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PubMed1985

A glutamate-sensitive neuronal system originating from the area postrema terminates in and transports acetylcholinesterase to the nucleus of the solitary tract.

The possible cellular mechanism of action of systemically administered monosodium-L-glutamate and the projections of glutamate-sensitive area postrema neurons have been studied in rats. Parenteral administration of monosodium-L-glutamate induced a selective degeneration of a particular population of AChE-containing area postrema neurons. Electron microscopic cytochemistry and X-ray microanalysis revealed the presence of calcium-containing electron-dense deposits in the mitochondria of degenerating area postrema neurons indicating the possible pathogenetic role of an enhanced intracellular calcium level in the mechanism of monosodium-L-glutamate-induced nerve cell degeneration. Degeneration of area postrema neurons was followed by the appearance of degenerating axon terminals in a well-defined region of the nucleus of the solitary tract, the area subpostrema. Degenerating area postrema neurons and axon terminals were rapidly engulfed by phagocytes predominantly of microglial character. AChE activity, localized to the basal lamina of the capillaries of the area subpostrema under normal conditions, could no longer be detected in rats treated with monosodium-L-glutamate 3-4 weeks previously. These findings provide evidence for the existence of a particular population of glutamate-sensitive, AChE-containing area postrema neurons which project and transport AChE to the nucleus of the solitary tract. This specific neuronal pathway connecting the area postrema with the nucleus of the solitary tract may play an important role in some of the functions attributed to the area postrema. The results also strengthen the hypothesis that brain capillary AChE activity may be of neuronal origin.

Acetylcholinesterase↗
PubMed1990

Reflex effect of vasopressin after blockade of V1 receptors in the area postrema.

This study investigated the effect of micropressure injection of the V1 arginine vasopressin (AVP) receptor antagonist into the area postrema on the ability of circulating AVP to augment baroreflex inhibition of renal sympathetic nerve activity (RSNA) in urethane-anesthetized rabbits. In addition, the effects of micropressure injections of AVP into the area postrema on RSNA, arterial pressure, heart rate, and baroreflex control of RSNA were evaluated. Injection of 100 ng (in a 10-nl volume) of AVP antagonist into the area postrema abolished the ability of AVP to enhance baroreflex inhibition of RSNA compared with phenylephrine (-8.84 +/- 0.89 before antagonist versus -4.83 +/- 0.44 %RSNA/mm Hg after antagonist). Normal baroreflex inhibition to phenylephrine (-3.95 +/- 0.26 versus -4.10 +/- 0.33 %RSNA/mm Hg) was unaltered. This dose of AVP antagonist given intravenously or into the adjacent medial nucleus tractus solitarius was without effect. Micropressure injection of AVP directly into the area postrema produced a dose-dependent decrease in RSNA without significant effects on arterial pressure or heart rate. Local injection of 4 +/- 0.6 ng (in a 4-nl volume) of AVP produced an average 27 +/- 3% decrease in resting RSNA. Continuous injection of AVP into the area postrema using short-duration, low-frequency pressure pulses significantly augmented the baroreflex inhibition of RSNA during phenylephrine infusion (during AVP injection, -7.12 +/- 1.60%RSNA/mm Hg; control, -3.38 +/- 0.55 %RSNA/mm Hg). These data support the hypothesis that circulating AVP acts at the area postrema to augment baroreflex inhibition of RSNA by a V1 receptor mechanism.

Animals↗
PubMed1988

Area postrema ablation and vascular reactivity in deoxycorticosterone-salt-treated rats.

In rats, central administration of the neurotoxin 6-hydroxydopamine prevents hypertension and certain functional vascular changes after deoxycorticosterone (DOC)-salt treatment. In this study, the effect of electrolytic ablation of the area postrema on blood pressure and vascular reactivity in DOC-salt-treated rats was examined. Four treatment groups of rats were studied (n = 5 in each): area postrema lesion, DOC-salt (DOC pivalate, 5 mg/wk s.c. for 5 weeks); sham lesion, DOC-salt; area postrema lesion, control; and sham lesion, control. Helically cut strips of carotid artery, aorta, and mesenteric artery were prepared for isometric force recording. Area postrema lesion attenuated hypertension in DOC-salt rats (mean arterial pressure, 107 vs 123 mm Hg in area postrema lesion and sham lesion rats, respectively; chronic aortic catheter). Vascular strips from sham lesion-control rats. These changes in vascular reactivity also were observed in area postrema lesion-DOC-salt rats. DOC treatment in rats on a normal sodium intake did not result in hypertension or increased vascular reactivity. In summary, integrity of the area postrema is necessary for hypertension but not for changes in vascular reactivity, in DOC-salt rats. It appears that 1) changes in vascular reactivity may be necessary, but they are not sufficient to produce DOC-salt hypertension, and 2) if these vascular changes are secondary to a central nervous system effect, they are mediated by a pathway distinct from the area postrema.

Animals↗
PubMed1988

Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides.

1. Multiple-barreled microelectrodes were used to record from neurons in the area postrema of anesthetized dogs and to test the responses of the neurons to a variety of substances in this structure, which is known to function as the chemoceptive trigger zone for emesis. 2. The neurons in area postrema were silent at rest but could be "found" by virtue of their response to ionophoretic glutamate. The glutamic response was brief and of short latency with high frequency of discharge. 3. Dog area postrema neurons were also excited by over 20 other substances, including acetylcholine, the biogenic amines, several peptides, and at least two hormones. Not all agents were excitatory, however. 4. The responses to all excitatory agents except glutamate were similar and unusual. All responses showed a relatively long latency (3-20 s), a long duration of excitation (30 s to many minutes), and a low discharge frequency (1-3 Hz). 5. There was a good correlation between substances that were excitatory on area postrema neurons and substances known to cause emesis. Because emesis due to intravenous application of these substances is known to be abolished in animals with ablation of the area postrema, it is very likely that recordings were from the neurons which trigger the response. 6. Because so many substances elicit the same type of response there is a possibility that all utilize a common second messenger. Neurons were not excited by ionophoresis of guanosine 3',5'-cyclic monophosphate (cGMP) but were excited by 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) and by forskolin, an activator of adenylate cyclase. 7. Behavioral studies were performed looking for emetic responses in awake dogs following intravenous injection of apomorphine, insulin, angiotensin II, and leucine enkephalin. For each a threshold concentration could be determined, which would consistently evoke emesis. 8. Dogs pretreated with phosphodiesterase inhibitors (theophylline, 3-isobutyl-1-methylxanthine, or RO 1724) showed a shift in the threshold concentration of the above substances that triggered emesis, such that emesis was evoked by lower concentrations than in the control. 9. These results suggest that neurons of the dog area postrema trigger the emetic reflex in response to specific receptors for a great variety of transmitters, peptides, and hormones, and that these receptors act through a common second messenger, cAMP.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1984

Lack of protection against ouabain cardiotoxicity after chronic ablation of the area postrema in cats.

We evaluated the hypothesis that the area postrema facilitates the cardiac arrhythmias caused by toxic doses of digitalis. The arrhythmic dose of ouabain was determined in four cats with chronic selective destruction of the area postrema, and in a control group of two sham-operated cats and three normal unoperated cats. The cats were anesthetized with pentobarbital, and polygraph records were made of end-tidal Pco2, arterial blood pressure, heart rate, and the electrocardiogram (lead II and a bipolar lead in the superior vena cava). The vagosympathetic trunks were cut bilaterally, and 1 h later an i.v. infusion of [3H]ouabain was begun at the rate of 1.71 nmol/kg/min. This was continued until ventricular tachycardia appeared, as determined electrocardiographically. The total ouabain dosage required for ventricular tachycardia was recorded, and the ouabain concentrations in the arterial plasma and in the myocardium were determined by liquid scintillation counting. No statistically significant difference was found between the chronically postremectomized cats and the controls in any of these measures of ouabain cardiotoxicity. These results indicate that the area postrema plays no important role in the cardiotoxic action of ouabain in pentobarbital-anesthetized, vagotomized cats.

Animals↗
PubMed1983

Responses of neurons of canine area postrema to neurotransmitters and peptides.

The responses of 122 neurons in the area postrema of anesthetized dogs to 17 common transmitters and peptides were determined. Recordings were made from one barrel of a seven-barrel ionophoretic electrode. All neurons were silent at rest, but most could be detected and excited by the application of glutamate. The glutamate response was a brief, high-frequency response of less than 1-sec duration. Excitatory responses were also found to histamine, norepinephrine, serotonin, dopamine, apomorphine, angiotensin II, neurotensin, leucine enkephalin, vasoactive intestinal polypeptide, thyrotropin releasing hormone, gastrin, vasopressin, and substance P. While most neurons tested were excited by dopamine and apomorphine, approximately half of those studied were also excited by each of the other substances. Inhibitory responses were found to norepinephrine (6 of 15 cells) and histamine (3 of 45 cells). No responses were found to acetylcholine, somatostatin, or cholecystokinin. The responses to all 13 excitatory substances other than glutamate were similar. Typically these responses had a latency of 2-20 sec and lasted for 30 sec to 5 min on their first application. The frequency of discharge was usually low (approximately 0.5 Hz). Multiple applications of these agents often induced a maintained spontaneous discharge of low frequency. Each application also induced a transient incremental discharge at a frequency that rarely exceeded 2 Hz. The area postrema has been proposed to be the "chemoreceptor trigger zone" for emesis (Borison and Wang, 1953). All of the agents which excite area postrema neurons, with the exception of serotonin and norepinephrine, are emetic, while none of the three agents without excitatory effects is known to be emetic. Thus these results provide strong support for the central role of the area postrema in emesis. The similarity of response to so many substances on small neurons suggests a common ionic and/or metabolic mechanism underlying the response. The prolonged nature of the response to brief administration of these agents would seem to be appropriate for neurons which subserve a sensation and behavior such as nausea and vomiting.

Action Potentials↗
PubMed1985

Immunohistological studies of masked indoleamine cells in the area postrema of the rat.

Masked indoleamine cells (MICS) in the area postrema and adjacent areas in the rat were immunohistochemically studied (the peroxidase-antiperoxidase method) using a serotonin antiserum. After pretreatment with nialamide (200-300 mg/kg), immunoreactive MICS could be observed. They were small cells (about 12 micron in diameter) with several processes and were distributed in nearly all parts of the area postrema and also in the nucleus tructus solitarii. Following a single intraventricular injection of 75 micrograms 5,6-dihydroxytryptamine, the immunoreactivity of these cells conspicuously decreased for several days. The submicroscopical structure of the cells was investigated using immunoelectron microscopy. Immunoreactive products were observed in the cytoplasm as particles with a diameter of 25-40 nm and high electron density, but these were not found in the nucleus or cell organelles.

5,6-Dihydroxytryptamine↗
PubMed1994

Modified cardiovascular sensitivity of the area postrema to vasopressin in spontaneously hypertensive rats.

Vasopressin has been shown to act at the area postrema to increase the sensitivity of the baroreceptor reflex. We have previously demonstrated that microinjection of vasopressin into the area postrema of Sprague-Dawley rats elicits pressor effects. We report here that vasopressin microinjection into the area postrema of spontaneously hypertensive rats is without effect on blood pressure, whereas microinjection into age-matched Wistar-Kyoto controls results in significant increases in blood pressure at 50 and 100 pg. These results suggest an altered sensitivity of the area postrema to vasopressin in this genetic model of hypertension.

Animals↗
PubMed1992

Efferent microvascular responses to electrical stimulation of the area postrema in rats.

As part of its role to transduce blood-borne and afferent neural stimuli to the brain, the area postrema conducts efferent projections monosynaptically to individual nuclei of the medulla oblongata and pons. We hypothesized that electrical activation of the area postrema would mimic this transduction process and couple microvascular responses in efferent sites to local increases in tissue metabolism reported previously. We used quantitative autoradiographic techniques and image analysis to measure capillary transfer constants for [14C]alpha-aminoisobutyric acid (AIB, a small, neutral amino acid) and blood flow (iodo[14C]antipyrine) in individual brainstem structures of anesthetized rats. The area postrema was stimulated electrically by means of a monopolar microelectrode positioned stereotaxically 100 microns deep in the dorsocentral aspect of the organ. There were no significant effects of stimulation on [14C]AIB influx or blood flow in control hindbrain structures where postremal projections are sparse or absent--the spinal trigeminal nucleus, reticular formation, or cerebellar vermis. Stimulation of the area postrema produced equivalent increases in transcapillary influx of [14C]AIB and capillary blood flow in the nucleus of the solitary tract, dorsal motor nuclei of the vagus nerves, ventrolateral medullary C1 region, locus coeruleus, dorsal tegmental nuclei, and lateral parabrachial nuclei. Formation of ratios interrelating rates of [14C]AIB influx and blood flow with previously assessed values of tissue glucose metabolism indicated that these measures increased proportionately during postremal stimulation. Such proportional increases in capillary [14C]AIB transfer and blood flow during tissue activation by area postrema stimulation are consistent with interpretation that the increase in blood flow resulted from recruitment of unused surface area in the capillary networks of individual efferent nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Angiotensin II-induced taste aversion learning in cats and rats and the role of the area postrema.

The capacity of angiotensin II (AII, 1 mg/kg, IP) to produce a taste aversion was studied in cats and rats with and without lesions of the area postrema. Using a one-bottle test, injection of AII produced an aversion in cats but not in rats. Using a two-bottle test, injection of AII produced a slight, but significant, decrease in sucrose preference in intact rats, but had no effect on rats with area postrema lesions. Lesions of the area postrema prevented the acquisition of a taste aversion in cats. These results, which show a clear species difference in the capacity of AII to produce a taste aversion, are discussed as supporting the hypotheses that there is a relationship between the sensitivity of the area postrema to a compound and the capacity of that compound to produce a taste aversion; and that excitation of the area postrema constitutes a sufficient condition for taste aversion learning to occur.

Angiotensin II↗
PubMed1977

Electron microscope study of thallium-induced alterations in the oligodendrocytes of the rat area postrema.

Thallotoxicosis following accidental ingestion of thallium in rodenticides and in cases of homicidal and suicidal ingestion are well documented in the literature. The mechanism of action of thallium, in particular the pathogenesis of its neurotoxic manifestations, is not entirely clear. This is the first electron microscopic investigation dealing with the effect of thallium on the oligodendrocytes of the area postrema. The area postrema is devoid of a blood-brain barrier, indicating that the hemoneural transport of thallous ions may be quite substantial in this region. Rats weighing 155-175 g were given intraperitoneal injections of 5 mg/kg thallous acetate for 7 days (35 mg/kg total dose). Following perfusion-fixation, ultrathin sections of area postrema were examined with an electron microscope. The oligodendrocytes exhibited pleomorphic vacuolated dense bodies in their perikaryon. The findings were also suggestive of the fact that either the multiplication of oligodendrocytes or their aggregation to form "giant cell" was operative.

Animals↗
PubMed1989

Binding of the 5-HT3 ligand, [3H]GR65630, to rat area postrema, vagus nerve and the brains of several species.

The radiolabelled derivative of the potent and selective 5-HT3 receptor antagonist, GR65630, has been shown to label 5-HT3 receptors in homogenates of rat entorhinal cortex. We now report on the specific binding of this radioligand in homogenates of 16 discrete brain areas from several species and nine areas of human brain. We have further characterised specific binding to homogenates of rat area postrema and vagus nerve. In all species examined (rat, mouse, rabbit and ferret) the highest level of specific [3H]GR65630 (0.2 nM) binding was found in homogenates of the area postrema (26-83 fmol/mg protein). Binding in forebrain areas varied with species, Rat and mouse brain had relatively high levels of binding in cortical areas. The ferret and rat had relatively high levels in forebrain dopamine-containing areas. Of the areas of human brain examined the amygdala showed the highest level of specific [3H]GR65630 (0.2 nM) binding (3.0 fmol/mg protein). Specific [3H]GR65630 (0.05-2 nM) binding to homogenates of rat vagus nerve and area postrema was saturable (Bmax: vagus nerve 89.1 fmol/mg protein, area postrema 44.4 fmol/mg protein) and of high affinity (Kd: vagus nerve 0.50 nM, area postrema 0.24 nM). Selective 5-HT3 receptor agonists and antagonists potently inhibited [3H]GR65630 (0.2 nM) binding to homogenates of rat area postrema and vagus nerve. There was a close correlation between drug affinities in each area.

Animals↗
PubMed1984

Distribution of FMRF-NH2-like immunoreactivity in rat and cat area postrema.

The distribution of FMRF-NH2-like immunoreactivity, visualized with immunohistochemical techniques, was plotted in a range from very dense to none. The rat area postrema had differential immunostaining with the greatest amounts occurring at its ventral and ventrolateral borders by the nucleus of the solitary tract. Immunoreactive cell bodies were located mainly in this region. Throughout the central region of the rat area postrema scattered immunostaining was consistently observed. The cat area postrema had a different, greater, and more complex pattern of immunostaining than the rat. Very dense to dense accumulations of immunostaining occurred in the ventromedial region of the area postrema bordering the solitary tract and dorsal vagal nuclei, while the central region possessed scattered amounts of immunoreactivity. Following colchicine treatment, no visible FMRF-NH2-like immunoreactive cell bodies were observed in the cat area postrema.

Animals↗
PubMed1982

Electron microscopic immunocytochemical localization of tyrosine hydroxylase in the area postrema of rat.

The ultrastructural morphology and specialized neuronal, vascular, and ventricular associations of tyrosine hydroxylase-labeled neurons are examined within the area postrema of rat brain. Specific antiserum to the purified enzyme is localized throughout the rostrocaudal and dorsoventral extent of the area postrema by means of the peroxidase-antiperoxidase technique. In all regions, peroxidase immunoreactivity for tyrosine hydroxylase is distributed throughout the cytoplasm of selectively labeled neuronal perikarya and processes. The perikarya contain a large nucleus, infolded nuclear membrane, numerous cytoplasmic organelles, and form axosomatic synapses with unlabeled terminals. The majority of the labeled processes are dendrites, which contain ribosomes, microtubules, mitochondria, and scattered vesicles. These dendrites are postsynaptic to unlabeled axon terminals and show membrane specializations with other labeled dendrites and perikarya. In contrast to dendrites, peroxidase-labeled profiles clearly distinguished as axons or axon terminals are sparse and never show membrane specializations with other neuronal or nonneuronal structures within the area postrema. Numerous large processes which could be either axons or dendrites are associated with blood vessels and the ventricular surface of the area postrema. With respect to blood vessels, processes are located either in direct apposition to the external glial membrane, or less frequently, within the perivascular space. The ventricular processes are either associated with blood vessels in the subpial space or distributed among the cilia and villi at the anterior margins of the area postrema. The neuronal and nonneuronal associations of the tyrosine hydroxylase-labeled processes are consistent with a receptor or chemosensor function for catecholamines in this circumventricular organ.

Animals↗
PubMed1989

5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret.

1. The purpose of the present study was to identify and investigate the role of 5-hydroxytryptamine3 (5-HT3) receptors in the area postrema in the control of cisplatin-induced emesis in the ferret. 2. Homogenate binding and autoradiography experiments using the high affinity 5-HT3 receptor ligand, [3H]-GR65630, identified the presence of a high concentration of 5-HT3 receptors in the area postrema of the ferret. 3. Intraperitoneal injection of the 5-HT3 receptor antagonists, GR38032F, GR65630A and MDL72222, at doses of 1, 0.1 and 1 mg kg-1 respectively, inhibited emesis induced by cisplatin, 9 mg kg-1 i.p. 4. Discrete injection of low doses of the 5-HT3 receptor antagonists directly into the area postrema region also inhibited cisplatin-induced (9 mg kg-1 i.p.) emesis. The dose ranges used were: GR38032F, 0.01-1 microgram; GR65630A, 0.001-0.1 microgram; MDL72222, 0.1-10 micrograms. 5. Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 micrograms) or methiothepin (30 micrograms) into the area postrema. Injection of the 5-HT3 receptor agonist, 2-methyl-5-HT, directly into the area postrema produced an incomplete emetic response. 6. These results confirm a role of 5-HT, and in particular 5-HT3 receptors, in the control of cisplatin-induced emesis, and show that at least one functional site for these receptors in modulating the emetic response is the area postrema, the locus of the chemoreceptor trigger zone.

Animals↗
PubMed1983

Attenuation of radiation- and drug-induced conditioned taste aversions following area postrema lesions in the rat.

The effects of lesions of the area postrema on the acquisition of radiation- and drug-induced (histamine and lithium chloride) conditioned taste aversions were investigated. The results indicated that area postrema lesions caused a significant attenuation of the aversion produced by pairing a novel sucrose solution with radiation (100 rad) or drug injection. Further, the area postrema lesions produced a similar level of attenuation of the taste aversion in all three treatment conditions. The results are discussed in terms of the implications of this finding for defining the mechanisms by which exposure to ionizing radiation can lead to the acquisition of a conditioned taste aversion.

Animals↗
PubMed1986

Role of the area postrema in radiation-induced taste aversion learning and emesis in cats.

The role of the area postrema in radiation-induced emesis and taste aversion learning and the relationship between these behaviors were studied in cats. The potential involvement of neural factors which might be independent of the area postrema was minimized by using low levels of ionizing radiation (100 rads at a dose rate of 40 rads/min) to elicit a taste aversion, and by using body-only exposures (4500 and 6000 rads at 450 rads/min) to produce emesis. Lesions of the area postrema disrupted both taste aversion learning and emesis following irradiation. These results, which indicate that the area postrema is involved in the mediation of both radiation-induced emesis and taste aversion learning in cats under these experimental conditions, are interpreted as being consistent with the hypotheses that similar mechanisms mediate both responses to exposure to ionizing radiation, and that the taste aversion learning paradigm can therefore serve as a model system for studying radiation-induced emesis.

Animals↗
PubMed1987

Ultrastructure of the area postrema of the monkey, Macaca fascicularis.

The area postrema of the monkey, Macaca fascicularis, were a pair of oval organs at the caudal end of the floor of fourth ventricle. Their ependymal lining was covered by well-developed microvilli with occasional overlying supraependymal cells. Two types of lining cells were present: pyramidad- and flattened cells. The pyramidal cell showed a long extending basal process resting on the underlying blood vessels. In transmission electron microscopy, the organ showed numerous fenestrated sinusoids characterized by a distinct perivascular space containing mast cells, macrophages and collagen fibrils. The parenchyma of the organ was composed of neurons and glial elements. Only one type of neuron ranging from 9.5 to 15 microns could be distinguished. The neurons contained an indented nucleus surrounded by organelle rich cytoplasm. The soma of the neuron was enclosed by glial element resembling astrocyte. The glial processes terminated on the blood vessel where they were "tunnelled" by a variable number of nerve fibres some of which gained a direct access to the external basal lamina of the perivascular space. Synapses in the neuropil predominantly of the axodendritic variety were observed. Axon terminals containing round agranular vesicles were seen to make synaptic contacts with the neuronal soma. No structural changes were observed in the area postrema following bilateral cervical vagotomy. However, degenerating axon terminals were observed in the subpostremal zone 7, 14 and 21 days after vagotomy suggesting a direct afferent projection into this region.

Animals↗