Physiology, Neurotransmitters


Article Author:
Zachary Sheffler


Article Editor:
Leela Sharath Pillarisetty


Editors In Chief:
Susan Jeno
Sarah Fabiano


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
6/4/2019 10:43:46 AM

Introduction

Neurotransmitters are chemicals that allow neurons to communicate with each other throughout the body. They enable the brain to provide a variety of functions, through the process of chemical synaptic transmission. These endogenous chemicals are integral in shaping everyday life and functions.[1]

Development

Neurotransmitters are involved in the processes of early human development, including neurotransmission, differentiation, the growth of neurons, and the development of neural circuitry. Certain neurotransmitters may appear at different points of development. For example, monoamines are present before the neurons are differentiated. Norepinephrine levels are high in the notochord, even in the very early stages of the embryo. Serotonin has a role in morphogenesis. Excitatory amino acids tend to appear later in ontogenesis. The levels of neurotransmitters and neuromodulators tend to increase as new synapses form. Others will appear in the perinatal period, like glutamate, and plateau afterward. Hypoxia and drug-exposure can disturb the formation of neuronal circuity, leading to long-term deleterious effects in the body.[2][3]

Function

There are a number of neurotransmitters used by the body for different functions, including acetylcholine, glutamate, GABA, glycine, dopamine, norepinephrine, and serotonin. Glutamate is the principal excitatory neurotransmitter used in the brain. It is also the primary mediator of nervous system plasticity.[4] Glutamate has been implicated in modifiable synapses, which researchers suspect are the memory-storage elements of the brain.[5] Gamma-aminobutyric acid (GABA) and glycine, conversely, serve as the major inhibitory neurotransmitters. GABA, for example, can account for approximately 40% of the inhibitory processing in the brain. Glycine is found primarily in the spinal cord.[6] Dopamine, another major neurotransmitter, plays an essential role in several brain functions, including learning, motor control, reward, emotion, and executive functions. Dopamine has also been implicated in psychiatric and neurological disorders.[7] Serotonin is a neurotransmitter that modulates multiple neuropsychological processes and neural activity — many drugs used in psychiatry and neurology target serotonin. Serotonin also has implications that affect gastrointestinal processes like bowel motility, bladder control, and cardiovascular function.[8] Norepinephrine is a monoamine that is synthesized in the central nervous system and sympathetic nerves. The locus coeruleus of the brain plays a vital role in the signaling of norepinephrine. The release of norepinephrine in the brain exerts effects on a variety of processes, including stress, sleep, attention, focus, and inflammation. It also plays a role in modulating the responses of the autonomic nervous system.[9] Histamine is another neurotransmitter that mediates homeostatic functions in the body, promotes wakefulness, modulates feeding behavior, and controls motivational behavior.[10]

Mechanism

Neurotransmission medication occurs via the vesicular release of neurotransmitters at presynaptic nerve terminals. Specifically, calcium-evoked exocytosis of the presynaptic vesicles is what enables the release of neurotransmitters into the synapse. Active zones, specialized areas on the presynaptic plasma membranes, tether the neurotransmitter-containing vesicles to the plasma membrane. Once an action potential triggers calcium influx into the presynaptic cleft, active zones undergo fusion with the vesicles, allowing neurotransmitter release [1]. There are multiple proteins involved in the fusion of neurotransmitter-containing vesicles and the active zone. The soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin-1, SNAP-25, and synaptobrevin-2 together form a SNARE complex, a key component in membrane fusion and ultimately exocytosis. A number of the proteins involved in this process may act as inhibitors and activators of the exocytosis of neurotransmitters from the presynapse.[11]

Clinical Significance

The neurotransmitter glutamate has been implicated in multiple neurodegenerative studies. Researchers agree that glutamate excitotoxicity undoubtedly has a role in the pathogenesis of Alzheimer disease, the most common neurodegenerative pathology affecting the elderly population. Research suggests glutamate excitotoxicity accelerates the progression of Alzheimer disease.[12] Glutamate is also implicated in the pathogenesis of Parkinson disease. Mutations in genes encoding the parkin and DJ1 proteins are present in Parkinson’s disease, which are involved in the regulation of excitatory glutamate synapses. These proteins may also protect neurons against glutamate excitotoxicity.[13][14]

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, is targeted in the treatment of anxiety disorder, insomnia, epilepsy, and other conditions. In particular, these drugs alter GABAergic function by targeting the GABAA and GABAB receptors.[15]

Not only does dopamine play an important role in multiple physiological processes, but it also has a role in the pathology of psychiatric and neurodegenerative diseases. Disturbances in the neurotransmission of dopamine are implicated in schizophrenia, psychosis, depression, Tourette syndrome, and attention deficit hyperactivity disorder. Regarding neurodegenerative diseases, dopamine is related to Parkinson’s disease, multiple sclerosis, and Huntington disease. There has been ample research on the role of dopaminergic neurons in Parkinson disease. Currently, research suggests that degeneration of dopaminergic neurons in the substantia nigra pars compacta is involved in the pathogenesis of Parkinson disease.[16]

Serotonin, a neurotransmitter that controls several neuropsychiatric processes, has been implicated in the pathogenesis of depression. Research has shown that patients with endogenous depression have low plasma levels of tryptophan, a precursor of serotonin. Furthermore, postmortem studies found an association between decreased serotonin levels in the brain and suicide, among depressed patients. In light of this, quite a few drugs have been developed that target serotonin in the treatment of depression. For example, tricyclic antidepressants work by increasing serotonin levels in the synapse.[17]

Norepinephrine is involved in the pathogenesis of neuropsychiatric disorders. Changes in locus coeruleus firing, dysregulation of norepinephrine function, synaptic receptor regulation, and norepinephrine availability are what result in pathogenesis. Conditions related to norepinephrine dysfunction include anxiety disorders, mood disorders, attention-deficit hyperactivity disorder, Alzheimer’s disease, and posttraumatic stress disorder. Furthermore, many symptoms in these disorders are directly attributable to norepinephrine dysfunction in the neural circuitry.[18]

A prominent contributor to the pathogenesis of IgE-mediated diseases is the neurotransmitter histamine. Produced in mast cells, histamine exerts its effects in the body by binding to certain histamine receptors. Two of the cardinal features of asthma, bronchospasm and mucosal edema, are directly related to histamine receptor stimulation.[19] Histamine is also implicated in the pathogenesis of multiple sclerosis, which is characterized by inflammatory demyelination in the central nervous system. In animal models, histamine has been shown to change the blood-brain barrier permeability. This change in permeability led to an increase of cells infiltrating the central nervous system, subsequently increasing neuroinflammation.[20]


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Physiology, Neurotransmitters - Questions

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What triggers the fusion of neurotransmitter vesicles within the presynaptic membrane?



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Which class of dopamine receptors signals diuresis?



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Which neurotransmitter has inhibitory activity?



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Which of the following neurotransmitters does not have inhibitory activity?



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The release of transmitter from nerve terminals into the synaptic cleft:



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Physiology, Neurotransmitters - References

References

Rizo J, Mechanism of neurotransmitter release coming into focus. Protein science : a publication of the Protein Society. 2018 Aug;     [PubMed]
Herlenius E,Lagercrantz H, Neurotransmitters and neuromodulators during early human development. Early human development. 2001 Oct;     [PubMed]
Herlenius E,Lagercrantz H, Development of neurotransmitter systems during critical periods. Experimental neurology. 2004 Nov;     [PubMed]
Zhou Y,Danbolt NC, Glutamate as a neurotransmitter in the healthy brain. Journal of neural transmission (Vienna, Austria : 1996). 2014 Aug;     [PubMed]
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Bowery NG,Smart TG, GABA and glycine as neurotransmitters: a brief history. British journal of pharmacology. 2006 Jan;     [PubMed]
Ko JH,Strafella AP, Dopaminergic neurotransmission in the human brain: new lessons from perturbation and imaging. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2012 Apr;     [PubMed]
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Passani MB,Panula P,Lin JS, Histamine in the brain. Frontiers in systems neuroscience. 2014;     [PubMed]
Südhof TC, Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013 Oct 30;     [PubMed]
Lau A,Tymianski M, Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Archiv : European journal of physiology. 2010 Jul;     [PubMed]
Wang Y,Chandran JS,Cai H,Mattson MP, DJ-1 is essential for long-term depression at hippocampal CA1 synapses. Neuromolecular medicine. 2008;     [PubMed]
Dong XX,Wang Y,Qin ZH, Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta pharmacologica Sinica. 2009 Apr;     [PubMed]
Jembrek MJ,Vlainic J, GABA Receptors: Pharmacological Potential and Pitfalls. Current pharmaceutical design. 2015;     [PubMed]
Rangel-Barajas C,Coronel I,Florán B, Dopamine Receptors and Neurodegeneration. Aging and disease. 2015 Sep;     [PubMed]
Coppen AJ,Doogan DP, Serotonin and its place in the pathogenesis of depression. The Journal of clinical psychiatry. 1988 Aug;     [PubMed]
Ressler KJ,Nemeroff CB, Role of norepinephrine in the pathophysiology of neuropsychiatric disorders. CNS spectrums. 2001 Aug;     [PubMed]
Akagi M, [Histamine in the pathogenesis of asthma]. Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 1998 Apr;     [PubMed]
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