Dose-related stimulation of feeding by systemic injections of monosodium glutamate

Monosodium glutamate (MSG) is an excitotoxin capable of both stimulating and lesioning neurons in circumventricular organs (CVOs) after systemic administration. In this study, MSG and equiosmotic concentrations of NaCl were administered subcutaneously to adult rats in order to observe the effects on food and water intake. MSG (0.5, 1, 2 and 6 g/kg), but not NaCl, stimulated feeding. The magnitude of the feeding was dose-related. After the highest dose, rats consumed 4.4 g of pelleted food. Since MSG does not cross the blood-brain barrier, we conclude that feeding was stimulated by an action of glutamate on CVOs. Doses of MSG that stimulated feeding did not alter blood glucose concentration. Neonatal MSG treatment, which is known to be more damaging to circumventricular neurons than adult treatment, greatly reduced or abolished subsequent MSG-induced stimulation of feeding in adults. Both MSG and NaCl stimulated drinking. Since the magnitude of the drinking response was similar for both solutes and was directly related to the osmotic strength of the solutions, we conclude that the drinking response after MSG was mediated by cellular dehydration.     

Gender differences between the effect of monosodium glutamate on food intake in rats

Monosodium glutamate (MSG) was recently reported to increase feeding in ad lib. fed rats [Reddy et al.(4)]. In the present study the responses of male and female adult rats to subcutaneous (SC) administration of MSG were compared. In female rats MSG 3 g/kg did not significantly affect food or water intake as compared with SC NaCl 0.9%; MSG 6 g/kg significantly reduced food intake but increased water intake. On the contrary, in male rats MSG 6 g/kg significantly increased food and water intake. It is concluded that there are differences between genders of rats in what concerns the effect of glutamate on food intake.     

Central but not peripheral glucoprivation is impaired in monosodium glutamate-treated rats

In the present study, newborn male Wistar rats were injected, subcutaneously, five times, every other day, with monosodium glutamate (MSG, 4 g/kg bw) or saline (as control, C), during the neonatal period. MSG animals developed destruction of the arcuate nuclei (ARC) with absence of NPY-immunoreactive cell bodies, which impaired both the food intake (baseline) and the 2-deoxy-D-glucose (2DG) glucoprivic feeding response. Increases in the immunoreactivity of corticotropin-releasing hormone-cell bodies in the paraventricular nuclei might have developed to compensate for the atrophy of the pituitary in MSG-treated rats. After systemic 2DG injection, neither the C nor the MSG rats increased their food intake, but they showed similar hyperglycemic responses, whereas plasma free fatty acids (FFA) increased only in the C group. In other groups, 2DG, norepinephrine (NE), neostigmine (NEO) and saline were intracerebroventricularly (i.c.v.) administered. In this condition, impairment of the hyperglycemic and food intake responses, associated to a lower increase in plasma FFA levels, were observed. As opposed to this, the MSG treatment gives support to NE effects, enhancing food intake, as well as plasma glucose and FFA levels. After NEO, plasma glucose increased only in the MSG group, while plasma FFA levels were elevated in the C rats. Taken together, the results obtained after MSG treatment point to a separate neural control of the hyperglycemic response and of the lipid mobilization when stimulated by central 2DG, NE or NEO administration. It seems likely that the excitatory neural pathway that controls lipid metabolism and is present in C rats was destroyed by the MSG treatment.     

Systemic glutamate induces degeneration of a subpopulation of serotonin-immunoreactive neurons in the area postrema of rats

Neuronal damage in the area postrema (AP) of adult Sprague-Dawley rats was induced by subcutaneous administration of monosodium glutamate (MSG; 9 mg/g b.wt.). Serotonin-immunoreactive (5-HT-IR) neurons were visualized in the AP 3 h or 7 days after control or MSG treatment. At 3 h post MSG, many 5-HT-IR neurons showed morphological signs of degeneration, such as, cytoplasmic vacuolization, chromatin clumping and dendritic hypertrophy. MSG treatment caused a 30% reduction of detectable AP 5-HT neurons after 7 days. We conclude that a subpopulation of serotonergic neurons in the AP is sensitive to the neuroexcitotoxic effect of systemic glutamate.     

Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats

According to previous studies, the area postrema (AP) of the hindbrain may play an important role in mediating the anorectic effect of the pancreatic hormone amylin. Peripheral amylin has been suggested to directly act on AP neurons to bring about its anorectic effect. Cyclic GMP may act as second messenger in this regard. In the present study, we wanted to further delineate the role of the AP in amylin's effect and to find out whether endogenous amylin might reduce feeding via the AP. Rats with chronic cannulas aiming at the AP were infused with various doses of amylin, its agonist salmon calcitonin (sCT) or a cyclic guanosine monophosphate (cGMP) analogue. Amylin and sCT inhibited food intake for about 2 h after food presentation, mainly by reducing meal size when infused into the AP [e.g., 1 h food intake after amylin (0.4 microg/rat) infusion in 12-h deprived rats: NaCl 4.0+/-0.5 vs. amylin 2.4+/-0.5, P<.05]. The effect was comparable in ad libitum fed and 12-h food-deprived rats with a minimal effective dose of 0.04 microg/rat. Similar to amylin and sCT, the cGMP analogue 8-Br-cGMP (200 nmol/rat) also reduced food intake and meal size. Infusion of the amylin antagonist AC 187 (30 microg) into the AP significantly reduced the anorectic effect induced by an intraperitoneal injection of amylin (5 microg/kg). Furthermore, AC 187 alone increased feeding when infused into the AP. This study is in line with previous work pointing to an important role of the AP in mediating the anorectic effect of amylin. Furthermore, we provide evidence for a physiological role of endogenous amylin to reduce food intake. This may also involve an action via the AP.     

Etomoxir, a fatty acid oxidation inhibitor, increases food intake and reduces hepatic energy status in rats

Etomoxir, an inhibitor of fatty acid oxidation, increases food intake and reported hunger in humans. Work with animal models suggests that other inhibitors of fatty acid oxidation stimulate feeding behavior by acting on the liver. In the following study, we assessed whether etomoxir would increase food intake in rats and to what degree the effects of etomoxir on feeding were associated with changes in hepatic energy status. The effects of etomoxir on hepatic energy status were assessed by measuring liver ATP, ADP, phosphorylation potential, and glycogen content. Blood glucose, free fatty acids, and ketone bodies were also measured to determine the availability of circulating fuels following etomoxir treatment. Etomoxir and methyl palmoxirate (MP; another inhibitor of fatty acid oxidation) increased food intake. Etomoxir, like MP, also reduced hepatic ATP/ADP ratio and phosphorylation potential. In combination with 2,5-anhydro-D-mannitol (an analogue of fructose that produces an increase in feeding by action on the liver), etomoxir synergistically increased food intake and reduced hepatic ATP/ADP ratio. In summary, etomoxir increased food intake and decreased hepatic energy status in the rat. This suggests that etomoxir stimulates feeding by action on the liver.     

Interaction of MSG taste with nutrition: perspectives in consummatory behavior and digestion

Studies in the taste system of mammals indicate that monosodium glutamate (MSG) produces a unique taste sensation termed umami. As a derivative of glutamic acid, MSG is a naturally occurring nutrient in many foods; its commercial use to improve food palatability for humans is well documented. Behavioral studies with experimental animals have revealed that preference for MSG in solutions and selection of MSG-flavored diets can be explained by sensory means with no appreciable effects on preference by postingestive consequences. However, preference for umami-flavored fluids is reduced by feeding rats low-protein diets or low quality protein. MSG-flavored diets, initially unpreferred, were subsequently highly selected. However, the adulteration of diets by MSG either did not or only slightly increased food intake. In light of the significant contribution of MSG to diet taste, apparently as a signal coupled to dietary proteins, physiological studies have been initiated to reveal its role as a stimulator of the cephalic phase of pancreatic exocrine secretion. Modified sham-feeding experiments with dogs have shown that oral stimulation by MSG produced significant stimulation of both pancreatic flow and protein output in conscious dogs.     

Opiates and the anorexia of uremia

Uremia results in a decrease in food intake. In the present study we investigated whether opiates known to stimulate feeding would alter food intake in rats made uremic by 1 and 5/6 nephrectomy. Morphine increased food intake in sham nephrectomized rats, but failed to alter food intake in uremic animals and depressed the ingestion of rat chow in a group of weight restricted rats. Butorphanol tartrate increased feeding in sham and uremic animals but did not alter intake in the weight restricted group. Higher doses of butorphanol were needed to stimulate feeding in the uremic rats compared to the sham group, suggesting a relative resistance to opioid-induced feeding in the uremic rats. The opiate antagonist, naloxone, suppressed food intake in the uremic and sham groups more effectively than in the weight restricted rats. These data suggest that the opioid feeding system functions in a reduced fashion in uremic rats, but probably is not the sole factor involved in producing the anorexia associated with uremia.     

Ghrelin and the short- and long-term regulation of appetite and body weight

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.     

Central administration of melanin-concentrating hormone (MCH) suppresses food intake, but not locomotor activity, in the goldfish, Carassius auratus

Melanin-concentrating hormone (MCH) is a hypothalamo-pituitary peptide, which was first identified in the salmon pituitary as a hormone affecting body color. Recently, MCH has been implicated in the regulation of feeding behavior and energy homeostasis in mammals. Despite a growing body of knowledge concerning MCH in mammals, however, there is little information about the effect of MCH on appetite and behavior in fish. The aim of the present study was to investigate the action of MCH on feeding behavior and spontaneous locomotor activity in the goldfish. We administered synthetic MCH by intracerebroventricular (ICV) injection and examined its effect on food intake and locomotor activity using an automatic monitoring system. Both types of synthetic MCH we employed, which are of fish and human origin, were effective in stimulating aggregation of melanin granules in the melanophores of goldfish scales. Cumulative food intake was significantly decreased by ICV injection of both MCHs in a dose-dependent manner. ICV injection of fish MCH at the same doses as those used for examination of food intake induced no marked changes in locomotor activity during the observation period. These results suggest that MCH influences feeding behavior, but not spontaneous locomotor activity, in the goldfish, and may exert an anorexigenic action in the goldfish brain, unlike its orexigenic action in mammals.     

Central insulin potentiates eating elicited by 2-deoxy-D-glucose

2-Deoxy-D-glucose (2DG) elicits glucoprivic food intake whether administered centrally or systemically. Insulin, on the other hand, elicits glucoprivic food intake when administered systemically but reduces food intake when administered centrally. The purpose of these experiments was to determine the interaction of centrally administered insulin with systemically administered 2DG on feeding. In the experimental condition, male Sprague-Dawley rats were administered 5 mU insulin into the third cerebral ventricle (i3vt) followed 2 h later by a subcutaneous injection of 250 mg/kg of 2DG. Contrary to expectations, third ventricular insulin significantly increased 2DG-induced hyperphagia. A replication using doses of insulin ranging from 1 to 10 mU revealed a dose-dependent response. Whereas the lowest dose of insulin (1 mU) did not reliably change food intake, doses of 2.5, 5, and 10 mU significantly enhanced 2DG-induced feeding. Consistent with previous reports, centrally administered insulin, when given alone, caused a significant reduction of 24-h body weight and chow intake. To assess if the insulin-induced hyperphagia was a result of leakage from the ventricles, we peripherally administered 5 mU of insulin and observed, if anything, a slight decrease of food intake. These studies suggest that in the presence of central glucoprivation, a distinct anabolic action of centrally administered insulin overrides the normally observed catabolic response and increases the hyperphagic feeding response induced by 2DG.     

Monosodium glutamate as a palatability enhancer in the European diet

Can monosodium glutamate (MSG) augment palatability in foods of the occidental diet? Its effects on the palatability of two experimental foods were investigated in 36 healthy young men and women. MSG improved palatability ratings, with an optimum at 0.6%. Weekly tests of free intake showed that subjects fed the experimental foods with 0.6% MSG added ate progressively more and faster, indicating increasing palatability with repeated exposure. The effects of MSG on familiar foods were investigated in a group of 65 institutionalized elderly persons. Spontaneous intake was measured at lunch time on 12 test days. Target foods (soup and vegetable) were served either without or with 0.6% MSG added. MSG facilitated intake of some but not all target foods, and was associated with positive (increased calcium and magnesium intake) or adverse (increased fat intake) nutritional effects. It is concluded that MSG can act as a palatability enhancer in the context of the French diet. It can facilitate long-term intake in both young and elderly persons but it should be utilized cautiously so as to improve nutrition.     

Lesions of the area postrema and underlying solitary nucleus fail to attenuate the inhibition of feeding produced by systemic injections of cholecystokinin in Syrian hamsters

A large body of evidence indicates that the intestinal hormone cholecystokinin (CCK) may serve as a signal for satiety. The abdominal vagus has been shown to be important for the satiety response to exogenous, and by inference, endogenous, CCK in rats and hamsters. Thus, it appears that stimulation of CCK receptors on afferent fibers of the abdominal vagus activates a gut-brain pathway to signal satiety. The present study was undertaken to further trace this viscerosensory pathway by examining food intake after administration of one of two doses (2.0 and 8.0 micrograms/kg) of CCK-octapeptide to intact hamsters and to hamsters sustaining lesions of the area postrema (AP) and underlying nucleus of the solitary tract (NST), regions containing neurons postsynaptic to vagal afferent fibers. As lesions of the AP/NST result in many alterations in ingestive behaviour and body weight regulation in rats, various aspects of feeding and drinking behaviour (spontaneous food intake, body weight maintenance, and responsiveness to a palatable drinking solution and osmotic stimulation) were also examined in lesioned hamsters. Aside from producing transient hypophagia and weight loss immediately after surgery, AP/NST lesions had no effects on these various parameters of ingestive behaviour. The lack of lesion effects on these particular parameters may be explained on the basis that hamsters are generally unresponsive to many of the stimuli for feeding and drinking which purportedly act on the vagus and/or AP/NST. Hamsters with AP/NST lesions were as responsive to the two tested doses of CCK as intact animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of monosodium glutamate on eating and drinking behavior in rats

The effect of monosodium glutamate (MSG) on eating and drinking behavior of rats was studied by means of preference tests in free choice situations. Low or high protein casein diets containing up to 3% MSG were selected indifferently compared to plain casein diet in 7 day trials. The acceptability of diets containing 7% MSG, particularly those of low protein level, was significantly reduced. Except for Day 1, the proportional intake (MSG flavored diet intake/total diet intake) of 9% protein--7% MSG diet was consistently lower than 18% protein--7% MSG diet. In brief exposure tests (10 min) solutions of MSG (0.02-8%) were preferred over deionized water. The acceptance of solutions containing higher concentrations of MSG was significantly reduced. The total volume intake of both choices (MSG flavored water and water) was significantly increased in tests using solutions containing 3-8% MSG. In long-term tests (1-14 days), solutions containing 0.05-1% MSG were preferred over water. The acceptance of a solution containing 5% MSG was significantly reduced. For maximum intake of moles of MSG, rats selected solutions which offered 3-5 x 10(-1) M MSG whether the experimental period was 10 min or up to 2 weeks. In a series of two choice preference tests using solutions where Na+ content and pH were kept equal, MSG was preferred over sodium acetate and over sodium glutamate but was less preferred than monosodium aspartate. The results of this study can be explained in terms of sensory quality.     

Acute increase in food intake after intraperitoneal injection of metformin in rats

We studied the effect of intraperitoneal injection of different doses of the antihyperglycemic agent metformin on food intake and plasma metabolites (glucose, free fatty acids, beta-hydroxybutyrate) in rats fed a high-fat (HF) or a high-carbohydrate (HC) diet. Unexpectedly, metformin, at a dose of 120 mg/kg b.wt. stimulated food intake in both HF- and HC-fed rats, without affecting blood glucose level. This result is in contrast with the hitherto performed studies that found an anorectic effect of metformin in rodents. It is postulated that the hyperphagic effect of metformin might be related to reduced energy availability to hepatic metabolic sensors controlling food intake, because metformin's known inhibitory effect on oxidative phosphorylation mainly affects the hepatoportal area, and blockade of oxidative phosphorylation in this area has been shown to stimulate feeding.     

Feeding-induced decrease in extracellular glutamate level in the rat nucleus accumbens: dependence on glutamate uptake

In vivo microdialysis combined with high-performance liquid chromatography and electrochemical detection was used to monitor extracellular glutamate levels in the medial nucleus accumbens of Sprague-Dawley rats during their feeding behaviour. Consumption of a palatable new diet or a diet to which rats were previously exposed caused a decrease in extracellular level of glutamate in the nucleus accumbens during and after feeding. The presentation of an inedible object (a piece of rubber) instead of the expected food caused a marked increase in extracellular glutamate levels. In contrast, if the piece of rubber was presented to rats that did not expect food delivery, the extracellular level of glutamate remained unchanged during the rubber presentation. The feeding-induced decrease in the extracellular glutamate level did not depend on food deprivation and was completely prevented by intraaccumbal infusions through the dialysis probe of 10 mM D,L-threo-beta-hydroxyaspartate (a glutamate uptake inhibitor). Intraaccumbal infusions of 10 microM S-(-)-raclopride L-tartrate (a D2/D3 dopamine receptor antagonist) or 1 microM tetrodotoxin (a voltage-dependent Na(+) channel blocker) also completely reversed the decrease in extracellular glutamate level in response to food intake. The D1/D5 dopamine receptor antagonist SCH-23390 (10 microM) administered into the nucleus accumbens had no significant effect on the feeding-induced decrease in extracellular glutamate level.From the data obtained we suggest that the decrease in the extracellular level of glutamate in the medial nucleus accumbens in response to feeding appears to arise from a temporal increase in glutamate uptake that is probably operated by dopamine inputs to the nucleus accumbens via D2/D3 receptors. Our findings also suggest that the dissociation between the expected biological value of a presented object and the reality might be an important determinant for regulation of glutamate release in this brain area during feeding behaviour.     

Effect of the diazepam-binding inhibitor-derived peptide, octadecaneuropeptide, on food intake in goldfish

An endogenous ligand of central-type benzodiazepine receptors (CBR), the endozepine octadecaneuropeptide (ODN), is a very potent inhibitor of food intake in rodents. Although endozepines have been localized and characterized in the trout hypothalamus, so far, the action of these neuropeptides on feeding behavior has never been investigated in fish. In the present study, we have examined the effect of i.c.v. administration of synthetic rat ODN, its C-terminal octapeptide (OP) and the head-to-tail cyclic analog cyclo(1-8)OP (cOP) on feeding behavior in the goldfish model. i.c.v. injection of graded doses of ODN (2.5-10 pmol/g body weight (BW)) induced a dose-dependent inhibition of food intake, a significant decrease in cumulative food intake during the 60-min period after feeding being observed at doses of 5 and 10 pmol/g BW. The inhibitory effect of a 10 pmol/g BW dose of ODN on food consumption (-39%) was mimicked by an equimolar dose of OP (-42%) and cOP (-53%). The food intake-suppressing activity of ODN (10 pmol/g BW) was not affected by pre-injection of the CBR antagonist flumazenil (200 pmol/g BW). In contrast, the anorexigenic effect of ODN (10 pmol/g BW) was totally suppressed by a selective antagonist of metabotropic endozepine receptors, cyclo(1-8)[dLeu(5)]OP. These data indicate that, in goldfish as in rodents, ODN is a potent inhibitor of food consumption, and that the anorexigenic effect of ODN is not mediated through CBR but through the metabotropic endozepine receptor.     

Experience-induced changes in taste identification of monosodium glutamate

Taste sensitivity for a given subject generally has been thought to be genetically determined and not plastic. Yet experience-inducible changes in human taste and olfactory sensitivities have been reported. To test a taste induction hypothesis, we exposed 17 Americans/Europeans to monosodium glutamate (MSG) in food and then compared their ability to identify MSG taste with that of 2 control groups (18 Americans/Europeans without MSG exposure and 18 Japanese). When tested on Day 11 or 12, the Americans/Europeans exposed to MSG were able to identify MSG at significantly lower concentrations than the Americans/Europeans without MSG exposure. Moreover, Japanese subjects who had prior extensive experience with MSG in Japanese food were able to identify MSG at significantly lower concentrations than the two American/European groups. The differences in identification ability between the two American/European groups challenge the notion of taste sensitivity as stable over time and support the hypothesis of an experience-inducible component in human taste.     

The orexigenic effect of peripheral ghrelin differs between rats of different age and with different baseline food intake, and it may in part be mediated by the area postrema

Ghrelin is mainly secreted during fasting. While an orexigenic effect of peripherally injected ghrelin has been reported, reproducing this effect has often proven difficult. Here, we hypothesized that ghrelin's effect to increase food intake may depend on the experimental conditions (e.g., age of animals). We therefore investigated the effect of an IP ghrelin injection (100 microg/kg) on food intake in rats of different age and at different times during the light-dark cycle, i.e. with different levels of baseline food intake. Ghrelin injected at dark onset in ad libitum fed young rats (body weight [BW] 92 g) slightly increased feeding while no such effect was observed in 12 h food deprived rats (BW 150 g). In the middle of the light phase, ghrelin significantly increased feeding up to 2 h after injection in ad libitum fed rats (BW 130 g; food intake 1 h after injection: NaCl 0.4 +/- 0.2 g versus ghrelin 1.2 +/- 0.3 g [p < 0.05]). In various subsequent experiments, older rats (BW 300-490 g) tested under the same conditions did not respond to a single ghrelin injection. However repeated ghrelin injection (15 microg/kg/day once daily at light onset) over 10 days significantly increased food intake in rats (BW 400-460 g) starting from day 4 of the experiment (24 h food intake: NaCl approx. 19.5 g, ghrelin 22.5 g). Interestingly, the latter effect was completely abolished in rats lesioned in the area postrema (AP). Cumulative food intake was also increased in SHAM but not in AP-X animals (e.g., after 7 days: SHAM/NaCl 135.1 +/- 5.3 g versus SHAM/ghrelin 149.7 +/- 3.5 g [p < 0.05], AP-X/NaCl 127.2 +/- 16.4 versus AP-X/ghrelin 127.9 +/- 5.3). We conclude that ghrelin's effect to increase food intake can best be demonstrated when basal food intake is low. Ghrelin increases feeding mainly in young, fast growing animals. Ghrelin may therefore link the high energy needs to body growth in young individuals. In older animals, peripheral ghrelin increased feeding when injected repeatedly over several days. At least under these conditions, ghrelin's effect was mediated by the AP/NTS region. Using repeated administration, ghrelin might be an interesting tool to increase feeding in patients suffering from wasting diseases such as cancer anorexia.     

Physiological evidence for ionotropic and metabotropic glutamate receptors in rat taste cells

Monosodium glutamate (MSG) elicits a unique taste in humans called umami. Recent molecular studies suggest that glutamate receptors similar to those in brain are present in taste cells, but their precise role in taste transduction remains to be elucidated. We used giga-seal whole cell recording to examine the effects of MSG and glutamate receptor agonists on membrane properties of taste cells from rat fungiform papillae. MSG (1 mM) induced three subsets of responses in cells voltage-clamped at -80 mV: a decrease in holding current (subset I), an increase in holding current (subset II), and a biphasic response consisting of an increase, followed by a decrease in holding current (subset III). Most subset II glutamate responses were mimicked by the ionotropic glutamate receptor (iGluR) agonist N-methyl-D-aspartate (NMDA). The current was potentiated by glycine and was suppressed by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5). The group III metabotropic glutamate receptor (mGluR) agonist L-2-amino-4-phosphonobutyric acid (L-AP4) usually mimicked the subset I glutamate response. This hyperpolarizing response was suppressed by the mGluR antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) and by 8-bromo-cAMP, suggesting a role for cAMP in the transduction pathway. In a small subset of taste cells, L-AP4 elicited an increase in holding current, resulting in taste cell depolarization under current clamp. Taken together, our results suggest that NMDA-like receptors and at least two types of group III mGluRs are present in taste receptor cells, and these may be coactivated by MSG. Further studies are required to determine which receptors are located on the apical membrane and how they contribute to the umami taste.