Area postrema
Encyclopedia
The area postrema is a medullary structure in the brain
that controls vomiting
. Its privileged location in the brain also allows the area postrema to play a vital role in the control of autonomic functions by the central nervous system
.
. Specialized ependymal cells are found within the area postrema. These specialized ependymal cells differ slightly from the majority of ependymal cells (ependymocytes), forming a unicellular epithelium lining of the ventricles and central canal
. The area postrema is separated from the vagal triangle by the funiculus separans, a thin semitransparent ridge. The vagal triangle overlies the dorsal vagal nucleus and is situated on the caudal end of the rhomboid fossa
or 'floor' of the fourth ventricle. The area postrema is situated just before the obex
, the inferior apex of the caudal ventricular floor. Both the funiculus separans and area postrema have a similar thick ependyma-containing tanycyte covering. Ependyma
and tanycytes
can participate in transport of neurochemicals into and out of the cerebrospinal fluid
from its cells or adjacent neurons, glia or vessels. Ependyma and tanycytes may also participate in chemoreception. The eminence of the area postrema is considered a circumventricular organ because its endothelial cells do not contain tight junctions, which allows for free exchange of molecules between blood and brain tissue. This unique breakdown in the blood-brain barrier
is partially compensated for by the presence of a tanycyte barrier.
and other peripheral trigger areas. The area postrema makes up part of the dorsal vagal complex, which is the critical termination site of vagal afferent nerve fibers, along with the dorsal motor nucleus of the vagus and the nucleus of the solitary tract. Vomiting and nausea are most likely induced by the area postrema through its connection to the nucleus of the solitary tract, which may serve as the beginning of the pathway triggering vomiting in response to various emetic inputs. However, this structure plays no key role for vomiting induced by the activation of vagal nerve fibers or by motion, and its function in radiation-induced vomiting remains unclear. Because the area postrema is located outside of the blood-brain barrier, peptide
and other physiological signals in the blood have direct access to neurons of brain areas with vital roles in the autonomic control of the body. As a result, the area postrema is now being considered as the initial site for integration for various physiological signals in the blood as they enter the central nervous system
.
, detects toxin
s in the blood
and acts as a vomit-inducing center. The area postrema is a critical homeostatic integration center for humoral and neural signals. Recent studies have implicated its function as a chemoreceptor trigger site for vomiting in response to emetic drugs. It is a densely vacularized structure that lacks tight junctions between endothelial cells, thereby allowing it to detect various toxins in the blood as well as in the cerebrospinal fluid
.
makes this particular region of the medulla
a key player in the autonomic control of various physiological systems, including the cardiovascular system and the systems controlling feeding and metabolism.
A recent study has indicated the existence of prolactin
-binding sites specific to the area postrema. The result of the current study has implicated the area postrema as a prolactin target area at which vascular prolactin has the ability to openly associate with neuronal components. Prolactin is a peptide hormone known in lower animals to play a significant role in osmoregulation
, originally functioning to influence electrolyte balance, and may now be believed to stimulate reproductive behaviors such as the water-drive before ovoposition in amphibians and lactation
in mammals.
Another recent study found that the administration of angiotensin II causes a dose-dependent increase in the arterial blood pressure without producing considerable changes in the heart rate
. Evidence from this study reveals that the change in the arterial blood pressure depends on the integrity of the area postrema and that this site partially contributes to the action of angiotensin.
, prevents the normal functions of the area postrema from taking place. This ablation is usually done surgically and for the purpose of discovering the exact effect of the area postrema on the rest of the body. Since the area postrema acts as an entry point to the brain for information from the sensory neurons of the stomach, intestines, liver, kidneys, heart, and other internal organs, a variety of physiological reflexes rely on the area postrema to transfer information. The area postrema acts to directly monitor the chemical status of the organism. Lesions of the area postrema are sometimes referred to as ‘central vagotomy’ because they eliminate the brain’s ability to monitor the physiological status of the body through its vagus nerve
. These lesions thus serve to prevent the detection of poisons and consequently prevent the body’s natural defenses from kicking in. In one example, experiments done by Bernstein et al. on rats indicated that the area postrema lesions prevented the detection of lithium chloride
, which can become toxic at high concentrations. Since the rats could not detect the chemical, they were not able to employ a psychological procedure known as taste aversion
conditioning, causing the rat to continuously ingest the lithium-paired saccharin solution. These findings indicate that rats with area postrema lesions do not acquire the normal conditioned taste aversions when lithium chloride
is used as the unconditioned stimulus. In addition to simple taste aversions, rats with the area postrema lesions failed to perform other behavioral and physiological responses associated with the introduction of the toxin and present in the control group, such as laying down on their bellies, delayed stomach emptying, and hypothermia. Such experimentation emphasizes the significance of the area postrema not only in the identification of toxic substances in the body but also in the many physical responses to the toxin.
. Drugs that treat Parkinson's disease using dopamine
have a strong effect on the area postrema. These drugs stimulate dopamine transmission and attempt to normalize motor functions affected by Parkinson's. This works because nerve cells, in particular, in the basal ganglia
, which has a crucial role in the regulation of movement and is the primary site for the pathology of Parkinson's, use dopamine as their neurotransmitter and are activated by medications that increase the concentrations of the dopamine or work to stimulate the dopamine receptors. Dopamine also manages to stimulate the area postrema, since this part of the brain contains a high density of dopamine receptors. The area postrema is very sensitive to changes in blood toxicity and senses the presence of poisonous or dangerous substances in the blood. As a defense mechanism, the area postrema induces vomiting to prevent further intoxication. The high density of dopamine receptors in the area postrema makes it very sensitive to the dopamine-enhancing drugs. Stimulation of the dopamine receptors in the area postrema activates these vomiting centers of the brain; this is why nausea is one of the most common side-effects of antiparkinsonian drugs.
and in the area postrema by activating opiate receptors, which in turn caused vomiting by the ferrets. Yet a pre-treatment with 6-hydroxydopamine, a dopaminergic neurotoxin, significantly reduced the number of emetic episodes in the ferrets following morphine exposure. This neurotoxin reduced levels of dopamine, noradrenaline, and homovanilic acid, a metabolite of dopamine, and is known to destroy noradrenergic and dopaminergic neurons in the medulla oblongata but not in other parts of the brain. Although this destructive neurological activity has potential to cause other problems, this study shows how the dopaminergic pathway in the medulla oblongata may be manipulated in order to reduce the nauseating side-effects associated with so many dopamine-increasing drugs.
treatment against type 1 and type 2 diabetes. A particular mechanism, employed by the drug pramlintide
, acts mainly on the area postrema and results in decreased glucagon
secretion, which in turn slows down gastric emptying and the satiety effect. This targeting of the area postrema allows an improvement of glycaemic control without causing weight gain. Since the drug acts on the area postrema, the doses must be titrated slowly to avoid inducing nausea in the patient.
There are also studies still currently underway to determine the effect of ablation of the area postrema on hypertension
and cardiovascular function. For example, studies in rats and rabbits indicate that angiotensin II- dependent hypertension is abolished by lesioning of the area postrema. The mechanism for this physiological reaction is still not fully understood, but the area postrema's ability to regulate cardiovascular function presents a very interesting direction for neuroendocrinology.
, a Swedish anatomist, anthropologist and professor of histology at the Karolinska Mediko-Kirurgiska Institutet in Stockholm. In 1896, he published a two-volume monograph on the gross anatomy of the human brain in which the area postrema was mentioned. This work was one of the most important works published in the 19th century on the anatomy of the human brain.
In 1937, a publication by King, L.S. claimed that the area postrema was made up solely of glial cells, but this was later disproved by the research of several scientists including Jan Cammermeyer, Kenneth R. Brizzee and Herbert L. Borison, who demonstrated the presence of neurons in the area postrema of several mammal species.
Scientists became increasingly interested in the research of vomiting in the 1950s, perhaps in part due to society's heightened awareness of radiation sickness
, a condition in which many patients having vomited after radiation exposure died. Intensive studies on vomiting began in the 1950s at the University of Utah
College of Medicine, where Borison held a strong presence as both a professor and a researcher. He had received his doctorate in 1948 from Columbia University
, establishing himself as an authority on brainstem and neurophysiology
. Prior to the research of Borison and his well-known colleague S.C. Wang, a doctor and assistant professor from Columbia University, it was believed that the human body's chemodetection and coordination of vomiting, or emesis, were controlled exclusively by the dorsal vagal nucleus. Yet this idea was "incompatible with the observation that emesis could still be induced by gastrointestinal irritants in dogs with chronic lesions of the dorsal vagal nucleus", and so Borison and Wang dedicated their research to solving this puzzle. Borison eventually explained that their results showed the existence of two areas in the brain related to emesis; one, a chemosensor for vomiting with no coordinating function, located in the fourth ventricle
and two, a coordinator of vomiting with no chemosensory function, located in the lateral reticular formation
of the medulla oblongata
.
In 1953, Borison and Wang determined that the chemosensor area acted as a vomiting trigger zone in the brain stem, which they named the chemoreceptor trigger zone (CTZ) for emesis. Using cats and dogs as model organisms, they found that the removal of this trigger zone from the brain allowed for the prevention of emesis in the animals directly following injection of certain chemicals into the blood stream, demonstrating the existence of a relationship between the trigger zone and the act of vomiting. The CTZ was anatomically located in the area postrema of the medulla oblongata. The area postrema had been anatomically identified and named nearly 60 years earlier, but its function had remained unknown until the work of Borison and Wang proposed its role in emesis, which was later confirmed by many laboratories.
Other scientists noted as pioneers in the field of research concerning the area postrema and the mechanism of vomiting in general are Larry McCarthy, A.D. Miller and V. J Wilson.
whole-cell recording techniques were used on rat brain slices. The results showed that most responses to ATP are excitatory and that they are mediated by particular P2 purinoceptors found in the area postrema. The role of the area postrema in flavor-conditioned aversion and preference was studied in 2001 by researchers at the Brooklyn College
at the City University of New York
. The experiment tested the effect of area postrema lesions in rats on their ability to learn flavor-conditioned aversion to flavors paired with toxic drug treatments, which indeed showed that lesions of the area postrema leads to impaired flavor aversion learning.
A 2009 study followed the development of the area postrema, using a macaque monkey model in an attempt to identify and characterize neurotransmission
in this region as well as to resolve outstanding incongruities across research. These scientists found, in culmination, that previous studies suggest noradrenalin and/or dopamine
cause CA fluorescence in the area postrema macaque-CA, meaning catecholaminergic or derived from an amine and functioning as a neurotransmitter
or hormone
or both. The study, however, found evidence of neurotransmitter secretion instead of release in vesicles. Also, their findings concluded GABA
is a major neurotransmitter in the area postrema, not glutamate. Ongoing research continues to unravel discrepancies among various rat, cat, and now macaque monkey models of research.
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
that controls vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. Its privileged location in the brain also allows the area postrema to play a vital role in the control of autonomic functions by the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
Anatomy
The area postrema is a small protuberance found at the inferoposterior limit of the fourth ventricleFourth ventricle
The fourth ventricle is one of the four connected fluid-filled cavities within the human brain. These cavities, known collectively as the ventricular system, consist of the left and right lateral ventricles, the third ventricle, and the fourth ventricle...
. Specialized ependymal cells are found within the area postrema. These specialized ependymal cells differ slightly from the majority of ependymal cells (ependymocytes), forming a unicellular epithelium lining of the ventricles and central canal
Central canal
For the engineering project, see Indiana Central Canal.The central canal is the cerebrospinal fluid-filled space that runs longitudinally through the length of the entire spinal cord. The central canal is contiguous with the ventricular system of the brain...
. The area postrema is separated from the vagal triangle by the funiculus separans, a thin semitransparent ridge. The vagal triangle overlies the dorsal vagal nucleus and is situated on the caudal end of the rhomboid fossa
Rhomboid fossa
The anterior part of the fourth ventricle is named, from its shape, the rhomboid fossa, and its anterior wall, formed by the back of the pons and medulla oblongata, constitutes the floor of the fourth ventricle....
or 'floor' of the fourth ventricle. The area postrema is situated just before the obex
Obex
The obex is the point in the human brain at which the fourth ventricle narrows to become the central canal of the spinal cord.The obex occurs in the caudal medulla.The decussating of sensory fibers happens at this point....
, the inferior apex of the caudal ventricular floor. Both the funiculus separans and area postrema have a similar thick ependyma-containing tanycyte covering. Ependyma
Ependyma
Ependyma is the thin epithelial membrane lining the ventricular system of the brain and the spinal cord. Ependyma is one of the four types of neuroglia in the central nervous system. It is involved in the production of cerebrospinal fluid ....
and tanycytes
Tanycytes
Tanycytes are special ependymal cells located in the floor of the third ventricle having processes extending deep into the hypothalamus. It is possible that their function is to transfer chemical signals from CSF to CNS....
can participate in transport of neurochemicals into and out of the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
from its cells or adjacent neurons, glia or vessels. Ependyma and tanycytes may also participate in chemoreception. The eminence of the area postrema is considered a circumventricular organ because its endothelial cells do not contain tight junctions, which allows for free exchange of molecules between blood and brain tissue. This unique breakdown in the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
is partially compensated for by the presence of a tanycyte barrier.
Connectivity
The area postrema connects to the nucleus of the solitary tract and other autonomic control centers in the brainstem. It is excited by visceral afferent impulses (sympathetic and vagal) arising from the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
and other peripheral trigger areas. The area postrema makes up part of the dorsal vagal complex, which is the critical termination site of vagal afferent nerve fibers, along with the dorsal motor nucleus of the vagus and the nucleus of the solitary tract. Vomiting and nausea are most likely induced by the area postrema through its connection to the nucleus of the solitary tract, which may serve as the beginning of the pathway triggering vomiting in response to various emetic inputs. However, this structure plays no key role for vomiting induced by the activation of vagal nerve fibers or by motion, and its function in radiation-induced vomiting remains unclear. Because the area postrema is located outside of the blood-brain barrier, peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
and other physiological signals in the blood have direct access to neurons of brain areas with vital roles in the autonomic control of the body. As a result, the area postrema is now being considered as the initial site for integration for various physiological signals in the blood as they enter the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
Chemoreception
The area postrema, one of the circumventricular organsCircumventricular organs
Circumventricular organs are so named because they are positioned at distinct sites around the margin of the ventricular system of the brain.They are among the few sites in the brain which have an incomplete blood–brain barrier...
, detects toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
s in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and acts as a vomit-inducing center. The area postrema is a critical homeostatic integration center for humoral and neural signals. Recent studies have implicated its function as a chemoreceptor trigger site for vomiting in response to emetic drugs. It is a densely vacularized structure that lacks tight junctions between endothelial cells, thereby allowing it to detect various toxins in the blood as well as in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
.
Autonomic Regulation
The area postrema’s position outside of the blood-brain barrierBlood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
makes this particular region of the medulla
Medulla
Medulla refers to the middle of something and derives from the Latin word for marrow. Its anatomical uses include:* Medulla oblongata, a part of the brain stem* Renal medulla, a part of the kidney* Adrenal medulla, a part of the adrenal gland...
a key player in the autonomic control of various physiological systems, including the cardiovascular system and the systems controlling feeding and metabolism.
A recent study has indicated the existence of prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
-binding sites specific to the area postrema. The result of the current study has implicated the area postrema as a prolactin target area at which vascular prolactin has the ability to openly associate with neuronal components. Prolactin is a peptide hormone known in lower animals to play a significant role in osmoregulation
Osmoregulation
Osmoregulation is the active regulation of the osmotic pressure of an organism's fluids to maintain the homeostasis of the organism's water content; that is it keeps the organism's fluids from becoming too diluted or too concentrated. Osmotic pressure is a measure of the tendency of water to move...
, originally functioning to influence electrolyte balance, and may now be believed to stimulate reproductive behaviors such as the water-drive before ovoposition in amphibians and lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
in mammals.
Another recent study found that the administration of angiotensin II causes a dose-dependent increase in the arterial blood pressure without producing considerable changes in the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
. Evidence from this study reveals that the change in the arterial blood pressure depends on the integrity of the area postrema and that this site partially contributes to the action of angiotensin.
Area Postrema Lesions
Damage to the area postrema, caused primarily by lesioning or ablationAblation
Ablation is removal of material from the surface of an object by vaporization, chipping, or other erosive processes. This occurs in spaceflight during ascent and atmospheric reentry, glaciology, medicine, and passive fire protection.-Spaceflight:...
, prevents the normal functions of the area postrema from taking place. This ablation is usually done surgically and for the purpose of discovering the exact effect of the area postrema on the rest of the body. Since the area postrema acts as an entry point to the brain for information from the sensory neurons of the stomach, intestines, liver, kidneys, heart, and other internal organs, a variety of physiological reflexes rely on the area postrema to transfer information. The area postrema acts to directly monitor the chemical status of the organism. Lesions of the area postrema are sometimes referred to as ‘central vagotomy’ because they eliminate the brain’s ability to monitor the physiological status of the body through its vagus nerve
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
. These lesions thus serve to prevent the detection of poisons and consequently prevent the body’s natural defenses from kicking in. In one example, experiments done by Bernstein et al. on rats indicated that the area postrema lesions prevented the detection of lithium chloride
Lithium chloride
Lithium chloride is a chemical compound with the formula LiCl. The salt is a typical ionic compound, although the small size of the Li+ ion gives rise to properties not seen for other alkali metal chlorides, such as extraordinary solubility in polar solvents and its hygroscopic...
, which can become toxic at high concentrations. Since the rats could not detect the chemical, they were not able to employ a psychological procedure known as taste aversion
Taste aversion
Conditioned taste aversion, also known as Garcia effect , and as "Sauce-Bearnaise Syndrome", a term coined by Seligman and Hager, is an example of classical conditioning or Pavlovian conditioning...
conditioning, causing the rat to continuously ingest the lithium-paired saccharin solution. These findings indicate that rats with area postrema lesions do not acquire the normal conditioned taste aversions when lithium chloride
Lithium chloride
Lithium chloride is a chemical compound with the formula LiCl. The salt is a typical ionic compound, although the small size of the Li+ ion gives rise to properties not seen for other alkali metal chlorides, such as extraordinary solubility in polar solvents and its hygroscopic...
is used as the unconditioned stimulus. In addition to simple taste aversions, rats with the area postrema lesions failed to perform other behavioral and physiological responses associated with the introduction of the toxin and present in the control group, such as laying down on their bellies, delayed stomach emptying, and hypothermia. Such experimentation emphasizes the significance of the area postrema not only in the identification of toxic substances in the body but also in the many physical responses to the toxin.
Effect of Dopamine
The area postrema also has a significant role in the discussion of Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. Drugs that treat Parkinson's disease using dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
have a strong effect on the area postrema. These drugs stimulate dopamine transmission and attempt to normalize motor functions affected by Parkinson's. This works because nerve cells, in particular, in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, which has a crucial role in the regulation of movement and is the primary site for the pathology of Parkinson's, use dopamine as their neurotransmitter and are activated by medications that increase the concentrations of the dopamine or work to stimulate the dopamine receptors. Dopamine also manages to stimulate the area postrema, since this part of the brain contains a high density of dopamine receptors. The area postrema is very sensitive to changes in blood toxicity and senses the presence of poisonous or dangerous substances in the blood. As a defense mechanism, the area postrema induces vomiting to prevent further intoxication. The high density of dopamine receptors in the area postrema makes it very sensitive to the dopamine-enhancing drugs. Stimulation of the dopamine receptors in the area postrema activates these vomiting centers of the brain; this is why nausea is one of the most common side-effects of antiparkinsonian drugs.
Potential Treatment
A 2002 study in Japan tested a drug that may be of use in curbing the emetic response to drugs that increase dopamine concentrations. The study investigated morphine-induced emesis in ferrets, explaining that morphine exposure triggered dopamine release in the medulla oblongataMedulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
and in the area postrema by activating opiate receptors, which in turn caused vomiting by the ferrets. Yet a pre-treatment with 6-hydroxydopamine, a dopaminergic neurotoxin, significantly reduced the number of emetic episodes in the ferrets following morphine exposure. This neurotoxin reduced levels of dopamine, noradrenaline, and homovanilic acid, a metabolite of dopamine, and is known to destroy noradrenergic and dopaminergic neurons in the medulla oblongata but not in other parts of the brain. Although this destructive neurological activity has potential to cause other problems, this study shows how the dopaminergic pathway in the medulla oblongata may be manipulated in order to reduce the nauseating side-effects associated with so many dopamine-increasing drugs.
Continuing Pathological Study
The area postrema is also indicated in an insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
treatment against type 1 and type 2 diabetes. A particular mechanism, employed by the drug pramlintide
Pramlintide
Pramlintide acetate is a relatively new adjunct for diabetes , developed by Amylin Pharmaceuticals.-Pharmacology:...
, acts mainly on the area postrema and results in decreased glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
secretion, which in turn slows down gastric emptying and the satiety effect. This targeting of the area postrema allows an improvement of glycaemic control without causing weight gain. Since the drug acts on the area postrema, the doses must be titrated slowly to avoid inducing nausea in the patient.
There are also studies still currently underway to determine the effect of ablation of the area postrema on hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and cardiovascular function. For example, studies in rats and rabbits indicate that angiotensin II- dependent hypertension is abolished by lesioning of the area postrema. The mechanism for this physiological reaction is still not fully understood, but the area postrema's ability to regulate cardiovascular function presents a very interesting direction for neuroendocrinology.
History of research
The area postrema was first named and located in the gross anatomy of the brain by Magnus Gustaf RetziusGustaf Retzius
Magnus Gustaf Retzius was a Swedish physician and anatomist who dedicated a large part of his life to researching the histology of the sense organs and nervous system.-Biography:...
, a Swedish anatomist, anthropologist and professor of histology at the Karolinska Mediko-Kirurgiska Institutet in Stockholm. In 1896, he published a two-volume monograph on the gross anatomy of the human brain in which the area postrema was mentioned. This work was one of the most important works published in the 19th century on the anatomy of the human brain.
In 1937, a publication by King, L.S. claimed that the area postrema was made up solely of glial cells, but this was later disproved by the research of several scientists including Jan Cammermeyer, Kenneth R. Brizzee and Herbert L. Borison, who demonstrated the presence of neurons in the area postrema of several mammal species.
Scientists became increasingly interested in the research of vomiting in the 1950s, perhaps in part due to society's heightened awareness of radiation sickness
Radiation Sickness
Radiation Sickness is a VHS by the thrash metal band Nuclear Assault. The video is a recording of a concert at the Hammersmith Odeon, London in 1988. It was released in 1991...
, a condition in which many patients having vomited after radiation exposure died. Intensive studies on vomiting began in the 1950s at the University of Utah
University of Utah
The University of Utah, also known as the U or the U of U, is a public, coeducational research university in Salt Lake City, Utah, United States. The university was established in 1850 as the University of Deseret by the General Assembly of the provisional State of Deseret, making it Utah's oldest...
College of Medicine, where Borison held a strong presence as both a professor and a researcher. He had received his doctorate in 1948 from Columbia University
Columbia University
Columbia University in the City of New York is a private, Ivy League university in Manhattan, New York City. Columbia is the oldest institution of higher learning in the state of New York, the fifth oldest in the United States, and one of the country's nine Colonial Colleges founded before the...
, establishing himself as an authority on brainstem and neurophysiology
Neurophysiology
Neurophysiology is a part of physiology. Neurophysiology is the study of nervous system function...
. Prior to the research of Borison and his well-known colleague S.C. Wang, a doctor and assistant professor from Columbia University, it was believed that the human body's chemodetection and coordination of vomiting, or emesis, were controlled exclusively by the dorsal vagal nucleus. Yet this idea was "incompatible with the observation that emesis could still be induced by gastrointestinal irritants in dogs with chronic lesions of the dorsal vagal nucleus", and so Borison and Wang dedicated their research to solving this puzzle. Borison eventually explained that their results showed the existence of two areas in the brain related to emesis; one, a chemosensor for vomiting with no coordinating function, located in the fourth ventricle
Fourth ventricle
The fourth ventricle is one of the four connected fluid-filled cavities within the human brain. These cavities, known collectively as the ventricular system, consist of the left and right lateral ventricles, the third ventricle, and the fourth ventricle...
and two, a coordinator of vomiting with no chemosensory function, located in the lateral reticular formation
Lateral reticular formation
Moving caudally from the rostral midbrain, at the site of the rostral pons and the midbrain, the medial RF becomes less prominent, and the lateral RF becomes more prominent....
of the medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
.
In 1953, Borison and Wang determined that the chemosensor area acted as a vomiting trigger zone in the brain stem, which they named the chemoreceptor trigger zone (CTZ) for emesis. Using cats and dogs as model organisms, they found that the removal of this trigger zone from the brain allowed for the prevention of emesis in the animals directly following injection of certain chemicals into the blood stream, demonstrating the existence of a relationship between the trigger zone and the act of vomiting. The CTZ was anatomically located in the area postrema of the medulla oblongata. The area postrema had been anatomically identified and named nearly 60 years earlier, but its function had remained unknown until the work of Borison and Wang proposed its role in emesis, which was later confirmed by many laboratories.
Other scientists noted as pioneers in the field of research concerning the area postrema and the mechanism of vomiting in general are Larry McCarthy, A.D. Miller and V. J Wilson.
Current research
Research has continued today around the world on the functions of the area postrema. Beyond its role in emesis, as studied intensely by the researchers of the mid-1900s, the activity of the area postrema has been closely linked to other autonomic functions such as regulation of food intake, body fluid homeostasis, and cardiovascular regulation through behavioral studies and electrophysiological studies. In 2007 in Japan, research was performed on the mechanism of excitability of area postrema neurons by extracellular ATP. Voltage clampVoltage clamp
The voltage clamp is used by electrophysiologists to measure the ion currents across the membrane of excitable cells, such as neurons, while holding the membrane voltage at a set level. Cell membranes of excitable cells contain many different kinds of ion channels, some of which are voltage gated...
whole-cell recording techniques were used on rat brain slices. The results showed that most responses to ATP are excitatory and that they are mediated by particular P2 purinoceptors found in the area postrema. The role of the area postrema in flavor-conditioned aversion and preference was studied in 2001 by researchers at the Brooklyn College
Brooklyn College
Brooklyn College is a senior college of the City University of New York, located in Brooklyn, New York, United States.Established in 1930 by the New York City Board of Higher Education, the College had its beginnings as the Downtown Brooklyn branches of Hunter College and the City College of New...
at the City University of New York
City University of New York
The City University of New York is the public university system of New York City, with its administrative offices in Yorkville in Manhattan. It is the largest urban university in the United States, consisting of 23 institutions: 11 senior colleges, six community colleges, the William E...
. The experiment tested the effect of area postrema lesions in rats on their ability to learn flavor-conditioned aversion to flavors paired with toxic drug treatments, which indeed showed that lesions of the area postrema leads to impaired flavor aversion learning.
A 2009 study followed the development of the area postrema, using a macaque monkey model in an attempt to identify and characterize neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
in this region as well as to resolve outstanding incongruities across research. These scientists found, in culmination, that previous studies suggest noradrenalin and/or dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
cause CA fluorescence in the area postrema macaque-CA, meaning catecholaminergic or derived from an amine and functioning as a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
or hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
or both. The study, however, found evidence of neurotransmitter secretion instead of release in vesicles. Also, their findings concluded GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
is a major neurotransmitter in the area postrema, not glutamate. Ongoing research continues to unravel discrepancies among various rat, cat, and now macaque monkey models of research.
External links
- Diagram at endotext.org
- Slide at upenn.edu
- NIF Search - Area Postrema via the Neuroscience Information FrameworkNeuroscience Information FrameworkThe Neuroscience Information Framework is a repository of global neuroscience web resources, including experimental, clinical, and translational neuroscience databases, knowledge bases, atlases, and genetic/genomic resources.-Description:...
