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Aim: The identification of umami taste among people is extremely variable. Based on functional magnetic resonance imaging (fMRI) the aim of this study was to investigate changes of brain activation in participants before and after they were familiarized with this peculiar taste., Material and Method: A total of 10 healthy, right-handed subjects (7 women, mean age 25 years) participated in this study. A computer-controlled gustometer was used to deliver the umami stimuli at supra-threshold concentrations. After the first session of fMRI experiments, participants went through two weeks of controlled exposure to umami taste, before the second session of fMRI experimentation., Results: Results from psychophysical assessment showed that umami became more familiar (p < 0.001) among the participants after the gustatory exposure. No significant differences for pleasantness and intensity were observed before and after umami training. FMRI data showed that a broader central-nervous network was activated before "umami training" as compared to imaging after "umami training". Significant activation was found in the primary and high level sensory specific gustatory area (insula and anterior cingulate cortex) before training, whereas, significant activation was observed in memory retrieval areas (parahippocampal gyrus) after training., Conclusion: The main finding of the present study suggests that repeated exposure to umami taste over a relatively short period of time does not produce an increased response at the level of taste primary and secondary areas, but that increased familiarity with umami leads to an increased activation of the parahippocampal gyrus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The effects of the red nucleus (RN) stimulation on the jaw-opening reflex (JOR) and the masseteric monosynaptic reflex (MMR) were studied in anesthetized rats. The JOR was evoked by electrical stimulation of the inferior alveolar nerve. The MMR was evoked by electrical stimulation of the mesencephalic trigeminal nucleus. The JOR and the MMR were recorded as electromyographic responses of the anterior belly of the digastric and the masseter muscles, respectively. The conditioning electrical stimulation of the RN facilitated both the JOR and the MMR bilaterally. The facilitatory effect on the JOR was much larger than that on the MMR. Additionally, microinjection of monosodium glutamate into the RN also elicited facilitation of the JOR and the MMR. The results suggest the RN plays an important role in reflex control of jaw movements.

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.

Recent demonstrations of the feeding-inhibitory properties of putative peptides derived from cocaine- and amphetamine-regulated transcript (CART) raise the question of interactions between CART peptides and other messenger molecules implicated in the control of food intake. The present study investigated the histochemical relationship of CART to the neuropeptides thyrotropin-releasing hormone (TRH), melanin-concentrating hormone (MCH), orexin/hypocretin and neuropeptide Y (NPY) in the hypothalamus. Double-label in situ hybridization showed that CART to a great extent is co-expressed with TRH in hypothalamic paraventricular nucleus neurons. This technique was also used to demonstrate that MCH, but not orexin/hypocretin, mRNA colocalized with CART in neurons of the dorsomedial hypothalamic nucleus/lateral hypothalamic area. CART-peptide immunoreactive cell bodies in this region, as well as in the arcuate nucleus and the medial posterodorsal nucleus of the amygdala, were all seen to have close appositions formed by NPY-immunoreactive nerve terminals. Lastly, in a study of mice treated with the neurotoxin, monosodium glutamate, which targets the arcuate nucleus, a near-total ablation of CART peptide immunoreactive cell bodies in this nucleus was accompanied by decreased terminal staining for CART peptide in the paraventricular hypothalamic nucleus, the arcuate nucleus itself and in the dorsomedial hypothalamic nucleus. These findings further define the position of hypothalamic CART neurons within the hierarchy of brain circuitries regulating energy balance, demonstrating the presence of CART peptide in several cell populations that form putative down-stream targets of NPY terminals, including hypophysiotropic TRH neurons and lateral hypothalamic MCH neurons.

Prolonged emotional stress is an important factor in the development of neurogenic hypertension, but its mechanism is still unclear. The purpose of the present study is to analyze the possible neural basis of hypertension induced by prolonged emotional stress. In the brain many nuclei are involved in emotional reaction, stress or defense response; among them the nucleus amygdaloideus centralis (AC) is the most important one which widely connects with other nuclei controlling emotion and stress, such as nucleus ventromedialis (NVM), nucleus dorsomedialis (NDM), nucleus paraventricularis (NPV) etc. These nuclei contain corticotropin releasing factor (CRF)- and substance P (SP)-immunoreactive cell bodies, nerve terminals and corresponding receptors. Our previous and present studies showed that microinjection of CRF or SP into these nuclei induced pressor responses. These data imply that excitation of the AC can activate many nuclei controlling emotion and stress via CRF and SP, and excessive activities of these nuclei may be the neural basis of hypertension induced by prolonged emotional stress. The present study revealed that (1) the AC pressor response to glutamate (Glu) could be reduced by preinjection of CRF antagonist (alpha-Helical CRF[9-41] or SP antagonist ([D-Pro(2), D-Phe(7), D-Trp(9)]-substance P) into bilateral NVM, (2) the NVM pressor response to Glu were decreased by pretreatment of the NDM with CRF- or SP-antagonist, (3) the AC-, NVM- or NDM-pressor responses were all attenuated by preinjection of CRF- or SP-antagonist into bilateral NPV or rostral ventrolateral medulla (RVL). The results indicate that excitation of the AC can indirectly activate the NPV and RVL to evoke pressor response via the NVM-NDM, CRF and SP are transmitters in each connection of this pathway; this is one component of the mechanism underlying the AC pressor response. Taken together with the findings of our previous studies, it provides neurophysiological basis for the above-mentioned implications.

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.

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., (Copyright 1998 Elsevier Science B.V.)

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 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.

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 purpose of the present study was to determine the overall cardiovascular and sympathetic nervous system responses to stimulation of neuronal cell bodies in the paraventricular nucleus (PVN) of the hypothalamus. Bilateral microinjections (50 nl) of monosodium glutamate or sodium acetate were made into the PVN of conscious unrestrained rats. Blood pressure, heart rate and plasma concentrations of norepinephrine and epinephrine were measured. The injection of sodium acetate as an osmotic control was without effect on any of the recorded variables. In contrast, the injections of glutamate were associated with a rapid increase in both blood pressure and heart rate. At doses of 15, 25, and 50 nmol blood pressure increased by 13 +/- 2, 14 +/- 3 and 16 +/- 1 mmHg while heart rate increased by 64 +/- 15, 73 +/- 8 and 50 +/- 8 bpm. These responses were associated with increases in plasma norepinephrine concentrations of 51 +/- 8, 100 +/- 16 and 62 +/- 13 pg/ml while epinephrine concentrations rose by 42 +/- 17, 58 +/- 18 and 38 +/- 17 pg/ml. The responses of glutamate (25 nmol) were not affected by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me)AVP (10 micrograms/kg) (blood pressure: pre 15 +/- 3 vs post 13 +/- 3 mmHg, heart rate: pre 77 +/- 9 bpm vs post 91 +/- 7 bpm, plasma norepinephrine: pre 106 +/- 22 vs post 121 +/- 28 pg/ml and plasma epinephrine: pre 61 +/- 25 vs post 34 +/- 30 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrical stimulation in the nucleus reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) produces facilitation and/or inhibition of spinal nociceptive transmission in behavioral and electrophysiological studies. The present study examined spinal neurotransmitter receptors mediating descending facilitation from the NGC/NGC alpha. As previously demonstrated, electrical stimulation in the NGC/NGC alpha at low intensities (approximately equal to 10 microA) produced facilitation and at greater intensities (approximately equal to 38 microA) inhibition of the tail-flick (TF) reflex. Intrathecal pretreatment with the non-selective serotonin (5-HT) receptor antagonist methysergide attenuated or completely abolished facilitation of the TF reflex produced by electrical stimulation in the NGC/NGC alpha; intrathecal pretreatment with atropine, phentolamine, naloxone or mecamylamine was without effect on stimulation-produced facilitation. Descending inhibition from the NGC/NGC alpha produced by electrical stimulation was attenuated or completely abolished by bilateral transection of the dorsolateral funiculi (DLF) of the cervical spinal cord. Descending facilitation produced by electrical stimulation, however, was unaffected or enhanced following DLF transections. Glutamate microinjections (1.7 nmol/0.17 microliters) into the NGC/NGC alpha produced a rapid, repeatable and short-duration facilitation of the TF reflex in rats with bilateral DLF transections and such facilitation was attenuated by intrathecal pretreatment with methysergide, but not atropine, xylamidine (5-HT2 selective receptor antagonist) or MDL-72222 (5-HT3 selective receptor antagonist). These findings suggest that facilitation of the TF reflex from the activation of the cell bodies in the NGC/NGC alpha is mediated by a descending serotonergic pathway traveling in the ventrolateral funiculi and by spinal 5-HT1 receptors.

In previous studies we have shown that electrical stimulation of the cortex or anterior pretectal nucleus (APT) inhibits the jaw-opening reflex (JOR). In the present study we investigated whether these effects are mediated by a relay in the periaqueductal gray matter (PAG) or rostroventromedial medulla (RVM). Experiments were performed on chloralose-urethane anesthetized rats. The JOR which was elicited by electrical stimulation of the mandibular incisor tooth was monitored by recording the evoked digastric muscle activity. Conditioning stimulation (20 ms train of 0.2 ms pulses at 400 Hz) was delivered to the facial area of the sensorimotor cortex, APT, PAG or nucleus raphe magnus (NRM) 50 ms prior to the test stimulus to the tooth that evoked the JOR. In addition, the effects of microinjections of glutamate into APT, PAG and NRM on the tooth-evoked JOR were also evaluated. The inhibition of the JOR by electrical and glutamate conditioning stimulation was found to be most potent for activation of the NRM and least potent for the APT. Local anesthetic (2% lidocaine, 0.3-0.6 microliters) block of the PAG could partially, significantly (P less than 0.05) and reversibly reduce both the APT and cortical-induced depression of the JOR. Lidocaine block of the ventromedial pons reversibly reduced the PAG, APT and cortical-induced inhibition of the JOR (P less than 0.05). Lidocaine block of the lateral RVM had powerfully (P less than 0.01) and reversibly reduced the PAG-induced inhibition, but had only a small effect (P less than 0.05) on the APT-induced inhibition and no significant effect on the cortical-induced inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

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 NH4Cl, 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.

Single electrode voltage clamp recordings were made during Pavlovian conditioning of single units of the motor cortex of cats. Units that developed a conditioned spike discharge in response to a click conditioned stimulus (CS) after pairing the click with glabella tap and local ionophoretic application of glutamate showed increases in input resistance and reductions of an early outward current induced by depolarizing commands and by return to holding potentials after hyperpolarizing commands. Changes in later currents were also found in some cells. Units that failed to develop a conditioned response did not show these changes. The decreases in membrane currents could contribute to an increased spike discharge in response to the CS as could the increased input resistance observed after conditioning. Conductance changes of this type may serve as engrams by which some forms of memory and learning are expressed across both vertebrate and invertebrate species.

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.

In attempts to activate lordosis-facilitating neural mechanisms in the ventromedial hypothalamus (VMH), neural excitatory agents were infused into the medial hypothalamus, and the effects of the infusions on the lordosis reflex and on the electrical activity of VMH neurons were studied. Surprisingly, bilateral intrahypothalamic infusion of glutamate (10 mM, 1.0 microliter/side) into behaving, ovariectomized, estrogen-treated rats displaying moderate lordotic responsiveness did not facilitate lordosis, but instead, resulted in a rapid (within a few minutes) and transient (recovery in about 20 min) inhibition of lordosis. Further experiments showed that this lordosis-inhibiting effect of glutamate was dose-related, and was completely blocked by prior infusion of a local anesthetic, procaine. Infusion of KC1 (1.5 or 15%, 1.0 microliter/side) also induced a dose-related, rapid and transient inhibition of lordosis, that was essentially identical to that induced by glutamate. Kainic acid (0.25 micrograms/0.5 microliter/side) also caused a rapid inhibition of lordosis, but the effect was long-lasting (days). The inhibition of lordosis by these agents was dissociated in time course, presence, and/or severity from effects on non-lordotic behaviors. Electrophysiological studies showed that all three agents tested could excite multiunit activity of the VMH, and that the time courses of these excitations were closely comparable to those of the inhibition of lordosis induced by the respective agents. Altogether, these studies indicated that the excitation of certain medial hypothalamic neurons can inhibit the lordosis reflex. The implied lordosis-inhibiting neural mechanisms are separate from facilitatory mechanism(s), according to differences in latency, duration, and procaine-sensitivity of response.

In the rat hypothalamus, cell bodies containing neurotensin-like immunoreactivity were mainly found in the medial preoptic area, the periventricular nucleus, the paraventricular nucleus, the supraoptic nucleus and the arcuate nucleus. [3H]neurotensin binding sites were observed throughout the hypothalamus with a dense accumulation of silver grains over the paraventricular nucleus, the arcuate nucleus and the median eminence region. By radioimmunoassay neurotensin-like immunoreactivity was also found in the neurointermediate lobe of the pituitary gland of various mammalian species and in human postmortem posterior pituitary glands. In the rat studies involving pituitary stalk transections and the neurotoxin monosodium glutamate indicated the presence of a neurotensinergic pathway from the arcuate nucleus to the neurointermediate lobe of the pituitary gland. [3H]neurotensin binding sites were found to be concentrated over the intermediate lobe of the pituitary gland and their presence was not affected by pituitary stalk transection, indicating their localization on endocrine cells of the intermediate lobe of the pituitary gland.

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 45Ca2+ 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.

Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A9 DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade.

Intrahypothalamic somatostatin-containing neurons were investigated immunohistochemically. In intact rats, immunoreactive cell bodies appeared in the rostral periventricular area, and immunoreactive beaded fibers were observed to terminate in the median eminence and to form delicate networks surrounding immunonegative cell bodies within the medial preoptic, suprachiasmatic, arcuate, ventromedial and premammillary nuclei. Intraventricular colchicine infusion resulted in the appearance of immunoreactive cell bodies in the arcuate, ventromedial and suprachiasmatic nuclei, and an increase in the number of cell bodies seen in the periventricular area. Complete deafferentation of the medial-basal hypothalamus excluding the rostral periventricular area caused the immunoreactive structures in the median eminence to disappear and enhanced the staining of periventricular cell bodies. In the arcuate and ventromedial nuclei, the immunoreactive fiber networks were left intact and the immunoreactive cell bodies were occasionally recognized. Horizontal knife cut between the arcuate nuclei and median eminence did not alter immunoreactivity in either region. Neonatal administration of MSG caused only the disappearance of arcuate nuclei. The results indicate that two kinds of somatostatin neuronal systems exist in rat hypothalamus: one is involved in the production of hormonal somatostatin and the other serves for the regulation of neuronal activities in restricted hypothalamic nuclei.

The growth hormone-releasing factor (GRF)-containing neuronal system was immunohistochemically studied in the rat hypothalamus. The immunolabeled cell bodies were determined by intraventricular administration of colchicine 24 h before killing. In intact animals, the neurons appeared in the ventral portion of the arcuate nucleus (group 1) and in the area surrounding the ventromedial nucleus (group 2). Most of the cell bodies also indicated immunoreactivity for tyrosine hydroxylase (TH). The immunoreactive fibers accumulated showing a palisade arrangement in the external layer of the median eminence. The rats treated neonatally with monosodium glutamate revealed group 2 neurons and a few immunoreactive fibers in the median eminence. Half-anterolateral deafferentation of the medial basal hypothalamus, which was performed to isolate group 1 neurons or both group 1 and 2 neurons from the other brain parts, did not remarkably affect the appearance of the fibers in the median eminence. However, the perikarya were hypertrophic and strongly immunolabeled for GRF and TH. It is concluded that the fibers containing GRF in the median eminence derive mostly from group 1 neurons, and that the neurons may be regulated by an inhibitory mechanism by other neurons on the outside of the deafferented hypothalamic islands. GRF synthesized in group 2 neurons may act on other neurons as a neurotransmitter-like substance.

The techniques of microelectrophoresis and antidromic identification have been utilized in the female rat anesthetized with urethane to localize the tuberoinfundibular neurons and to determine their pharmacological sensitivity to dopamine (DA), norepinephrine (NE) and glutamate (GLUT). Extracellular recordings were made of 149 single units in the arcuate (ARC) nucleus; 79 of which were antidromically identified (43 were spontaneously active and 36 were silent) and the remaining 70 cells were determined to be spontaneously active but could not be antidromically identified (unidentified ARC neurons). The mean latency of the antidromically activated potentials was 9,5 msec, which gave a conduction velocity of 0.05 mm/msec. The spontaneous firing rate of antidromically identified ARC neurons varied from less than 1/sec to 8/sec while unidentified cells discharged at rates from less than 3/sec to 10/sec. These data indicate that ARC neurons exist which are capable of conducting impulses and send their axons into the external layer of the ME. Successful drug applications were made on 104 ARC neurons; of the 43 antidromically identified units, 37 were spontaneously active and 6 were silent. There were 61 spontaneously active, unidentified neurons. Two distinct pools of antidromically identified ARC neurons were found based on their sensitivity to NE and DA. Neurons displaying excitation to NE(N = 23) were either inhibited (N = 10) or non-responsive (N = 13) to DA applied electrophoretically; no NE-sensitive ARC neurons were excited by DA. The second pool of neurons (N = 14) was excited by DA. These neurons when tested with NE were either reproducibly inhibited (N = 3) or nonresponsive (N = 11); no DA-sensitive neurons were excited by NE. In the unidentified ARC neurons, iontophoretically applied NE and DA gave reproducible effects on individual neurons, so that some neurons were excited by both NE and DA, some were inhibited by both, and still others were excited by one and inhibited by the other chemical. Glutamate (GLUT) had a powerful excitant action on nearly all the neurons tested, increasing the electrical activity of the spontaneously active neurons as well as initiating activity in quiescent ARC neurons. These data are suggestive of a tuberoinfundibular neuronal system whose activity is modulated by either DA or NE. This evidence is certainly compatible with a functional role for both DA and NE in regulating pituitary function by altering the activity of presumed neurosecretory neurons which release hypophysiotropic hormones.

These studies were undertaken to determine whether the kindling process induces persistent alterations in the functional status of neurons of the substantia nigra pars reticulata, a brain area identified previously as a site important in regulating the expression of generalized motor seizures. Extracellular, single-unit recordings of pars reticulata neurons were made in chloral hydrate-anesthetized, fully kindled rats (2-3 weeks after the last seizure), or unkindled control rats of the same age and weight. Kindling caused no alterations in several electrophysiological parameters examined. For instance, neither the number of active pars reticulata cells encountered, nor their firing rates, were significantly different between kindled and control groups. In addition, kindling failed to alter the sensitivities of pars reticulata neurons to iontophoretic application of two inhibitory transmitters, gamma-aminobutyric acid and glycine, and two transmitters that excite these cells, glutamate and acetylcholine. These results suggest that while kindling produces enduring increases in seizure susceptibility, it causes no persistent interictal changes in either basal activity or several measures of transmitter sensitivity of substantia nigra pars reticulata neurons.

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.

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.

Physostigmine, a choline-esterase inhibitor, is known to elevate endogenous levels of acetylcholine. Intravenously administered physostigmine causes a rise in blood pressure via its action in the central nervous system. Exact site of this action of physostigmine is not known. In this paper, it was demonstrated that microinjections of tetrodotoxin (a fast sodium channel blocker), lidocaine (a local anesthetic) and scopolamine (a cholinergic muscarinic receptor blocker) into the rostral ventrolateral medullary pressor area abolished the pressor action of intravenously administered physostigmine. These results demonstrate that the rostral ventrolateral medulla is the site of action of intravenously administered physostigmine and this action is mediated via cholinergic muscarinic receptors.

Immunocytochemical localization of neuropeptide Y (NPY) was performed in the hypothalamus of rats of which the arcuate nucleus had been destroyed with monosodium L-glutamate in the neonatal period. The treatment produced a disappearance of most of the NPY cell bodies normally found in the arcuate nucleus. The concentration of fibers was decreased in the paraventricular nucleus, but not in the other hypothalamic nuclei. The treatment also induced the appearance of a large number of immunoreactive cell bodies in the paraventricular nucleus. These results strongly suggest that arcuate NPY neurons are projecting to the paraventricular nucleus and that the arcuate nucleus probably exerts some inhibitory tonic influence on NPY paraventricular neurons.

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.

In anaesthetized cats the effect on antidromically identified single sympathetic preganglionic neurones (SPN) in the third thoracic segment of microelectrophoretically applied monoamines, amino acids and acetyl choline was examined. 5-Hydroxytryptamine (5-HT) creatinine sulphate and bimaleate excited a majority of SPN. A few cells were inhibited by 5-HT creatinine sulphate. These effects were observed on spontaneously active SPN (cardiac and non-cardiac type) and on silent SPN. Noradrenaline, adrenaline and dopamine inhibited all 'types' of SPN, including spontaneously active neurons, silent neurones activated by glutamate or DL-homocysteic acid and neurones synaptically activated by electrically stimulating a brain stem excitatory region. Acetyl choline had no effect on different types of SPN.

The effects of electrical and chemical stimulation of the expiratory neuronal population in the region of the retrofacial nucleus, the so called 'Bötzinger complex' (Böt. c.), on respiratory activity were investigated in vagotomized cats under pentobarbitone anaesthesia. Some of the experiments were performed on paralyzed or bilaterally thoracotomized, artificially ventilated animals. Sustained tetanic electrical stimulation (20 to 100-Hz, 0.5-ms current pulses at intensities of 5-60 microA) induced strong depressant effects on the inspiratory motor output which could lead to complete apnoea. The apnoeic response was accompanied by tonic activation of expiratory muscles; the appearance and the strength of tonic expiratory activity were dependent upon the frequency of stimulation. Brief tetani (40 to 100 ms trains of 0.5-ms rectangular pulses at 100-300 Hz) timed either during the inspiratory or the expiratory phase caused depression of inspiratory activity and prolongation of expiratory time, respectively. These effects increased gradually as the onset of stimulation was progressively delayed during each respiratory phase. The effects of sustained tetanic stimulation were mimicked by microinjections (25-100 nl) of 0.5 M L-glutamate or 0.16 M DL-homocysteic acid in the same region, thus indicating that they were the result of the stimulation of cell bodies and not of axons of passage. The present results support the hypothesis that Böt. c. neurons play an important role in the control of the breathing pattern by exerting inhibitory influences on inspiratory activity and, possibly, by contributing to the off-switch mechanisms. Furthermore, they suggest that these neurons are involved in the central control of expiratory activity.

Acute administration of monosodium-L-glutamate (MSG) to rats induces the degeneration of acetylcholinesterase (AChE)-positive neurons of the area postrema (AP). Chronic treatment with MSG results in the disappearance of AChE activity of area subpostrema (ASP) capillaries. It is concluded that processes of AChE-positive AP neurons terminate within the ASP and may contribute to the AChE activity of ASP capillaries.

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.

The serum LH and FSH rise after gonadectomy and the serum TSH rise after thyroidectomy were examined in rats that received monosodium-L-glutamate (MSG) as neonates. The rise in serum gonadotrophins after gonadectomy was significantly delayed in both adult and peripubertal MSG-treated rats when compared to control castrates. Serum LH and FSH levels, however, eventually achieved levels in MSG-treated rats that were not significantly different than those of controls. The serum TSH rise after thyroidectomy was significantly delayed in adult female MSG-treated rats, but not in prepubertal female MSG-treated rats. Pituitary responsiveness to both exogenous LH-RH and TRH was unaffected by neonatal MSG treatment, with one exception: pituitary responsiveness to HL-RH of orchidectomized peripubertal males was blunted significantly. The results are discussed in terms of the possible neurotoxic effects of neonatal MSG treatment, as well as the altered hypothalamic sensitivity to gonadal steroids.

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.

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. Neonatal MSG treatment resulted in a dramatic decrease of GH-RH immunoreactivity in the median eminence (ME), but not complete disappearance as reported earlier. 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 apparently non-specific accumulation of c-fos proto-oncogene mRNA was found in rat hippocampus as a result of injection of either glutamate, noradrenaline, or physiological saline. There was no c-fos gene induction following an electroconvulsive shock.

It is generally believed that morphine activates a descending system(s) of inhibition, an effect contributing significantly to the analgesia produced. There has arisen, however, considerable controversy on this point. To address whether morphine inhibits spinal nociceptive transmission when given into the brainstem, the effects of focal electrical stimulation and monosodium S-glutamate (Glu) given in the periaqueductal gray (PAG), the locus coeruleus/subcoeruleus (LC/SC) and/or the nucleus raphe magnus (NRM) on spinal unit responses to noxious heating (50 degrees C) of the skin were examined and compared with effects produced by morphine (Mor). Focal electrical stimulation in 46 sites in the midbrain, dorsolateral pons and ventromedial medulla reliably inhibited unit responses to noxious heating of the skin (mean 34% of control). Microinjections of Glu (50 nmol, 0.5 microliter) were made into 17 sites in the midbrain, 10 sites in the LC/SC and 11 sites in the NRM, inhibiting unit responses to a mean 57% at 22 of the 38 sites of microinjection. Mor (10-20 micrograms, 0.5 microliter) was microinjected into 15 sites in the midbrain, 13 sites in the LC/SC and 11 sites in the NRM, inhibiting unit responses to heat to 63% of control at 24 sites of microinjection. The effects of morphine were shown to be receptor specific by antagonism with naloxone administered either intravenously or into the brainstem at the same site of microinjection as morphine. In 31 sites in the midbrain, dorsolateral pons and ventromedial medulla, microinjections of both Mor and Glu into the same sites attenuated unit responses to heating of the skin to a mean 77% and 71% of control, respectively. The results support the hypothesis that Mor acts supraspinally to modulate spinal nociceptive transmission by activating an endogenous descending inhibitory system(s). Focal electrical stimulation, glutamate and morphine modulated spinal nociceptive transmission by activation of descending inhibitory systems whose cell bodies of origin are in the PAG, the LC/SC or the NRM.

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.

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.

(1) Extracellular action potentials were recorded from laminae IV--VI dorsal horn cells, using multibarrel carbon fibre micro electrodes. The amplitude and shape of the extracellular spike, the receptive field, and the response to iontophoretic glutamate ion, were investigated for each cell. (2) Of the 172 units isolated, 48 (28%) could be recorded from over a range of microelectrode tip depths greater than 100 micrometers. The sensitivity of these 'trackable' cells to glutamate was investigated at different depths; 13/48 (27%) had zones where they were insensitive to glutamate. (3) From the data on spike shapes and glutamate sensitivity, it is argued that dendritic spikes can occur in these cells.

Adult male and female rats treated neonatally with monosodium glutamate (MSG) exhibit lesions in the arcuate nucleus of the hypothalamus. Immunohistochemical analysis of the distribution of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD), neurotensin (NT) and gonadotropin-releasing hormone (GnRH) reveals substantial destructions of tuberoinfundibular dopamine and NT systems accompanied by a marked reduction of immunoreactivity in the median eminence. GAD immunoreactivity in the arcuate nucleus and median eminence is greatly reduced, while GnRH containing structures in the mediobasal hypothalamus are not noticeably affected. Evaluation of autoradiograms after intravenously administered [3H] estradiol in the ventral hypothalamus indicate an almost complete loss of target neurons in the arcuate nucleus but not in the nearby ventromedial nucleus. The results suggest that: (a) NT- and dopamine-containing neurons of the arcuate nucleus project to the median eminence via tuberoinfundibular NT and dopaminergic pathways; (b) GABA in the median eminence originates to a major extent from neurons of the arcuate nucleus through a tuberoinfundibular GABAergic system; (c) GnRH is produced in the rat outside the arcuate nucleus; (d) the MSG-induced lesion in the basal tuberal region abolishes or strongly diminishes estradiol target neurons in the arcuate nucleus.

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 microgram/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.

By injecting monosodium L-glutamate into either one of the forebrain hemispheres of the developing chicken brain and examining the behavioural effects which ensue, it has been possible to demonstrate that there is functional lateralization for control of a number of behaviours. Glutamate treatment of the left hemisphere retards visual discrimination learning and auditory habituation, as does glutamate treatment of both hemispheres, but treatment of the right hemisphere is without effect on these behaviours. An imbalance generated by administering glutamate to the left hemisphere causes a marked increase in aggressive and sexual behaviour, which does not occur either after treatment of both hemispheres or treatment of the right hemisphere. A preliminary study on the distribution of radioactive glutamate is also reported.