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The cardiac actions of microinjecting sodium glutamate (0.5-2 nmol) among sympathetic premotor neurons of the subretrofacial nucleus in the rostral ventrolateral medulla (RVLM) were studied in chloralose-anesthetized cats after bilateral vagotomy, sinoaortic denervation, adrenalectomy, and alpha1-receptor blockade. Glutamate microinjections increased heart rate by 25.9 +/- 1.8 beats/min (17. 5%), systolic rate of rise in left ventricular pressure (LVdP/dt) by 1,443 +/- 110 mmHg/s (119%), and arterial blood pressure by 26.9 +/- 1.7 mmHg (50%), whereas they shortened the electrocardiogram P-R interval in 85 of 103 cases by 7.5 +/- 1.2 ms (11.4%), triggering junctional rhythms on five occasions. The increase in LVdP/dt usually led the rise in blood pressure, and its magnitude greatly exceeded any increase attributable to changes in heart rate, diastolic filling, or afterload. Right-sided microinjections caused significantly greater tachycardias than did left-sided microinjections, but only left-sided microinjections triggered junctional rhythms (5 of 52 vs. 0 of 51; P < 0.05), whereas microinjections on either side raised LVdP/dt equally. Subretrofacial neurons thus drive positive chronotropic, inotropic, and dromotropic actions via the cardiac sympathetic nerves, whereas subsets among them preferentially control different aspects of cardiac function.

The mitochondrial uncoupling protein (UCP) has usually been found only in brown adipose tissue. We recently observed that a chronic administration of the beta 3-adrenergic agonist CL-316,243 (CL) induced the ectopic expression of UCP in white fat and skeletal muscle in genetic obese yellow KK mice. The aim of the present study was to examine whether UCP could be induced in nongenetic obese animals produced by neonatal injections of monosodium L-glutamate (MSG). The daily subcutaneous injection of CL (0.1 mg/kg) to MSG-induced obese mice for 2 wk caused significant reductions of body weight (15%) and white fat pad weight (58%). Northern and Western blot analyses showed that CL induced significant expressions of UCP in the white fat and muscle, as well as in brown fat. Immunohistochemical observations revealed that the UCP stains in white fat were localized on multilocular cells and that those in muscle were localized on slow-twitch fibers rich in mitochondria. Immunoelectron microscopy confirmed the mitochondrial localization of UCP in the myocytes. The guanosine 5'-diphosphate (GDP) binding to mitochondria in brown fat doubled after the CL treatment. Moreover, significant GDP binding was detected in the white fat and muscle of the CL-treated mice, at about one-fourth and one-thirteenth the activity of brown fat, respectively, suggesting that ectopically expressed UCP is functionally active. We concluded that the beta 3-adrenergic agonist CL can induce functionally active UCP in white fat and slow-twitch muscle fibers of obese mice.

Simultaneous recordings were made in chloralose-anesthetized cats from muscle vasoconstrictor (MVC), visceral vasoconstrictor (VVC), and renal (RSN) sympathetic fibers. Their barosensitivity was demonstrated, after which all baroreceptor nerves were cut. Multiple microinjections of sodium glutamate (5 nl, 0.1 M) were made in a grid pattern covering the rostral ventrolateral medulla (RVLM) pressor area on seven sides of four animals. Injections increased blood pressure by up to 87 +/- 22 mmHg and MVC, VVC, and RSN activities by up to 169 +/- 55, 62 +/- 23, and 67 +/- 36%, respectively. The relative responses between nerves (taken in pairs) showed significant inhomogeneity across injections into 5/7, 6/7, and 1/7 RVLMs for MVC vs. VVC, MVC vs. RSN, and VVC vs. RSN, respectively. Calculation showed that overall, less than half the response spikes due to RVLM glutamate injections could be accounted for by a hypothetical population of neurons that excited MVC, VVC, and RSN outflows in fixed proportion. Sites that exclusively drove MVC, VVC, or RSN outflows were found in 7/7, 3/7, and 5/7 RVLMs, respectively. Sites that selectively drove either nerve of a given pair were ubiquitous. The RVLM territories from which the three outflows could be activated overlapped but showed clear differences. Their shapes and sizes differed between animals and even between sides. They covered the subretrofacial (SRF) nucleus plus a variable rostromedial extension. The data support the view that the RVLM neurons driving these three sympathetic outflows are largely, perhaps entirely, separate populations.

The temperature dependence of the canine and rat chorda tympani nerve responses to various taste stimuli was examined. The temperature dependence greatly varied with species of stimuli. In the dog, the tonic responses to fructose, sucrose, acetic acid, and guanosine 5'-monophosphate (GMP) and the response induced by the synergism between monosodium glutamate (MSG) and GMP showed peaks at approximately 30 degrees C, whereas those to NaCl, NH4Cl, and MSG showed peaks between 10 and 20 degrees C. In the rat, the tonic response to NH4Cl increased with an increase in temperature up to 45 degrees C, whereas the responses to other stimuli examined showed peaks at approximately 30 degrees C. The responses to glycine, sucrose, and quinine showed sharp temperature dependence, and the responses to acids (HCl and acetic acid) and salts (NaCl and KCl) showed relatively flat dependence. The effects of the temperature change on dose-response curves for fructose, NH4Cl, and GMP were examined using dogs. The temperature change did not practically affect the thresholds for these stimuli and affected the magnitude of the responses to higher concentrations of stimuli. The origins of the temperature dependence were discussed in terms of taste receptor mechanisms.

Effects of electrical and chemical stimulation of the ventromedial (VMH) and lateral hypothalamic (LH) nuclei on glucose uptake in peripheral tissues were studied by the 2-deoxy-D-[3H]glucose (2-[3H]DG) method in anesthetized rats. Electrical stimulation of the VMH increased the rate constant of glucose uptake in brown adipose tissue (BAT; 8 times), heart (3 times), and skeletal muscles (1.5 times) but not in white adipose tissue, diaphragm, and brain, without detectable changes in plasma insulin levels. Chemical stimulation of the VMH by microinjection of L-glutamate also enhanced the rate constant of glucose uptake in BAT, heart, and skeletal muscles preferentially, which indicates that the enhancement of glucose uptake in these tissues is derived from activation of VMH neurons. The increased rate of glucose uptake in BAT in response to VMH stimulation was effectively suppressed by surgical sympathetic denervation, suggesting a mediation of the sympathetic nerve in this effect. On the other hand, electrical stimulation of the LH had no appreciable effect on 2-[3H]DG uptake in any tissues. It is concluded that glucose uptake in certain peripheral tissues is accelerated selectively by activation of VMH neurons, the action of which is independent of plasma insulin but which is probably via the sympathetic nervous system.

The taste responses to the "umami" substances such as monosodium glutamate (MSG), GMP, and IMP were recorded from the chorda tympani nerve of mongrel dogs and beagles. A large synergism was observed between MSG and two species of nucleotides (GMP and IMP) in most mongrel dogs and between MSG and three species of nucleotides (GMP, IMP, and AMP) in beagles. The extent of the synergism between MSG and the nucleotides was much larger than that observed in any other animals examined except for humans. In the presence of GMP, the response magnitude of the chorda tympani nerve to MSG was increased but that to NaCl, HCl, sucrose, quinine, and glycine was unchanged. It was concluded that the canine taste responses to the umami substances closely resemble those in humans, and the dog is a suitable animal model for studies on the responses to the umami substances.

Oxygen consumption and locomotor activity were studied in mice developing obesity after neonatal administration of monosodium glutamate (MSG) and in untreated controls. MSG-treated mice became obese in the absence of increased food intake. Locomotor activity was significantly less in MSG-treated mice 2, 10, and 20 wk after weaning. Oxygen consumption expressed in terms of the Lee index was not significantly different at 2 wk after weaning although at 10 and 20 wk it was significantly lower in MSG-treated mice. Plasma thyroxine was not different between MSG-treated and control mice. It is suggested that diminished energy expenditure is the major factor in the etiology of obesity after neonatal administration of MSG.

The study was designed to examine, by electrophysiological techniques, influences of rostral periventricular structures on neurons in the hypothalamic paraventricular nucleus (PVN) in a large animal (the cat) in which stimulating and recording sites could be precisely identified. Extracellular single action potentials were recorded from the PVN in pentobarbital sodium-anesthetized and hemispherectomized cats. Of 246 neurons tested, 24-47% were inhibited and 9-21% were excited by electrical stimulation of the subfornical organ (SFO), the nucleus preopticus medianus (POMn), and the organum vasculosum of the lamina terminalis (OVLT). The onset latencies of inhibition (19-26 ms) were shorter than those of excitation (28-80 ms). Responses of both neurosecretory and nonneurosecretory neurons were similar to the stimulation of all sites tested. Among these sites, the POMn had the strongest influence on the PVN in view of the proportion of the responsive neurons. Moreover, antidromically evoked action potentials in the PVN neurons (n = 10) were only observed after stimulation of the POMn. Chemical stimulation of POMn and SFO by microinjection of sodium glutamate (50-100 nl, 0.5 M) also inhibited 16 of 38 PVN cells; the remaining neurons were unaffected. These results suggest that activation of the POMn, OVLT, and the SFO neurons mainly inhibits the PVN neurons in the cat.

Within 1.5 h after force-feeding rats one meal of enzymatic hydrolysates of casein, gelatin, lactalbumin, or yeast, alpha-aminoisobutyric acid (AIB) transport in liver slices was stimulated two- to threefold. A complete amino acid mixture also increased AIB transport. Of the 15 amino acids or derivatives tested individually, the dispensable amino acids, especially glycine and alanine, were more stimulatory than the essential amino acids; feeding a mixture of amino acids lacking glycine and alanine increased AIB uptake only slightly. The effects were significantly greater in meal-fed than in ad libitum-fed rats. Increased hepatic concentrations of cyclic AM were usually associated with the increase in AIB transport. Feeding glucose inhibited the increases in transport and cyclic AMP concentration induced by casein hydrolysate or in the stimulation of AIB transport by dietary amino acids. The increases in AIB uptake appeared unrelated to the exchange of endogenous amino acids with medium AIB.

We investigated whether a decrease in arcuate nucleus dopamine (DA) levels resulting from neonatal treatment with monosodium glutamate (MSG) affects the anterior pituitary DA receptors in adult male rats. MSG treatment resulted in a significant reduction in medial basal hypothalamic (MBH) DA levels, no change in its norepinephrine (NE) and epinephrine (E) concentrations, and a marked increase in circulating prolactin (PRL). Scatchard analyses of DA binding characteristics to anterior pituitary membranes using [3H]spiperone revealed linear plots, suggesting a single class of high-affinity, low-capacity binding sites. The DA binding capacity was significantly higher in MSG-treated rats than in controls with no change in affinity. The data indicate that anterior pituitary DA receptors change in accordance with altered physiological conditions. The increase in the number of DA receptors following destruction of the arcuate nucleus is probably a direct effect of reduced DA levels reaching the anterior pituitary gland.

The number of pituitary gonadotropin-releasing hormone (GnRH) receptors increases during sexual maturation in the rat and probably reflects changes in hypothalamic GnRH secretion. As GnRH is synthesized in various hypothalamic nuclei, including the arcuate nucleas (ARC), we investigated the effects of monosodium glutamate (MSG)-induced lesions of the ARC in the rat. In males and females treated with MSG during the first 10 days of life, GnRH receptor content (GnRH-RC) was unchanged from controls at 10 days but was decreased at 20 and 30 days of age (P less than 0.01). Serum concentrations of luteinizing hormone (LH) were similar in MSG-treated and control males but were significantly lower in 10-day-old females (P less than 0.01). Injections of GnRH (3 micrograms every 8 h on days 18 and 19) restored GnRH-RC to control values in MSG-treated rats. Both MSG and untreated control rats showed similar LH responses to acute injections of GnRH, but responses were attenuated (P less than 0.05) after 2 days pretreatment with GnRH in rats that had received MSG. Ovarian GnRH-RC was similar in both MSG-treated and untreated controls. These data indicate that MSG-induced lesions of the ARC reduce pituitary GnRH-RC in immature rats, and the more marked effects in females suggest a more significant role in the ARC in the control of GnRH secretion during maturation in females. The lack of MSG-induced changes in ovarian GnRH-RC indicates that GnRH from the arcuate nucleus is not responsible for the increase in ovarian GnRH receptors seen during sexual maturation.

Recent evidence suggests that neurons in the caudal ventrolateral medulla (CVLM) exert a tonic inhibition on the neurons in the rostral ventrolateral medulla (RVLM) that are essential for the maintenance of arterial pressure (AP). To test the hypothesis that selective activation of cell bodies in the CVLM can inhibit the discharge of neurons in the RVLM, activity from 88 neurons in the RVLM was recorded extracellularly while 2-30 nl sodium glutamate (Glu; 0.15 M) were microinjected into depressor sites of the CVLM of urethan-anesthetized male Wistar rats. Results obtained from spontaneously breathing and artificially ventilated rats were essentially similar and are presented together. Twenty-five neurons were characterized as cardiovascular because they were inhibited by baroreceptor activation and showed rhythmicity of their spontaneous activity in synchrony with the cardiac cycle. Activation of cell bodies in the CVLM inhibited the firing rate of 23 of these cardiovascular neurons and excited 2. The remaining 63 neurons could not be considered cardiovascular because they either were not barosensitive or lacked cardiac cycle-related rhythmicity. Injection of Glu into the CVLM inhibited 26 of these neurons, excited 22, and had no effect on 15. These results provide direct evidence for the existence of an inhibitory pathway from neurons located in the CVLM to cardiovascular neurons in the RVLM.

Acute unilateral nephrectomy (AUN) results in natriuresis from the remaining kidney through reflex pathways involving the central nervous system and requiring an intact pituitary gland. The natriuresis is accompanied by an increase in the plasma concentration of a peptide or peptides derived from the N-terminal fragment (NTF) of proopiomelanocortin. We measured plasma immunoreactive NTF-like material (IR-NTF) before and after AUN in control rats and rats treated neonatally with monosodium glutamate (MSG), a procedure that produces neuroendocrine dysfunction by destroying cell bodies in the hypothalamic arcuate nucleus, median eminence, and other brain regions. In control rats, IR-NTF increased from 85.8 +/- 54.9 (SD) to 207 +/- 98.1 fmol/ml after AUN (P less than 0.02) as sodium excretion (UNaV) doubled. In MSG-treated rats, AUN produced no change in plasma IR-NTF concentration (58.8 +/- 21.3 vs. 68.3 +/- 18.5 fmol/ml (P = NS), nor did UNaV increase. Tissue content of IR-NTF was reduced in the arcuate nucleus and anterior lobe of pituitaries from MSG-treated rats compared with controls, but was no different in the neurointermediate lobe. These results indicate that the hypothalamic lesion produced by neonatal administration of MSG prevents both the increase in plasma IR-NTF concentration and the natriuresis after AUN, and therefore lend further support to the concept of a causal relationship between these two consequences of AUN.

The effects of three taste solutions on the cephalic phase of pancreatic secretion were studied in conscious dogs. Male beagle dogs weighing 9-11 kg were prepared with gastric and duodenal fistulas. Gustatory receptors were stimulated for 5 min with 100 ml of 0.5% agar solutions containing 0.05, 0.12, and 0.3 M of either sodium chloride, sucrose, or monosodium glutamate (MSG). Pancreatic juice was collected every 5 min before and after stimulation, and volume flow and protein output were measured. Pancreatic secretory responses were found to vary with the type of taste stimulus. Sucrose was a better stimulus than MSG for both protein output and volume flow. Taste stimulation with sodium chloride produced a lower pancreatic response than those with sucrose or MSG.

Mice treated with monosodium glutamate (MSG) in the neonatal period grow into obese, stunted adults without overeating. We have previously demonstrated normal control of brown adipose tissue (BAT) thermogenic function in the MSG-treated mouse and have concluded that thermoregulation at a lower than normal body temperature for most of the time is a major cause of its obesity. The objective of the present experiments was to find out whether adrenalectomy would prevent obesity in the MSG-treated mouse, as it does in hyperphagic obese rodents, and whether the thermoregulatory anomaly would be prevented by this procedure. MSG-treated mice that were adrenalectomized at 5 wk of age and studied at 10 wk of age did not become obese. Adrenalectomy increased body temperature of MSG-treated mice to normal (male mice) or almost normal (female mice). Adrenalectomy increased BAT mitochondrial guanosine 5'-diphosphate binding in MSG-treated mice, indicative of an increased thermogenic state, but had the same effect in control mice. We conclude that obesity in the MSG-treated mouse is secondary to the high level of corticosterone in its blood, which raises its metabolic efficiency, an effect of corticosterone also seen in normal lean mice, and causes it to thermoregulate at a low energy-conserving level. This latter effect is peculiar to the MSG-treated mouse and is not seen in corticosterone-treated normal mice.