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We used an umami substance, monosodium glutamate (MSG), as a simple stimulant to clarify the mechanism of the formation of emotional behavior. A 60 mM MSG solution was fed to spontaneously hypertensive rats (SHR), used as a model of attention-deficit hyperactivity disorder, from postnatal day 25 for 5 weeks kept in isolation. Emotional behaviors (anxiety and aggression) were then assessed by the open-field test, cylinder test and social interaction test. MSG ingestion during the developmental period resulted in a significant reduction in aggressive behavior but had few effects on anxiety-like behavior. Several experiments were performed to identify the reason for the reduced aggression with MSG intake. Blood pressure in the MSG-treated SHR was comparable to that of the controls during development. Argyrophil III staining to detect the very early phase of neuronal damage revealed no evidence of injury by MSG in aggression-related brain areas. Assessment of plasma amino acids revealed that glutamate levels remained constant (∼80 μM) with MSG ingestion, except for a transient increase after fasting (∼700 μM). However, lactate dehydrogenase assay in an in vitro blood-brain barrier model showed that cell toxicity was not induced by indirect MSG application even at 700 μM, confirming that MSG ingestion caused minimal neuronal damage. Finally, vagotomy at the sub-diaphragmatic level before MSG ingestion blocked its effect on aggressive behavior in the isolated SHR. The data suggest that MSG ingestion during the developmental period can reduce aggressive behavior in an attention deficit-hyperactivity disorder model rat, mediated by gut-brain interaction.

We studied the effect of stimulation of the red nucleus (RN) on the jaw-opening reflex (JOR) in anesthetized rats. The JOR was evoked by electrical stimulation of the tooth pulp of a lower incisor, and was recorded as the electromyographic responses of the anterior belly of the digastric muscle, bilaterally. Conditioning electrical stimulation of the RN was found to suppress the JOR bilaterally. Microinjection of monosodium glutamate into the RN also suppressed the JOR bilaterally. The suppressive effect of the magnocellular part of the RN was significantly larger than that of the parvicellular part of the RN. These results imply that the RN is involved in control of the JOR evoked by noxious stimulus.

Glutamatergic post-synaptic receptors are closely related to the known excitotoxic effects of high doses of L-glutamate. Several behavioral abnormalities, glial reaction, and an increase of expression of the NMDA receptor sub-units have been observed in the rat hippocampus after early monosodium glutamate exposure. Thus, a quantitative morphological study was carried out to determine the effects of early exposure to monosodium glutamate on post-synaptic structures that mediate glutamate excitatory neurotransmission in the hippocampal CA1 field. Four milligrams per gram body weight of monosodium glutamate was subcutaneously injected into neonatal Wistar rats, at 1, 3, 5, and 7 days. Cell loss and several cytoarchitectonic parameters were evaluated in pyramidal cells from the hippocampal CA1 field in the treated rats at 60 days of age. An untreated group of rats were used as controls. Cell number in the hippocampus of experimental rats was 11.5% less than that in control animals. In addition, both dendritic arborization and dendritic spine density were adversely affected, and thin and mushroom-shaped spines became proportionally more numerous, while the opposite occurred to stubby spines. These results strongly suggest the occurrence of cell death and also show some cytoarchitectural modifications in the surviving neurons. These could lead to functional alterations in the hippocampal integrative activity, due to an early cytoexcitotoxic effect of monosodium glutamate.

Neonatal treatment of rodents by intraperitoneal injections of monosodium glutamate (MSG) destroys many retinal ganglion cells whose neurons belong to the circadian system; howertheless, adults always synchronize their locomotor activity rhythm (LAR) to the light/dark cycle. Recent studies have shown that light-induced phase shifts of LAR are associated with the c-fos induction in suprachiasmatic nuclei (SCN) of nocturnal rodents. In this study, the circadian system was analyzed in treated and control hamsters maintained in constant darkness and exposed to light at circadian times (CTs) 13 and 18 during subjective night, 1 and 6 h after the onset of LAR. The period of the LAR and delay (CT13) and advance (CT18) phase shifts of LAR were not significantly different between MSG-treated and control hamsters. Temporospatial variations of Fos induction after light exposure were similar in both MSG-treated and control hamsters although the total number of Fos immunoreactive (Fos-ir) nuclei in the SCN was always lower in treated hamsters. However, the decrease in Fos-ir was significant only for the caudal third of the SCN of treated hamsters, the part where retinal afferents are most dense. The effect of light exposure on Fos expression in SCN of MSG-treated and control hamsters was the same at CT13 and CT18: (1) Fos-ir nuclei were significantly more numerous at CT18 than at CT13 in the rostral SCN; (2) dorsal Fos-ir cells were observed in the SCN only at CT18; (3) a ventral subgroup expressed Fos protein in intermediate SCN only at CT13. This study demonstrates that MSG-treatment does not significantly modify the phase-shifting effects of light on either the LAR or the associated cellular activation.

We examined the effects of systemic or oral ad libitum monosodium glutamate (MSG) administration on glutamate levels in plasma, and on glutamate release from the arcuate nucleus of the hypothalamus (estimated using brain microdialysis). Systemic MSG administration (0.25, 0.5, 1 or 2 g/kg, i.p.) to adult rats caused dose-dependent increases in glutamate levels within arcuate nucleus dialysates. These levels increased during the initial 20 min after systemic MSG administration, and peaked during the second 20-min interval (maximally to 116 +/- 7%, 146 +/- 15%, 790 +/- 191% and 1230 +/- 676% of basal values, respectively). Plasma glutamate levels, measured simultaneously, were increased maximally during the initial 20 min after MSG administration. These increases were 10-, 13-, 76- and 163-fold after doses of 0.25, 0.5, 1 and 2 g/kg, i.p., respectively. In feeding experiments, consumption of 2.3 g/kg of MSG by previously-trained rats during an 1-h period increased plasma glutamate levels to 352 +/- 61% of basal values 140 min after the start of the feeding period. No changes were observed in glutamate levels of arcuate nucleus dialysates. These findings may explain why ad libitum dietary consumption of MSG apparently lacks neurotoxic potential.

Housing rats under continuous illumination (LL) disrupts circadian rhythms controlled by a pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The neural mechanisms underlying this effect are not well understood. The present study examined the effects of LL on circadian rhythms and on light-induced expression of Fos protein in the SCN, intergeniculate leaflet (IGL), and ventrolateral geniculate nucleus (vLGN) in adult rats treated neonatally with monosodium glutamate (MSG). Such treatment is known to lead to acute degeneration of retinal ganglion cells. Despite degeneration of the optic nerve, neonatal MSG treatment (2 mg/g SC on postnatal days 1,3,5,7, and 9) had no effect on daily temperature rhythms in the adult animal under a light-dark cycle. However, the disintegration of circadian rhythms under LL conditions observed in adult rats treated neonatally with 10% saline was prevented in MSG-treated rats. Furthermore, neonatal MSG treatment attenuated light-induced expression of Fos protein in the IGL and vLGN, but not in the SCN. These data suggest that neonatal MSG treatment alters the response of the circadian system to LL and that cells within the IGL/vLGN region may mediate this response.

Taste enhancing effects of sodium saccharin (Sac) on D-phenylalanine (D-Phe), first found in mice, were examined by comparing single fiber responses to various taste stimuli in the monkey chorda tympani nerve. Fifteen fibers sampled were divided into the following 5 groups according to their responsiveness to 5 prototypical taste stimuli; 8 sucrose-, 2 quinine-, 2 acid-, 2 NaCl- and one monosodium glutamate (MSG)-best fibers. Out of 8 sucrose-best fibers, 5 fibers showed enhancement of D-Phe responses after the stimulation with Sac, but neither the remaining 3 sucrose-best fibers nor other fibers showed the enhancement. These results suggest that (1) the enhancement of D-Phe responses by Sac also occurs in the monkey peripheral taste system, and (2) there exist distinct receptor sites for D-Phe responsible for occurrence of the enhancement, and (3) taste cells possessing the D-Phe receptor site are innervated by a limited subpopulation of sucrose-best fibers.

Neonatal Wistar rats were subcutaneously injected with 0.1, 1, or 2 mg/g b.wt. of monosodium glutamate (MSG) at 1, 3, 5, 7, and 9 days after birth. The animals were observed for degeneration of pyramidal cells in the hippocampus. The histological change disappeared when the animals were concurrently injected with glutamate diethyl ester (GDEE), an antagonist of the glutamate receptor. When ligh-dark discrimination learning was carried out at 10 weeks old, the correct response in the acquisition period was impaired in the animals given 1 and 2 mg/g of neonatal MSG. Their retention scores were also impaired in comparison with the control animal. The behavioral impairment recovered with pre-treatment with GDEE. No significant changes were observed in the concentrations of transmitter substances, including amino acids and monoamines. These results suggest that neonatal MSG destroys the hippocampus and impairs acquisition and retention of discrimination learning through the mechanism of glutamate receptors.

Monosodium glutamate (MSG) subcutaneously administrated to neonatal rats induces several neurochemical alterations in the brain, which have been associated with an excitotoxic process triggered by an over activation of glutamate receptors; however there are few systematic studies about initial changes in intracerebroventricular (i.c.v.) Glu levels produced by MSG in the brain. Thus, to characterize these changes, rat pups were injected with a MSG solution at 1, 3, 5 and 7 postnatal days (PD), and i.c.v. Glu levels and hippocampal total content of related amino acids (Asp, Glu, Gln, Gly, Tau, Ala and GABA) were estimated before, immediately and after each injection. Behavioral and EEG responses were also monitored after MSG administrations. Significant rise in i.c.v. Glu levels were found, mainly in response to the first and second injection. Moreover, the total content of all amino acids evaluated also increased during the first hour after the first MSG administration but only Glu and GABA remained elevated after 24 h. These biochemical modifications were accompanied with behavioral alterations characterized by: screeching, tail stiffness, head nodding, emprosthotonic flexion episodes and generalized tonic-clonic convulsions, which were associated with electroencephalographic pattern alterations. Altered behavior found in animals treated with MSG suggests an initial seizure situation. Although four MSG administrations were used, the most relevant findings were observed after the first and second administrations at PD1 and PD3, suggesting that only two MSG injections could be sufficient to resemble a seizure and/or excitotoxic model.

Neonatal monosodium glutamate (MSG) administration increases adiposity, decreases energy expenditure and is associated with arcuate nucleus (Arc) destruction. Disrupted brown adipose tissue (BAT) thermogenesis underlies some of these effects, although, interscapular BAT temperature (T(IBAT)) has not been measured. Therefore, we tested the effects of neonatal MSG or vehicle administration in Siberian hamsters and, when they were adults, measured T(IBAT) during acute cold exposure. The Arc and its projection to the hypothalamic paraventricular nucleus (PVH) are both components of the CNS outflow circuits to IBAT, with the latter implicated in BAT thermogenesis that could be compromised by MSG treatment. Using a viral transneuronal tract tracer, pseudorabies virus (PRV), we also tested whether the components of these circuits were intact. As adults, MSG-treated hamsters had significantly increased body mass and some white fat pad masses, markedly reduced Arc Nissl and neuropeptide staining, and PVH neuropeptide fiber staining. Cold-exposed (18 h at 5 degrees C) MSG- and vehicle-treated hamsters initially maintained T(IBAT), but the ability of the former waned after 2 h being significantly decreased by 18 h. PRV immunoreactive fibers/cells were not altered by neonatal MSG treatment despite substantial Arc and PVH destruction. MSG- and vehicle-treated hamsters given an exogenous norepinephrine challenge showed identical increases in the duration and peak of T(IBAT). Thus, the inability of MSG-treated animals to sustain T(IBAT) in the cold is not due to any obvious MSG-induced deletions of central sympathetic outflow circuits to IBAT, but appears to be extrinsic to the tissue nevertheless.

It has been argued whether the ‘umami substances’ such as monosodium glutamate (MSG) and disodium 5′-guanylate (GMP) stimulate the salt receptor or the unique receptor to the umami substances. We examined effects of amiloride, which inhibited the canine chorda tympani nerve responses to salts such as NaCl, KCl and NH 4 Cl, in a competitive manner, on the nerve responses to the umami substances and differentiated between the umami and salt components. Amiloride shifted the dose-response curves for MSG to a higher concentration region, suggesting that amiloride inhibits the response to MSG in a competitive manner. The response to GMP alone and that induced by synergism between relatively low concentrations of MSG and GMP were not inhibited by amiloride. These results suggested that the response to MSG alone is the salt response and the response to GMP alone or that induced by the synergism is the umami response. The presence of MSG shifted the dose-response curves for GMP to a lower concentration region, suggesting that MSG increases the affinity of GMP to umami receptors. The present results favor the conclusion that GMP acts as an agonist and MSG acts as a modulator for the umami receptor in the dog. The synergism can be explained by an allosteric model where the umami receptor is assumed to have two binding sites, one for GMP and another for MSG.

Environmental enrichment is known to influence the development of the nervous system and it provides beneficial effects in various kinds of brain lesions. Enriched housing conditions also influence the development and functioning of the visual system. The aim of the present study was to investigate whether retinal degeneration induced by neonatal monosodium glutamate (MSG) in rats can be ameliorated by expanded cage size or enriched environment. Control rats were kept in a regular cage, another group of pups was kept in an expanded cage and a third group was kept under complex environmental enriched conditions from the first postnatal day. Half of the rats received MSG treatment on postnatal days 1, 5, and 9, while the other half of the groups received only saline treatment. Retinas were removed at 5 weeks of age and processed for histological analysis. Microscopical analysis revealed a substantial inner retinal degeneration in MSG-treated animals: the retinal thickness was less than 25% of the normal retinas, and the inner layers were completely fused. Expanded cage environment had a significant protective effect: the layers of the retina were well visible, and the thickness of the entire retina had a nearly 50% amelioration. Best results were obtained in retinas from rats living in enriched environment: the retina suffered only an approximately 25% reduction in thickness, and all layers were significantly thicker than in MSG-treated retinas. In summary, the present study showed that expanded field provided some degree of neuroprotection, while a complex environmental enrichment led to a manifest protection against retinal degeneration induced by neonatal MSG treatment in rats.

Alpha-melanocyte stimulating hormone (alpha-MSH), a putative endogenous antipyretic agent, is synthesized largely within neurons in the arcuate nucleus. To test the hypothesis that destruction of this area would increase the febrile response, male Wistar rats, treated as neonates with intraperitoneal injections of monosodium glutamate (MSG) or saline, were given intracerebroventricular (i.c.v.) injections of prostaglandin E1 (20 ng; 200 ng) or purified interleukin-1 (20 U) and body temperature was monitored. The fevers displayed by the MSG-treated animals were significantly greater (P less than 0.05) than those of the controls for the lower dose of PGE1 at 10-30 min and for IL-1 at 3-6 h after the injections. MSG-treated rats showed significant reduction (P less than 0.01) in alpha-MSH content of the medial basal hypothalamus and lateral septum when compared to saline controls. Body temperature response of non-febrile animals to high ambient temperature was not affected by the MSG treatment. These data support the hypothesis that alpha-MSH is an endogenous antipyretic in the rat.

In rodents, parenteral administration of monosodium glutamate (MSG) induces marked degeneration of the retina and arcuate nucleus (AN) and disrupts daily rhythms of food intake. We quantified the effects of neonatal MSG (2 mg/g SC, postnatal days 1, 3, 5, 7, 9) on the expression of feeding and activity rhythms in adult rats under schedules of light-dark (LD), constant dark (DD), restricted daily feeding and total food deprivation. AN lesions were confirmed by neuropeptide Y (NPY) immunocytochemistry and Nissl stain. Compared to age-matched control rats, the amplitude (quantified as LD ratios) of daily food intake and food-bin activity rhythms was significantly attenuated in MSG rats in LD 12:12 and on the first day of DD. Control rats, but not MSG rats, showed lower amplitude rhythms in DD compared to LD. The phase angle of feeding and activity rhythms did not differ between groups in either condition. In a short LD cycle (2:2), control rats, but not MSG rats, showed significant inhibition (masking) of activity during the 2 h light periods. When food access was restricted to a 4 h daily meal, MSG rats showed enhanced expression and persistence of food-entrained anticipatory activity rhythms by comparison with control rats. These results indicate that attenuation of daily feeding rhythms in MSG rats is due in part to loss of direct inhibitory effects of light on behavior, and that the AN likely modulates, but does not mediate entrainment of feeding-related rhythms to daily cycles of LD or food access.

Monosodium glutamate (MSG) was shown to penetrate placental barrier and to distribute to embryonic tissues using [3H]glutamic acid ([3H]Glu) as a tracer. However, the distribution is not even; the uptake of MSG in the fetal brain was twice as great as that in the maternal brain in Kunming mice. Other maternal mice were given per os MSG (2.5 mg/g or 4.0 mg/g body weight) at 17-21 days of pregnancy, and their offspring behaviors studied. The results showed that maternal oral administration of MSG at a late stage of pregnancy decreased the threshold of convulsion in the litters at 10 days of age. Y-maze discrimination learning was significantly impaired in the 60-day-old filial mice. On the other hand, no significant difference in spatial learning or tail flick latency was measured between the experimental animals and the controls. The filial mice of MSG-treated mothers could either not grasp a rope tightly, or grasped the rope tightly but could not crawl along the rope at the beginning of the training. However, such mice, after training, could grasp and crawl along the rope as well as controls. Obvious neuronal damage was not detected in the periventricular organs or the hypothalamus under a light microscope. The rate of weight gain for experimental animals was greater than for controls throughout the period from 20 to 90 days. Mating of treated males with treated females resulted in pregnancies and normal offspring, indicating that oral administration of MSG at a late stage of pregnancy did not affected the reproductive capacity of the offspring. The possible differences and relationship between MSG-induced damage to developing human and rodent brain are discussed.

We examined effects of high doses of monosodium glutamate (MSG) on extracellular glutamate levels in rat striata, using in vivo microdialysis. Parenteral doses (0.5, 1.0 and 2.0, but not 0.25, g/kg, i.p.) caused dose- and time-dependent increases, peaking after 40 min (at 174 +/- 47%, 485 +/- 99% and 1021 +/- 301% of basal levels, respectively). In contrast, dietary MSG (1.49 +/- 0.10 g/kg/h) was ineffective.

The present study has examined the effect on age-dependent natural killer (NK) cell cytotoxic (NKCC) activity after the destruction of the arcuate nucleus (AR) of the hypothalamus in newborn mice with the neurotoxin monosodium glutamate (MSG). The NKCC activity was determined at different ages from the 18th day to the 54th week. This treatment resulted in depressed NKCC activity and in disappearance of its age-dependent pattern. A high correlation between NKCC depression and decreased numbers of large granular lymphocytes was also noted in the MSG-treated mice. The conclusion is that normal development of NKCC activity requires the maturation of AR functions.

Neuronal damage in the area postrema (AP) of 12–14-week-old male rats was induced by subcutaneous administration of monosodium glutamate (MSG). An immunocytochemical method was used to visualize catecholaminergic neurons in the AP after MSG-treatment. Some tyrosine hydroxylase-immunoreactive neurons exhibited marked signs of degeneration, while others appeared undamaged. We conclude that catecholamine-synthesizing neurons in the AP are differentially sensitive to the neuroexcitotoxic effect of systemic glutamate.

The immunocytochemical distribution of the pentapeptides, methionine- and leucine-enkephalin (Enk) were examined in the mediobasal hypothalamus of control mice and mice with a neurotoxic lesion of the arcuate nucleus due to neonatal treatment of monosodium glutamate (MSG). In control mice immunoreactive Enk cells and fibers were present in the arcuate nucleus. Enk fibers were found in the subependymal, internal and external layers of the median eminence. At 60 days of age, mice receiving neonatal injections of MSG displayed symptoms of neuroendocrine deficiencies. Histochemical methods revealed a loss of Enk immunoreactivity from the arcuate nucleus and all layers of the median eminence. These results suggest that the lack of Enk cells and fibers in the mediobasal hypothalamus of MSG-treated animals is partially responsible for the endocrine dysfunctions exhibited by these animals.

Immunocytochemical localization of alpha-MSH was performed in the brain of rats of which the arcuate nucleus has been destroyed by treatment with monosodium glutamate in the neonatal period. In these animals, alpha-MSH cell bodies normally found in the arcuate nucleus were almost completely absent. The reactive fibers found in the ACTH-beta-LPH pathway were also markedly decreased. On the other hand, alpha-MSH cell bodies located in the dorsolateral hypothalamus as well as fibers located outside the ACTH-beta-LPH pathway were not decreased. These results strongly suggest that alpha-MSH cell bodies in dorsolateral hypothalamus have projections completely different from those located in the arcuate nucleus.

By immunocytochemical techniques, the neuronal cell bodies containing ACTH, β-LPH and α-MSH have only been found in the area of the arcuate nucleus of the hypothalamus, whereas positive nerve fibers have been observed in many hypothalamic and extra-hypothalamic areas. The possible contribution of neurons which could be located in other brain areas has been studied in the rat by experiments involving hypothalamic deafferentation or destruction of the acurate nucleus. Fourteen days after deafferentation, no immunoreactive fibers could be detected in extrahypothalamic areas whereas the concentration of positive cell bodies and fibers remained unchanged within the hypothalamic island. In rats which had been injected in the neonatal period with monosodium glutamate (MSG), which selectively destroys the arcuate nucleus, only a few immunostained cell bodies were observed in hypothalamic region lateral to the arcuate nucleus. As compared to control animals, the concentration of immunostained fibers in both hypothalamic and extrahypothalamic regions was markedly decreased. These results strongly suggest that neuronal cell bodies producing ACTH, β-LPH and α-MSH are located in the region of the arcuate nucleus and send axonal projections into many brain areas.

Two to 10 days after complete unilateral surgical isolation of the medial basal hypothalamus (MBH) or 3 months following neonatal monosodium glutamate (MSG) treatment, the presence of growth hormone-releasing hormone (GH-RH) immunoreactive neuronal structures was studied in rats using vibratome sections and GH-RH immunocytochemistry. (1) Neontal MSG treatment resulted in a dramatic decrease of GH-RH immunoreactivity in the median eminence (ME), but not complete disappearance as reported earlier. (2) Unilateral complete deafferentation of the MBH caused only a slight decrease in GH-RH immunostaining in the posterior regions of the ipsilateral median eminence (ME). At this level GH-RH accumulation was observed in scattered transected fibers lateral to the cut, outside of the MBH. Our findings indicate that the arcuate nucleus is the major source of GH-RH immunoreactive structures in the ME. Although, however, in very small numbers, the existence of other sources of GH-RH terminals cannot be excluded.

The present in investigation was designed to determine the chronic effects of neonatal monosodium glutamate (MSG) administration (4 g/kg s.c.) and the acute effects of MSG (1 g/kg i.p.) on episodic growth hormone (GH) and prolactin (PRL) secretion and brain somatostatin (SRIF) in unanesthetized, chronically cannulated male rats. Adult rats showed the typical physical characteristics that result from neonatal MSG administration. Analysis of episodic GH secretion showed a significant reduction in : (1) the amplitude of GH secretory peaks. and (2) the mean 5.5-h plasma level of GH. Bursts of plasma PRL were inhibited by MSG, but the mean 5.5-h plasma levels were not affected. SRIF concentrations in the medial basal hypothalamus were reduced by 60% after neonatal MSG. Acute administration of MSG to adult rats caused an immediate, long-lasting suppression of rhythmic GH secretion and a rapid, transient release of PRL. These results suggest: (1) neonatally administered MSG causes a marked disturbance in episodic GH and PRL secretion in adult rats; (2) MSG induces a decrease in hypothalamic SRIF and possibly GH-releasing factor; and (3) the acute effects of MSG on GH and PRL may be due to the inhibition and/or excitation of a complex neuronal network involving monoaminergic and peptidergic systems.

In 4-day-old mice monosodium glutamate (MSG) was injected subcutaneously at a dose of 2 mg/g body weight. Immediately thereafter mice were randomly returned to the nest or isolated at room temperature of 23 °C. At 0 (control) 15 and 30 min, and 1, 2, 3, 6, 9, 12 and 18 h after injection mice were decapitated, heads frozen and blood collected. In a second group of similarly treated mice, some were isolated individually either at 23 °C or 33 °C and killed 3 h after injection. Control mice received no injections. Glutamic acid (Glu) was measured in samples of arcuate nucleus (ARH), lateral nucleus of the thalamus (LT) microdissected from frozen-dried sections of brain, and in plasma in all mice. Consistent with prior findings 21 , marked increases in Glu concentration occurred in ARH of MSG-treated mice but not in LT. In the ARH of mice returned to the nest, Glu reached maximal concentrations at 1 h and steadily declined to approach normal values by 3 h. However, in mice isolated at 23 °C Glu 3evels in the ARH continued to rise after 1 h to reach peak values at 3 h and remained substantially elevated 6 h after treatment. Pups isolated at 23 °C had considerably higher Glu levels in ARH at 3 h than those isolated at 33 °C. Plasma concentrations of Glu tended to parallel those in the ARH of mice in corresponding groups. The importance of temperature and of rigidly controlling it during the measurement of neurochemical events in the immature organism is emphasized.

Neurotoxin induced nerve cell degeneration has been studied in sensory ganglia of newborn and in the area postrema of adult rats following the administration of the selective sensory neurotoxin, capsaicin and the amino acid excitotoxin, glutamic acid, respectively. Light microscopic histochemical, autoradiographic, electroncytochemical and X-ray microanalytical studies revealed that degeneration of certain small-sized, type B primary sensory neurons, induced by capsaicin, was associated with a marked accumulation of calcium predominantly in mitochondria of the damaged ganglion cells. Similarly, monosodium glutamate treatment resulted in the appearance of calcium-containing electron-dense granules in mitochondria of degenerating area postrema neurons. In addition, after a combined administration of 45 Ca 2+ and capsaicin or monosodium glutamate, significantly higher levels of radioactivity have been detected by liquid scintillation spectroscopy in the Gasserian ganglia and the area postrema, respectively. It is concluded that an enhancement in intracellular calcium level may be intimately involved in the process of neuronal cell death and may represent a common basic mechanism responsible for the development of cellular events leading ultimately to the degeneration of nerve cells.

Female and male rats were treated with monosodium glutamate (MSG; 4 mg/g b.wt.) as neonates and the capability of the pituitary gland to secrete growth hormone (GH) in response to an intravenous injection of human GH-releasing factor (GRF) was evaluated under pentobarbital anesthesia on 109 days of life. Immunoreactive GRF content in the pituitary stalk-median eminence tissue in MSG-treated rats was less than 20% of that of control. A significant dose-dependent plasma GH response was observed after the administration of two doses of human GRF (0.25 and 1 μg/kg b.wt.,i.v.) in both control and MSG-treated rats. The responses between MSG-treated and control rats were comparable in female rats, but they were significantly reduced in male MSG-treated rats. These results show that the pituitary's responsiveness to exogenous GRF is well preserved in MSG-treated rats despite prolonged and severe depletion of endogenous GRF and there exists a sex difference in the effect of MSG on GH secretion elicited by GRF.

Rats with bilateral electrolytic lesions in the general region of the ventromedial hypothalamic (VMH) nucleus develop hyperinsulinemia, excessive food intake and obesity. Monosodium glutamate (MSG) destroys neurons of the arcuate hypothalamic (AH) nucleus and produces hyperinsulinemic but hypophagic obesity. Bipiperidyl mustard (BPM) primarily destroys VMH neurons, but has produced only a slight obesity even when rats were maintained on high-fat diets. In the present study, rats treated with MSG (AH lesion) were hyperinsulinemic, moderately obese and hypophagic; BPM rats (primarily VMH lesion) were not different from controls when fed standard chow diets. However, MSG/BPM rats (AH + VMH lesion) were hyperinsulinemic, massively obese and hyperphagic. Thus, two components of the electrolytic lesion syndrome previously attributed to VMH damage (hyperinsulinemia and obesity) were reproduced simply by MSG treatment alone. The third component (hyperphagia) occurred only when both AH and VMH were lesioned, suggesting that neurons in both nuclei may perform a satiety function and may be able to substitute for one another in this respect. Since MSG treatment is required for all components of both obesity syndromes described here, this underscores the importance of MSG-sensitive neurons in mechanisms of obesity. The combined treatment approach also represents the first rat model of hyperinsulinemic, hyperphagic obesity that can be entirely produced by systemic administration of neurotoxins.

Microinjections of monosodium glutamate (MSG; 300 microgram/0.5 microliter) into the hippocampus of the adult rat result in only marginal damage to local neurons. Perforant path transections, removing glutamatergic afferents to hippocampal granule cells, make the latter markedly more vulnerable to a subsequent MSG injection. The principle of modulating toxic effects of MSG by interfering with its neurotransmitter role may have significant impact on our understanding of human neurodegenerative disorders.

A lesion of the arcuate nucleus (ARC) was produced by subcutaneous administration of monosodium glutamate (MSG) to neonatal female rats. The onset and the amplitude of the circadian corticosterone rhythm in the MSG-treated rats were the same as those in the saline-injected controls. When rats were blinded at 35 days of age, the corticosterone rhythm free-runned in both groups. The results indicate that the neurons in the ARC do not play an essential role in the mediation circadian signals from the suprachiasmatic nucleus to the pituitary-adrenocortical system. MSG-treatment, however, seems to delay the phase shift of free-running corticosterone rhythm through yet unknown mechanisms.

Chronic infusion of a high dose of monosodium glutamate (approximately 8 nmol/min) into the rat left striatum, over a period of 1 week, caused degeneration of striatal neurones. This was accompanied by a significant loss of neurochemical markers for both GABAergic and cholinergic interneurones. These results indicate that the sustained presence of elevated concentrations of glutamate will, in time, give rise to changes similar to those seen in human neurodegenerative disorders, such as Huntington's disease.

In rats, microinjection of the opioid agonist morphine (15-45 nmol/0.5 microliter) and the excitatory amino acid monosodium glutamate (30-60 nmol/0.5 microliter) into identical brainstem sites within the mesencephalic periaqueductal gray matter (PAG; 23 sites) and the rostral ventromedial medulla (RVM; 22 sites) produced an increase of tail flick and hot plate response latencies. At both PAG and RVM sites, there was a statistically significant relationship between the effect obtained with morphine and with glutamate on the two nociceptive responses. While morphine and glutamate produced indistinguishable inhibition of tail flick and hot plate response latencies in the PAG, the tail flick inhibition following RVM morphine, but not RVM glutamate, displayed a clear plateau. One parsimonious interpretation of these data is that (1) glutamate directly increases the activity in the bulbospinal pathway, and (2) morphine inhibits an evoked or tonic suppression of a bulbospinal projection.

Adult Sprague-Dawley rats were pretreated with 6 g/kg of monosodium glutamate (MSG). After one month, specific binding of 125I-angiotensin II was measured in membrane preparations from the brain. A 40-45% decrease in the number of 125I-angiotensin II binding sites was observed in brain tissues containing circumventricular organs. No decrease in binding sites was observed in the thalamus/hypothalamus brain region, which resides totally within the blood-brain barrier. The results suggest that MSG can destroy angiotensin-sensitive neurons in circumventricular structures, which are located primarily outside the blood-brain barrier.

The anterior pretectal nucleus (APT) has been recently implicated in sensorimotor integration and has been shown to have suppressive influences on tail flick behaviour and on nociceptive responses of spinal dorsal horn neurones in rats. The present study tested the effect of stimulation of the APT on the rat's digastric jaw-opening reflex elicited by orofacial stimuli. Either ipsilateral or contralateral electrical stimulation at histologically confirmed sites within and immediately subjacent to the APT produced a suppression of the reflex that had an onset of 20-30 ms, peaked around 50 ms and lasted for 200-300 ms; in some cases, a brief period of reflex facilitation preceded the onset of inhibition and the inhibition was sometimes followed by a facilitatory period. No prolonged period of suppression induced by electrical stimulation was noted in these anaesthetized rats. The injection of monosodium glutamate at comparable sites within and subjacent to APT induced reflex suppression that lasted several minutes. These findings represent the first documentation of APT-induced modulation in the trigeminal sensorimotor system, but support recent evidence suggesting the involvement of APT in sensorimotor integration and modulation.

In order to study the effects of treatment with monosodium glutamate (MSG) during the neonatal period on the intrinsic circadian timekeeping system in rats, the locomotor activity of blinded MSG-treated and control (saline-treated) rats was analyzed with power spectral analysis and cross-correlation. In contrast to a robust free-running circadian rhythm in the control rats, a significant shortening of the circadian period and rapid decomposition into ultradian components were noted in the MSG-treated rats. Computer-assisted stereometry of the hypothalamic nuclei revealed that, in addition to the well-known severe damage in the arcuate nuclei (ARC), the volumes of the suprachiasmatic nuclei (SCN) and ventromedial hypothalamic nuclei (VMH) were also reduced significantly in the MSG-treated rats. Although no gross histological damage was apparent in either the SCN and VMH, neonatal MSG treatment appears to impair the function of SCN to integrate many minor oscillations in the brain into a single, definite and precise circadian period.

Three different types of monolayer cultures from 8-day chick embryo neural retina can be generated by differential manipulation of culture media and substrata. They are: (i) a purified monolayer of neurons; (ii) a purified monolayer of nonneuronal, flat cells; and (iii) complex cultures containing both neurons and nonneurons. Autoradiographic studies showed that Na + -dependent, high affinity glutamate uptake occurs in about 30% of the neurons present in purified neuronal cultures, and in practically 100% of the flat cells in the purified nonneuronal monolayers or the complex cultures. These different culture preparations were used to investigate the well-known toxicity of monosodium glutamate (MSG) for retinal cells. Two different routes of administration were compared, namely: (i) in vivo preexposure of the embryos to MSG for 24 h, followed by dissociation and culture of the retina in MSG-free medium; and (ii) incorporation of MSG into the culture medium. MSG effects on flat cells were similar irrespective of the route used: flat cells showed a very dramatic reduction in number and a more spindle-like shape in MSG-treated cultures as compared with control cultures. The route of administration, however, had significant influence on the response of retinal neurons to MSG. After 3 days in vitro there were 50% fewer neurons in purified neuronal cultures when the cells were obtained from embryos pretreated in vivo with MSG than in controls, but there were no differences between controls and cultures exposed to MSG in vitro. However, MSG-containing medium preexposed for 30 min to a monolayer of nonneuronal flat cells became toxic for retinal neurons: purified retinal neurons exposed in vitro to this flat cell/MSG ‘conditioned medium’ showed a neuronal loss equivalent to that caused by an in vivo pretreatment with MSG. This observation is consistent with the hypothesis that MSG toxic effects on retinal neurons may be mediated by the nonneuronal cells. Autoradiographic studies showed that the total number of glutamate-labeled retinal neurons was similar in control cultures, in cultures from embryos pretreated in vivo with MSG and in cultures exposed in vitro to flat cell/MSG conditioned medium. This suggests that neurons with the capacity to take up glutamate via a high-affinity mechanism are not sensitive to the toxic effects of MSG.

Neuropeptide Y (NPY) when administered intracerebroventricularly is a potent stimulator of feeding and drinking in rats. In these studies we demonstrated that, in contrast, in mice NPY inhibits drinking induced by water deprivation and that associated with food intake. In addition, we found that mice failed to respond to the rat dipsogen angiotensin II. Old mice demonstrated hypodipsia compared to young mice and NPY failed to inhibit drinking in older mice. Monosodium glutamate (MSG) administered neonatally produces lesions of the arcuate nucleus, an area rich in NPY cell bodies. NPY inhibited drinking and enhanced feeding in MSG treated mice. NPY also significantly inhibited the intake of water flavored with 8% sucrose and 0.1% quinine. NPY failed to alter ingestion of 0.2% or 5% saline. These studies support the contention that marked species differences exist in the regulation of water intake between rats and mice.

Immunocytochemical analysis using antisera generated against the brain peptide somatostatin (SRIF) was examined in the brain of normal mice and in mice with chemical lesions of the arcuate nucleus produced neonatally by the administration of monosodium glutamate (MSG). In the normal mouse brain, SRIF immunoreactivity was seen in perikarya of the preoptic and hypothalamic periventricular nuclei. The normal distribution of SRIF fibers was apparent in several hypothalamic nuclei including the arcuate nucleus and in the internal and external zones of the median eminence. Extrahypothalamic sites of SRIF immunoreactive neurons and fibers were also observed throughout the telencephalon. At 60 days of age, certain neuroendocrine deficiencies, including growth parameters and obesity, were apparent in MSG-treated newborn mice. Analysis of SRIF projections in the brain of MSG-treated mice demonstrated a neurotoxic effect on arcuate neurons and a loss of SRIF projections to this region as well. Other components of the SRIF system in brain appeared unaffected. SRIF fibers of the arcuate region seem to originate from neuronal perikarya of the periventricular nucleus suggesting that MSG-induced endocrine deficiencies may be due to SRIF interactions at the level of the arcuate nucleus.

Lesion of the hypothalamic arcuate nucleus of the mouse by neonatal application of monosodium glutamate (MSG) increased the binding of [3H]dihydromorphine to membranes prepared from the midbrain. A saturation curve of [3H]dihydromorphine binding indicated that MSG increased the number of the opiate receptors. The MSG-treated mice also exhibited an enhanced response to morphine and naltrexone regarding thermal pain sensitivity. The physiological implications of opiate receptors up-regulations upon arcuate nuclear lesion are discussed.

Monosodium glutamate and bipiperidyl mustard both produce mediobasal hypothalamic lesions and have been reported to alter the subsequent feeding behavior and/or insulin levels of treated animals. In our previous studies bipiperidyl mustard alone had no effects on insulin levels or feeding, but in combination with glutamate produced hyperphagic obesity. Administration of exogenous cholecystokinin octapeptide also has been shown to affect feeding behavior and plasma insulin. In order to determine if endogenous cholecystokinin played a role in the effects of glutamate or bipiperidyl mustard, concentrations of cholecystokinin in the pituitary glands of lesioned rats were measured. Bipiperidyl mustard alone increased cholecystokinin content while combined lesioning with glutamate prevented the increase. The potential role of cholecystokinin-containing elements of the hypothalamus and pituitary in modulation of feeding is discussed.

Synergism between 5′-nucleotides and l -amino acids in the rat taste nerve responses was investigated. The synergism was examined between low concentration of the nucleotides which induce only a negligibly small response and various concentrations of amino acids. A marked synergism was found between 5′-nucleotides and all the amino acids examined. Purine 5′-nucleotides such as GMP, deoxy GMP, GDP, GTP, AMP or IMP exhibited the synergistic effect on the responses to amino acids, while pyrimidine 5′-nucleotides such as CMP or UMP exhibited practically no synergistic effect. The presence of GMP led to a shift of the concentration-response curves for amino acids to a lower concentration region without affecting the response of the saturation level. These curves were analyzed under the assumption that there exist two types of receptor sites with different dissociation constants for each amino acid. The results suggest that GMP leads to a decrease in dissociation constants, especially for high affinity sites without affecting maximal responses. Monosodium glutamate (Glu) itself, which is known as a typical ‘flavor potentiator’, exhibited no enhancing effect on the responses to 4 primary taste stimuli. The mechanism of how Glu and the 5′-nucleotides ‘potentiate’ flavor of food is discussed.