Area postrema

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Area postrema
Gray709.png
Rhomboid fossa. (Area postrema labeled at bottom center.)
Human caudal brainstem posterior view description.JPG
Human caudal brainstem posterior view description (Area postrema is #8)
Details
Part of Medulla
Identifiers
Acronym(s)AP
MeSH D031608
NeuroNames 772
NeuroLex ID birnlex_2636
TA98 A14.1.04.258
TA2 6009
FMA 72607
Anatomical terms of neuroanatomy

The area postrema, a paired structure in the medulla oblongata of the brainstem, [1] is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and transduce them into neural signals and networks. [2] [3] [4] Its position adjacent to the bilateral nuclei of the solitary tract and role as a sensory transducer allow it to integrate blood-to-brain autonomic functions. Such roles of the area postrema include its detection of circulating hormones involved in vomiting, thirst, hunger, and blood pressure control. [1] [5]

Contents

Structure

The area postrema is a paired protuberance found at the inferoposterior limit of the fourth ventricle. [1] [5] Specialized ependymal cells are found within the area postrema. These cells differ slightly from the majority of ependymal cells (ependymocytes), forming a unicellular epithelial lining of the ventricles and central canal. The area postrema is separated from the vagal trigone by the funiculus separans, a thin semitransparent ridge. [1] [5] The vagal trigone 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 the 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. [1] [5]

The area postrema is considered a circumventricular organ because of its proximity to the ventricular system. [2] In a morphological study, area postrema capillaries in the ventral subregion of area postrema were shown to be relatively impermeable like those of the brain, whereas medial and dorsal area postrema capillaries had microscopic characteristics of high permeability, a characteristic called sinusoidal. [6] Subregional capillary density of the area postrema was highest near the ventricular interface, and was nearly twice as dense as the capillary densities of the adjacent solitary nucleus (SN), and dorsal motor nucleus of the vagus nerve. [6] A tanycyte barrier partially compensates for high capillary permeability in the area postrema. [7]

Physiological subregional studies of the area postrema indicated that its blood volume is relatively large, and blood flow and transit time for blood markers relatively slow, thereby amplifying the sensing capability for circulating compounds, such as hormones or transmitters. [8]

Micrograph of the area postrema (arrows) in a transverse section through the lower brainstem of a squirrel monkey (Saimiri sciureus). Hematoxylin and eosin stain; Bar=100 microns (0.1 millimeter). Area postrema micrograph.jpg
Micrograph of the area postrema (arrows) in a transverse section through the lower brainstem of a squirrel monkey (Saimiri sciureus). Hematoxylin and eosin stain; Bar=100 microns (0.1 millimeter).

Connections

The area postrema connects to the solitary nucleus, or nucleus tractus solitarii (NTS), and other autonomic control centers in the brainstem. It is excited by visceral afferent impulses (sympathetic and vagal) arising from the gastrointestinal tract and other peripheral trigger zones, and by humoral factors. [2] 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 NTS.

Nausea is most likely induced via stimulation of the area postrema via its connection to the NTS, 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 nausea induced by the activation of vagal nerve fibers or by motion, and its function in radiation-induced vomiting remains unclear. [9]

Because the area postrema and a specialized region of NTS have permeable capillaries, [2] peptides and other hormonal signals in the blood have direct access to neurons of brain areas with vital roles in the autonomic control of the body. [2] [6] As a result, the area postrema is considered a site of integration for various physiological signals in the blood as they enter the central nervous system. [2] [3]

Function

Chemoreception

The area postrema, one of the circumventricular organs, [10] detects toxins in the blood and acts as a vomit-inducing center. The area postrema is a critical homeostatic integration center for humoral and neural signals by means of its function as a chemoreceptor trigger zone for vomiting in response to emetic drugs. It is a densely vascularized structure with subregional capillary specializations for high permeability for circulating blood signals, allowing it to detect various chemical messengers in the blood and cerebrospinal fluid. [4] [6] Capillary blood flow appears to be uniquely slow in the area postrema, prolonging the contact time for blood-borne hormones to interact with neuronal receptors involved in regulation of blood pressure, body fluids, and emetic responses. [4] [8]

Autonomic regulation

The fenestrated sinusoidal capillaries of the area postrema and a specialized region of NTS make this particular region of the medulla critical in the autonomic control of various physiological systems, including the cardiovascular system and the systems controlling feeding and metabolism. [2] [6] Angiotensin II causes a dose-dependent increase in arterial blood pressure without producing considerable changes in the heart rate, an effect mediated by the area postrema. [11]

Clinical significance

Damage

Damage to the area postrema, caused primarily by lesioning or ablation, 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. [12] 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 lying down on their bellies, delayed stomach emptying, and hypothermia. [13] 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 disease. 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. [14]

History

The area postrema was first named and located in the gross anatomy of the brain by Magnus Gustaf Retzius, a Swedish anatomist, anthropologist and professor of histology. In 1896, he published a two-volume monograph on the gross anatomy of the human brain in which the area postrema was mentioned.[ citation needed ] In 1975, evidence of neurons in the area postrema of several mammal species was published. [15]

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. Studies 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.[ citation needed ]

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, 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 its role in emesis was later confirmed. [16]

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 clamp 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. [17] 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. [18] 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. [19]

Potential treatments

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 oblongata 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 homovanillic acid, a metabolite of dopamine, and is known to destroy noradrenergic and dopaminergic neurons. Here, 6-hydroxydopamine was injected directly into the medulla oblongata but not in other parts of the brain. 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. [20]

Continuing pathological studies

The area postrema is also indicated in an insulin 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. [21]

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. [22] [23] 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.

Related Research Articles

<span class="mw-page-title-main">Vagus nerve</span> Cranial nerve X, for visceral innervation

The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that carries sensory fibers that create a pathway that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right vagus nerves—but they are typically referred to collectively as a single subsystem. The vagus is the longest nerve of the autonomic nervous system in the human body and comprises both sensory and motor fibers. The sensory fibers originate from neurons of the nodose ganglion, whereas the motor fibers come from neurons of the dorsal motor nucleus of the vagus and the nucleus ambiguus. The vagus was also historically called the pneumogastric nerve.

<span class="mw-page-title-main">Blood–brain barrier</span> Semipermeable capillary border that allows selective passage of blood constituents into the brain

The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system, thus protecting the brain from harmful or unwanted substances in the blood. The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.

<span class="mw-page-title-main">Enteric nervous system</span> Vital system controlling the gastrointestinal tract

The enteric nervous system (ENS) or intrinsic nervous system is one of the main divisions of the autonomic nervous system (ANS) and consists of a mesh-like system of neurons that governs the function of the gastrointestinal tract. It is capable of acting independently of the sympathetic and parasympathetic nervous systems, although it may be influenced by them. The ENS is nicknamed the "second brain". It is derived from neural crest cells.

<span class="mw-page-title-main">Medulla oblongata</span> Structure of the brain stem

The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involuntary) functions, ranging from vomiting to sneezing. The medulla contains the cardiac, respiratory, vomiting and vasomotor centers, and therefore deals with the autonomic functions of breathing, heart rate and blood pressure as well as the sleep–wake cycle.

<span class="mw-page-title-main">Brainstem</span> Posterior part of the brain, adjoining and structurally continuous

The brainstem is the stalk-like part of the brain that interconnects the cerebrum and diencephalon with the spinal cord. In the human brain, the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is continuous with the thalamus of the diencephalon through the tentorial notch.

<span class="mw-page-title-main">Substance P</span> Chemical compound (polypeptide neurotransmitter)

Substance P (SP) is an undecapeptide and a type of neuropeptide, belonging to the tachykinin family of neuropeptides. It acts as a neurotransmitter and a neuromodulator. Substance P and the closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Solitary nucleus</span> Sensory nuclei in medulla oblongata

The solitary nucleus is a series of sensory nuclei forming a vertical column of grey matter in the medulla oblongata of the brainstem. It receives general visceral and/or special visceral inputs from the facial nerve, glossopharyngeal nerve and vagus nerve ; it receives and relays stimuli related to taste and visceral sensation. It sends outputs to various parts of the brain. Neuron cell bodies of the SN are roughly somatotopically arranged along its length according to function.

<span class="mw-page-title-main">Nucleus ambiguus</span>

The nucleus ambiguus is a group of large motor neurons, situated deep in the medullary reticular formation named by Jacob Clarke. The nucleus ambiguus contains the cell bodies of neurons that innervate the muscles of the soft palate, pharynx, and larynx which are associated with speech and swallowing. As well as motor neurons, the nucleus ambiguus contains preganglionic parasympathetic neurons which innervate postganglionic parasympathetic neurons in the heart.

<span class="mw-page-title-main">Myenteric plexus</span> Part of the enteric nervous system

The myenteric plexus provides motor innervation to both layers of the muscular layer of the gut, having both parasympathetic and sympathetic input, whereas the submucous plexus provides secretomotor innervation to the mucosa nearest the lumen of the gut.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

The chemoreceptor trigger zone (CTZ) is an area of the medulla oblongata that receives inputs from blood-borne drugs or hormones, and communicates with other structures in the vomiting center to initiate vomiting. The CTZ is located within the area postrema, which is on the floor of the fourth ventricle and is outside of the blood–brain barrier. It is also part of the vomiting center itself. The neurotransmitters implicated in the control of nausea and vomiting include acetylcholine, dopamine, histamine, substance P, and serotonin. There are also opioid receptors present, which may be involved in the mechanism by which opiates cause nausea and vomiting. The blood–brain barrier is not as developed here; therefore, drugs such as dopamine which cannot normally enter the CNS may still stimulate the CTZ.

<span class="mw-page-title-main">Subfornical organ</span>

The subfornical organ (SFO) is one of the circumventricular organs of the brain. Its name comes from its location on the ventral surface of the fornix near the interventricular foramina, which interconnect the lateral ventricles and the third ventricle. Like all circumventricular organs, the subfornical organ is well-vascularized, and like all circumventricular organs except the subcommissural organ, some SFO capillaries have fenestrations, which increase capillary permeability. The SFO is considered a sensory circumventricular organ because it is responsive to a wide variety of hormones and neurotransmitters, as opposed to secretory circumventricular organs, which are specialized in the release of certain substances.

The vascular organ of lamina terminalis (VOLT), organum vasculosum of the lamina terminalis(OVLT), or supraoptic crest is one of the four sensory circumventricular organs of the brain, the others being the subfornical organ, the median eminence, and the area postrema in the brainstem.

<span class="mw-page-title-main">Circumventricular organs</span> Interfaces between the brain and the circulatory system

Circumventricular organs (CVOs) are structures in the brain characterized by their extensive and highly permeable capillaries, unlike those in the rest of the brain where there exists a blood–brain barrier (BBB) at the capillary level. Although the term "circumventricular organs" was originally proposed in 1958 by Austrian anatomist Helmut O. Hofer concerning structures around the brain ventricular system, the penetration of blood-borne dyes into small specific CVO regions was discovered in the early 20th century. The permeable CVOs enabling rapid neurohumoral exchange include the subfornical organ (SFO), the area postrema (AP), the vascular organ of lamina terminalis, the median eminence, the pituitary neural lobe, and the pineal gland.

<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

<span class="mw-page-title-main">Vomiting</span> Involuntary, forceful expulsion of stomach contents, typically via the mouth

Vomiting is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.

<span class="mw-page-title-main">Respiratory center</span> Brain region controlling respiration

The respiratory center is located in the medulla oblongata and pons, in the brainstem. The respiratory center is made up of three major respiratory groups of neurons, two in the medulla and one in the pons. In the medulla they are the dorsal respiratory group, and the ventral respiratory group. In the pons, the pontine respiratory group includes two areas known as the pneumotaxic center and the apneustic center.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.

<span class="mw-page-title-main">Cancer and nausea</span>

Cancer and nausea are associated in about fifty percent of people affected by cancer. This may be as a result of the cancer itself, or as an effect of the treatment such as chemotherapy, radiation therapy, or other medication such as opiates used for pain relief. About 70 to 80% of people undergoing chemotherapy experience nausea or vomiting. Nausea and vomiting may also occur in people not receiving treatment, often as a result of the disease involving the gastrointestinal tract, electrolyte imbalance, or as a result of anxiety. Nausea and vomiting may be experienced as the most unpleasant side effects of cytotoxic drugs and may result in patients delaying or refusing further radiotherapy or chemotherapy.

References

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  11. ↑ Veljković, S.; Jovanović-Mićić, D.; Japundzić, N.; Samardzić, R.; Beleslin, D. B. (1989). "The area postrema and the hypertensive effect of angiotensin". Metabolic Brain Disease. 4 (1): 61–65. doi:10.1007/BF00999495. PMID   2704347. S2CID   12032912.
  12. ↑ Dictionary of Biological Psychology By Philip Winn (2001) Routledge
  13. ↑ Bernstein, I. L.; Chavez, M.; Allen, D.; Taylor, E. M. (1992). "Area postrema mediation of physiological and behavioral effects of lithium chloride in the rat". Brain Research. 575 (1): 132–137. doi:10.1016/0006-8993(92)90432-9. PMID   1324085. S2CID   21897766.
  14. ↑ David E. Golan and Armen H. Tashjian "Principles of Pharmacology: the Pathophysiologic Basis of Drug Therapy"
  15. ↑ Klara, P. M.; Brizzee, K. (1975). "The ultrastructural morphology of the squirrel monkey area postrema". Cell and Tissue Research. 160 (3): 315–26. doi:10.1007/BF00222042. PMID   807331. S2CID   950178.
  16. ↑ John Kucharczyk; David J. Stewart; Alan D. Miller (1991). Nausea and vomiting: recent research and clinical advances. Boca Raton: CRC Press. ISBN   0-8493-6781-6. OCLC   24066772.
  17. ↑ Kodama, N.; Funahashi, M.; Mitoh, Y.; Minagi, S.; Matsuo, R. (2007). "Purinergic modulation of area postrema neuronal excitability in rat brain slices". Brain Research. 1165: 50–59. doi:10.1016/j.brainres.2007.06.003. PMID   17658494. S2CID   6422014.
  18. ↑ Touzani, K.; Sclafani, A. (2002). "Area postrema lesions impair flavor-toxin aversion learning but not flavor-nutrient preference learning". Behavioral Neuroscience. 116 (2): 256–266. doi:10.1037/0735-7044.116.2.256. PMID   11996311.
  19. ↑ Pangestiningsih, T. W.; Hendrickson, A.; Sigit, K.; Sajuthi, D.; Nurhidayat; Bowden, D. M. (2009). "Development of the area postrema: An immunohistochemical study in the macaque". Brain Research. 1280: 23–32. doi:10.1016/j.brainres.2009.05.028. PMC   8850980 . PMID   19460361.
  20. ↑ Yoshikawa, T.; Yoshida, N. (2002). "Effect of 6-hydroxydopamine treatment in the area postrema on morphine-induced emesis in ferrets". Japanese Journal of Pharmacology. 89 (4): 422–425. doi: 10.1254/jjp.89.422 . PMID   12233822.
  21. ↑ Day, C. (2005). "Amylin analogue as an antidiabetic agent". The British Journal of Diabetes & Vascular Disease. 5 (3): 151–154. doi:10.1177/14746514050050030701.
  22. ↑ Averill, D. B.; Matsumura, K.; Ganten, D.; Ferrario, C. M. (1996). "Role of area postrema in transgene hypertension". Hypertension. 27 (3 Pt 2): 591–597. doi:10.1161/01.HYP.27.3.591. PMID   8613209.
  23. ↑ Bishop, V. S.; Hay, M. (1993). "Involvement of the Area Postrema in the Regulation of Sympathetic Outflow to the Cardiovascular System". Frontiers in Neuroendocrinology. 14 (2): 57–75. doi:10.1006/frne.1993.1003. PMID   8486207. S2CID   36991707.
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