveling acetylcholine impact on human cortical plasticity. Journal of Neuroscience, 8 August 2012, 32(32): 10795-10796.

 

[viii]Demeter E and Sarter M. Leveraging the cortical cholinergic system to enhance attention. Neuropharmacology, January 2013, 64(1): 294-304.

 

[ix] Labudda K, Brand M, Mertens M, Ollech I, Markowitsch HJ and Woermann FG. Decision making under risk condition in patients with Parkinson’s disease: A behavioural and fMRI study. Behavioral Neurology. 2010, 23(3): 131-143.

 

[x] Freberg L. Discovering Biological Psychology, Second Edition. (Wadsworth Publishing, 2009)

 

[xi] Steinberg EE and Janak PH. Establishing causality for dopamine in neural function and behavior with optogenetics. Brain Research, 9 September 2012.

 

[xii] Mukherjee S and Manahan-Vaughn D. Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning. Neuropharmacology, 26 June 2012.

 

[xiii] Meyer JH. Neurochemical imaging and depressive behaviours. Current Topics in Behavioral Neuroscience, 28 September 2012.

 

[xiv] Sukel K. Decision-making: Beyond dopamine. The Dana Foundation Website, 17 January 2012. http://www.dana.org/news/features/detail.aspx?id=34974

 

[xv] Vazey EM and Aston-Jones G. The emerging role of norepinephrine in cognitive dysfunctions of Parkinson’s disease. Frontiers in Behavioral Neuroscience. 2012, 6:48.

 

[xvi] Ben-Ari Y, Woodin MA, Sernagor E, Cancedda L, Vinay L, Rivera C, Legendre P, Luhmann HJ, Bordey A, Wenner P, Fukuda A, van den Pol AN, Gaiarsa JL and Cherubini E. Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Frontiers in Cellular Neuroscience, 2012, 6:35.

 

[xvii] Young L and Alexander B. The Chemistry Between Us. (Current, 2012)

 

[xviii] Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, and Phillips PE. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature, 18 October 2012, 490(7420): 402-406.

 

[xix] Sah R and Geracioti TD. Neuropeptide Y and post-traumatic stress disorder. Molecular Psychiatry. 17 July 2012.

 

[xx] Counts SE, Perez SE, Ginsberg SD and Mufson EJ. Neuroprotective role for galanin in Alzheimer’s disease. EXS, 2012, 102: 143-162.

 

[xxi] Difeliceantonio AG, Mabrouk OS, Kennedy RT and Berridge KC. Enkephalin surges in dorsal neostriatum as a signal to eat. Current Biology. 23 October 2012, 22(20): 1918:1924.

 

[xxii] Angulo MC, Kozlov AS, Charpak S and Audinat E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. The Journal of Neuroscience, 2004, 24(31): 6920-6927.

 

[xxiii] Navarrete M, Perea G, Fernandez de Sevilla D, Gomez-Gonzalo M, Nunez A, Martin ED and Arague A. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biology, 2012, 10(2):e1001259.

 

[xxiv] Fields RD. Release of neurotransmitters from glia. Neuron Glia Biology, 2010, 6(3): 137-139.

Pristiq tapered over 8 months ending Spring 2011 after 18 years of polydrugging that began w/Zoloft for fatigue/general malaise (not mood). CURRENT: 1mg Klonopin qhs (SSRI bruxism), 75mg trazodone qhs, various hormonesLitigation for 11 years for Work-related injury, settled 2004. Involuntary medical retirement in 2001 (age 39). 2012 - brain MRI showing diffuse, chronic cerebrovascular damage/demyelination possibly vasculitis/cerebritis. Dx w/autoimmune polyendocrine failure.<p>2013 - Dx w/CNS Sjogren's Lupus (FANA antibodies first appeared in 1997 but missed by doc).

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VERY informative, thanks, Barb.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

All postings © copyrighted.

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Lots of 'scientists once thought' type-comments in there.

 

Shame in human terms, the damage done on faulty assumptions.

"Well my ship's been split to splinters and it's sinking fast
I'm drowning in the poison, got no future, got no past
But my heart is not weary, it's light and it's free
I've got nothing but affection for all those who sailed with me.

Everybody's moving, if they ain't already there
Everybody's got to move somewhere
Stick with me baby, stick with me anyhow
Things should start to get interesting right about now."

- Zimmerman

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I forgot to include link

http://www.dana.org/media/detail.aspx?id=39884#_edn4

 

The more we learn, the less we really know about the brain.

Pristiq tapered over 8 months ending Spring 2011 after 18 years of polydrugging that began w/Zoloft for fatigue/general malaise (not mood). CURRENT: 1mg Klonopin qhs (SSRI bruxism), 75mg trazodone qhs, various hormonesLitigation for 11 years for Work-related injury, settled 2004. Involuntary medical retirement in 2001 (age 39). 2012 - brain MRI showing diffuse, chronic cerebrovascular damage/demyelination possibly vasculitis/cerebritis. Dx w/autoimmune polyendocrine failure.<p>2013 - Dx w/CNS Sjogren's Lupus (FANA antibodies first appeared in 1997 but missed by doc).

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I forgot to include link

http://www.dana.org/media/detail.aspx?id=39884#_edn4

 

The more we learn, the less we really know about the brain.

 

Which makes it that much more outrageous that pharmaceutical companies and doctors think they know what they're doing with their horrible drugs.

 

Good article - an understandable explanation of a complex subject. Thank you.

Psychotropic drug history: Pristiq 50 mg. (mid-September 2010 through February 2011), Remeron (mid-September 2010 through January 2011), Lexapro 10 mg. (mid-February 2011 through mid-December 2011), Lorazepam (Ativan) 1 mg. as needed mid-September 2010 through early March 2012

"Never attribute to malice that which is adequately explained by stupidity." -Hanlon's Razor


Introduction: http://survivingantidepressants.org/index.php?/topic/1588-introducing-jemima/

 

Success Story: http://survivingantidepressants.org/index.php?/topic/6263-success-jemima-survives-lexapro-and-dr-dickhead-too/

Please note that I am not a medical professional and my advice is based on personal experience, reading, and anecdotal information posted by other sufferers.

 

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Thanks for the link, Barb.

 

The Dana Foundation appears to be an independent philanthropy focused on health and medicine, like the Gates Foundation.

 

The article contains links to these other very interesting articles:

 

Dale's Principle http://www.d.umn.edu/~jfitzake/Lectures/DMED/NeuralCommunication/Neurotransmission/DalesLaw.html and on Wikipedia http://en.wikipedia.org/wiki/Dale%27s_principle

 

The more accurate stating of Dale's Principle is "neurons release the same set of transmitters at all of their synapses" -- meaning they each release multiple transmitters.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

All postings © copyrighted.

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Thank you for posting this, Barb. It makes the idea of "balancing serotonin" seem even more ludicrous.

2003-2011: Paroxetine,Citalopram,Effexor; Aug/Sept 2011: Effexor to Mirtazapine; Oct 2011: C/T Mirtazapine back to Effexor; Nov/Dec 2011: Fast Tapered Effexor - w/d hell; Feb 2012: Reinstated Effexor 37.5mg; June 2012: Dropped to 35.6mg; Jan 2016: Propranolol 2.5mg per day for general anxiety; Feb 2016: Finasteride 0.25mg per week to slow hair loss; 18th May - 8th June 2019: Started Vyvanse 7.5mg and increased by 7.5mg weekly to 30mg (lowest “therapeutic” dose for adults).; 21st June 2019 - 12th July: Cross tapered from venlafaxine brand Rodomel to Efexor (1/4 > 1/2 > 3/4 weekly before ditching Rodomel); 13th July 2019: Cut Vyvanse dose to 15mg; 15th July 2019: Akathisia returned after years of being free; 16th July 2019: Went back up to Vyvanse 30mg

Supplements: Omega-3, Vitamin D, Zinc, Phosphatidylserine 

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