Excitatory Amino Acid Systems Research Articles

Cholinergic systems in the nucleus of the solitary tract of rats.

The pharmacological and physiological properties of excitatory amino acid and ACh systems in the nucleus of the solitary tract (NTS) were studied in slices of rat brain stem by extracellular and intracellular recordings from neurons activated by solitary tract (ST) stimulation. These neurons were characterized as having several long dendrites with multiple varicosities. Synaptic activation of the medial NTS (mNTS) neurons by ST stimulation was mediated by non-N-methyl-D-aspartate (NMDA) glutamate (Glu) receptors, because the excitation was blocked by 6-cyano-7-nitro-quinoxaline-2,3-dione but not by NMDA, nicotinic, or muscarinic antagonists. Identified mNTS neurons were excited by iontophoresis of both Glu and ACh. The most sensitive region of the cell was on the dendrites approximately 100 micrometer from the cell body for both putative neurotransmitters. Nicotinic and/or muscarinic excitatory ACh responses were detected on the mNTS neurons. Our observations suggest that both types of ACh receptors may contribute to the attenuation of the baroreceptor reflex, but the functional correlation of this receptor profile remains to be determined.

Cellular and molecular mechanisms of opioid tolerance and dependence: Progress and pitfalls

Recent cellular models of opioid tolerance and dependence have incorporated the idea that excitatory amino acid systems may have an important role in these phenomena. Fundytus and Coderre have developed a model that suggests a prominent role for metabotropic glutamate receptors in the initiation and the development of opioid tolerance and dependence. This Commentary briefly reviews Fundytus and Coderre's model of tolerance and dependence, offering comparisons and contrasts with the model of Mao, Price, and Mayer, which suggests a central role for N-methyl-D-aspartate receptors. Strengths and weaknesses of these models are discussed, as well as potential revisions that may lead to a more complete model of these phenomena.

Dopamine D 1 receptor modulation of glutamate receptor messenger RNA levels in the neocortex and neostriatum of unilaterally 6-hydroxydopamine-lesioned rats

The effect of treatment with the D 1 dopamine receptor agonist SKF 38393 on the expression of metabotropic glutamate receptor 1, 3, 4 and 5 receptor subtypes and of the glutamate N-methyl- d-aspartate ionotropic receptor subunits NR1, NR2A and NR2B was analysed using in situ hybridization. We studied the neocortex and neostriatum of normal rats and of rats treated with 6-hydroxydopamine, a neurotoxin that, after intracerebral injection into the ventral tegmental area, causes selective degeneration of the ascending dopamine pathway. In the 6-hydroxydopamine-lesioned rats, metabotropic glutamate receptor subtype 3 messenger RNA levels were ipsilaterally increased in the neocortex and neostriatum, while the levels of metabotropic glutamate receptor subtype 4 messenger RNA were bilaterally increased in both regions. When administered to the 6-hydroxydopamine-lesioned rats, the D 1 receptor agonist SKF 38393 (3×20 mg/kg, s.c.) produced a bilateral decrease in the expression of the metabotropic glutamate receptor subtype 1 and 5 receptor messenger RNA levels in the neocortex and neostriatum. In the neostriatum, SKF 38393 attenuated the ipsilateral increase in the expression of striatal metabotropic glutamate receptor subtype 3 messenger RNA produced by the 6-hydroxydopamine lesion. Furthermore, SKF 38393 produced a bilateral decrease in the levels of NR1 receptor subunit messenger RNA and, in contrast, an increase in the striatal NR2B messenger RNA levels. All these effects were abolished by the D 1 receptor antagonist SCH 23360. These results indicate a differential D 1 receptor-mediated modulation of the expression of some glutamate receptor subtypes in the neostriatum and neocortex, in agreement with the idea of a functional coupling between dopamine and excitatory amino acid systems in both regions. Thus, pharmacological targeting of excitatory amino acid systems could provide alternative or complementary treatment strategies for diseases involving dopaminergic systems in the striatum (e.g., Parkinson's disease) and cortex (e.g., schizophrenia).

Potentiation of D2-dopamine receptor-mediated suppression of zif 268 by non-competitive NMDA receptor antagonists in reserpinized rats

Striatopallidal output neurons, which coexpress D2-dopamine receptors and NMDA receptors, are logically a potential site of interaction between corticostriatal glutamatergic input and dopaminergic systems. Recent hypotheses about the etiology of schizophrenia have implicated both excitatory amino acid and dopamine systems. The present study was designed to examine, in vivo, the interaction between D2-dopamine receptors and NMDA receptors in the regulation of the expression of the early immediate genes (IEGs), zif 268 and jun B, in striatopallidal neurons. We tested whether coadministration of NMDA antagonists interacted with the actions of the D2 agonist, quinpirole, on IEG expression following dopamine depletion with reserpine. When rats were pretreated with the non-competitive NMDA receptor antagonists, MK 801 (1 mg/kg) or PCP (20 mg/kg), together with quinpirole, the quinpirole reversal of reserpine induction of zif 268 mRNA was potentiated in all regions examined. MK 801 alone had no significant effect on reserpine induction of zif 268 mRNA. Pretreatment with the competitive NMDA receptor antagonist, CPP (5 mg/kg), did not significantly alter the dose response of zif 268 mRNA expression to quinpirole in any region. There was no significant effect of MK 801 on jun B mRNA expression, either on the response to quinpirole or when administered alone with reserpine. Our findings provide evidence of an interaction between the NMDA receptor channel system and the D2-dopamine system on a molecular level in striatopallidal neurons carrying output from the basal ganglia.

Striatal Excitatory Amino Acid Receptor Subunit Expression in the D1A-Dopamine Receptor-Deficient Mouse

The influence of dopamine receptor deletion on the expression and distribution of striatal excitatory amino acid (EAA) receptor subunits comprising the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtypes were examined in the D_1A dopamine (DA) receptor-deficient mouse. EAA receptor subunit immunofluorescent staining was altered by the DA receptor genetic mutation. The NMDA-R₁ subunit was used as a marker for NMDA-type receptors. The number of striatal neurons expressing this subunit decreased and there was a modest attenuation in the neuropil staining in the mutants in contrast to littermate controls. The R₁ subunit for the glutamate receptor (GluR₁) was used as an indicator of the AMPA receptor subtype. Immunostaining for this subunit also showed changes induced by deletion of the DA receptor subtype. In contrast to the NMDA-R₁ subunit, neuropil staining for the GluR₁ subunit was elevated in the mutant in comparison to littermate controls, such that the immunofluorescent reaction obscured detection of the subunit protein in striatal interneurons. The results are discussed in relation to the potential impact on functional interactions between the EAA and DA systems in the striatum.

The role of N-Methyl- D-Aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes

The study of excitatory amino acids (EAAs) has recently resulted in new and fundamental concepts in neuroscience. This progress has led to a growing awareness of the crucial role that brain EAAs systems play in a variety of physiological and pathological processes. The N-methyl- D-aspartate (NMDA) receptor, presently the most well understood subtype of EAAs receptors, has been implicated in crucial physiological processes such as synaptogenesis, learning and memory. Dysfunctions of NMDA receptors seem to play a crucial role in the neurobiology of disorders such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemic stroke. This paper is a review of emerging data indicating that alterations of NMDA receptor function may be pivotal to the pathophysiology of four common psychiatric syndromes: schizophrenia, major depression, posttraumatic stress disorder, and alcoholism. Special emphasis is placed on the current state of development of pharmacological strategies aiming at the modulation of NMDA receptor-mediated neurotransmission in these disorders.

Fibromyalgia and Headache. Failure of Serotonergic Analgesia and N-Methyl-D-Aspartate-Mediated Neuronal Plasticity: Their Common Clues

A defect in serotonergic analgesia and a hyperalgesic state are proposed as features common to headache and fibromyalgia. The benefit to both migraine and fibromyalgia from inhibiting ionotropic N-methyl-D-aspartate receptor activity implies that redundant hyperalgesia-related neuroplastic changes are crucial for severe or chronic migraine and primary fibromyalgia. The fact that migraine and primary fibromyalgia share some pivotal set-up of serotonergic and excitatory amino acid systems led us to analyse epidemiological data supporting the hypothesis that analgesic disruption and a consequent hyperalgesic state are mechanisms of both migraine and fibromyalgia. Beyond demonstrating the comorbidity between migraine and primary fibromyalgia, the data suggest that migraine may represent a risk factor for fibromyalgia.

The Role of Glutamate in Physical Dependence on Opioids

The present review will evaluate the interactions between κ-opioid receptors and glutamate within the locus coeruleus (LC) during the development of opioid dependence and on expression of withdrawal from dependence on opioids. Hyperactivity of noradrenergic neurons in the LC has been proposed to play a critical role in the physiological and behavioral responses that comprise opioid withdrawal. Several studies indicate that the excitatory amino acid system, in particular, glutamate and its receptors, participate in both the withdrawal-associated increase in LC neuronal activity and the expression of opioid withdrawal behaviors. Most studies on opioid dependence have focused on the prototypical opioid morphine, which produces its physical dependence through agonist actions at the μ-opioid receptor. Butorphanol (Stadol®), which exhibits a markedly different profile of opioid receptor activity than does morphine, produces its physical dependence primarily through actions at the κ-opioid receptor. Studies from our laboratories using a rodent model in which butorphanol administration induces dependence indicate further that the κ-opioid receptor is an important regulator of glutamate release within the LC. Glutamate exerts actions within the LC that mediate expression of behavioral symptoms of butorphanol withdrawal.

Interactions between GABAergic and serotoninergic systems with excitatory amino acid neurotransmission in the hypothalamic control of gonadotropin secretion in prepubertal female rats

The present studies were designed to study the interrelationships between GABAergic, serotoninergic and excitatory amino acids systems (EAAs) in the control of gonadotropin secretion in prepubertal female rats. For this purpose we determined the effects of N-methyl- d-aspartate (NMDA), an exogenous agonist of EAAs receptors, on LH and FSH secretion in 16-day-old female rats in which the GABA-A and GABA-B receptors were blocked by bicuculline and baclofen or serotonin (5-HT) depleted by p-choloroamphetamine (PCA). In addition the effects of the GABAergic and serotoninergic systems on LH and FSH secretion were evaluated in animals treated with dibenzocycloalkenimine (diocilpine MK-801), an antagonist of NMDA neurotransmission. While muscimol, a GABA- A agonist, induced a significant increase in LH and FSH levels ( P<0.01), baclofen, a GABA-B agonist, had an inhibitory effect on these hormones ( P<0.01). MK 801, a NMDA receptor antagonist, not only suppressed the stimulatory effect of NMDA on LH and FSH but also blocked the stimulatory effect of muscimol without modifying the inhibitory action of baclofen on both gonadotropins. Bicuculline, a GABA-A receptor antagonist, did not modify the release effect of NMDA on LH and FSH. 5-HTP, a precursor of 5-HT that increases the levels of this neurotransmitter in the central nervous system significantly increased ( P<0.01) the plasma levels of LH and FSH, and this effect was blocked by the NMDA receptor antagonist MK-801. We conclude that the stimulatory effects of GABAergic and serotoninergic systems in prepubertal female rats are connected with the activation of EAA neurotransmission, while the stimulatory effects of NMDA appear to be independent of serotoninergic and GABAergic actions on LH and FSH secretion. Since both GABA and serotonin systems change their effects on LH and FSH during sexual maturation from a stimulatory action in prepubertal to an inhibitory action in adult rats and since NMDA neurotransmission has a stimulatory effect on gonadotropin secretion both in prepubertal and adult rats, it is clear that the interrelationships between GABAergic and serotoninergic systems with EAAs in the gonadotropin control are different in prepubertal and in adult rats.

Analgesic responses of male mice exposed to the odors of parasitized females: effects of male sexual experience and infection status.

The present study shows that parasites influence both the responses of males to infected females and the responses of male hosts to females. Male mice exposed for 30 min to the odors of females infected with the nematode parasite Heligmosomoides polygyrus displayed a naloxone-sensitive, opioid-mediated analgesia, whereas males exposed for 1 min showed a shorter duration and lower amplitude naloxone-insensitive "nonopioid" analgesia that involved serotoninergic (5-HT) and excitatory amino acid (N-methyl-D-aspartate [NMDA] receptor) systems. The male mice distinguished between the odors of infected and physically stressed females, displaying greater analgesia after exposure to the odors of infected than stressed females. The analgesic responses to the odors of infected females were also affected by the males' prior sexual experience; sexually experienced males exhibited significantly greater analgesia than sexually naive males. In contrast, male mice infected with H. polygyrus failed to show a nonopioid analgesia after exposure to the odors of infected females and displayed a markedly lower level of opioid analgesia than uninfected mice. These results show that male mice can discriminate between the odors of parasitized and nonparasitized females and find the odors of parasitized estrous females aversive.

N-methyl- d-aspartate receptor activation by guanidinosuccinate but not by methylguanidine: Behavioural and electrophysiological evidence

Levels of methylguanidine (MG) and guanidinosuccinate (GSA) are known to be highly increased in uraemic patients. In the present work, the effects of these uraemic guanidino compounds on the excitatory amino acid system were investigated in vivo and in vitro. It was found that convulsions induced by intracerebroventricular GSA injection in mice were antagonized by N-methyl- d-aspartate (NMDA) receptor blockade, whereas those induced by MG were not significantly altered. Application of GSA (between 25 and 10,000 μM) to mouse spinal cord neurones in primary dissociated cell cultures, evoked depolarizing, inward whole-cell currents in a dose-dependent fashion and with reversal potential at 0 mV; MG did not produce such effects. GSA-induced whole-cell currents were caused by NMDA receptor activation since NMDA receptor antagonists (2-amino-5-phosphonovalerate, Mg 2+ and ketamine) blocked GSA-evoked whole-cell currents completely and reversibly, whereas co-application of a non-NMDA receptor antagonist (6-cyano-7-nitroquinoxaline-2,3-dione) did not affect GSA-induced current. Evoked field potentials in CA1 region of rat hippocampal slices were completely abolished by GSA, and this effect was antagonized by NMDA receptor blockade. All data were consistent with selective agonist action of GSA upon the NMDA-type glutamate receptor. In view of the results presented here, it should be examined whether NMDA receptors contribute to the neurological complications of renal failure through GSA-induced inappropriate or excessive activation of NMDA receptors.

Regional distribution of the 5-HT innervation in the brain of normal and lurcher mice as revealed by [ 3H]citalopram quantitative autoradiography

The neurological cerebellar mutant lurcher is characterized by a primary degeneration of Purkinje cells as well as a retrograde secondary partial degeneration of cerebellar granule cells and inferior olivary neurons. Since serotonin (5-HT) has been implicated in the modulation of excitatory amino acid systems of the cerebellum, the 5-HT innervation of the normal and lurcher mice was examined by quantifying uptake sites using [ 3H]citalopram autoradiography, and by biochemical assays of the indoles 5-HT, 5-hydroxy- l-tryptophan and 5-hydroxyindole-3-acetic acid using high-performance liquid chromatography. Comparable results were found between [ 3H]citalopram binding and 5-HT tissue concentrations in different brain regions. The highest [ 3H]citalopram labelling was observed in defined structures of the mesencephalic and upper pontine regions, in limbic structures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling of uptake sites was documented in cerebellum and brainstem reticular formation. In lurcher mutants, the histology confirmed cell degeneration and the reduction in width, leading to 65%, 45% and 25% atrophies of total cerebellum, deep nuclei and inferior olivary nucleus, respectively. The [ 3H]citalopram labelling corrected for surface loss was 45% and 20% higher in cerebellar deep nuclei and red nucleus, respectively, but remained unchanged in the cerebellar cortex and inferior olivary nucleus. Moreover, higher labelling was found in nucleus raphe dorsalis, ventral tegmental area, inferior colliculus, locus coeruleus, pontine central grey and anterior thalamic nuclei, areas known to be part of cerebellar afferent and efferent systems. The present results indicate that in such pathological conditions as described for the lurcher mutant, the 5-HT system may modulate motor function not only at the level of the cerebellum, but also in other forebrain structures functionally related to the motor system.

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam.

Differential effects of the N-methyl- d-aspartate and non- N-methyl- d-aspartate receptors of the excitatory amino acids system on LH and FSH secretion. Its effects on the hypothalamic luteinizing hormone releasing hormone during maturation in male rats

The present experiments describe the effect of NMDA and kainate agonists of the NMDA and non-NMDA subtype of receptors respectively of the excitatory amino acids (EAAs) system in prepubertal (16 days of age) and peripubertal (30-day-old rats) male rats on the in vitro hypothalamic release of GnRH, and on the in vivo LH and FSH levels as well as the effect of testosterone on these effects. The addition of NMDA or kainate to the medium containing APOA-MBH areas significantly increased ( P < 0.01) the GnRH release as compared with the respective controls. The increase in GnRH release observed with kainate was significantly higher ( P < 0.01) than those observed with NMDA. NMDA administration increased significantly ( P < 0.01) serum LH levels at both ages of sexual maturation while no effect was observed by kainate administration. MK 801, an antagonist of NMDA neurotransmission, and testosterone abolished the LH release response to NMDA. Contrary to that observed on LH, while NMDA did not modify serum FSH concentrations a significant increase ( P < 0.01) was observed with kainate administration in prepubertal and peripubertal rats on this pituitary hormone, and CNQX, an antagonist of non-NMDA neurotransmission, and testosterone administrations blocked this FSH release effect of kainate. The NMDA and kainate release effect on LH and FSH respectively was'significantly higher in prepubertal than in peripubertal rats. At both ages NMDA released more LH than kainate FSH. In conclusion, our experiments demonstrated that both subtypes of glutamate receptors NMDA and non-NMDA subtypes of EAAs increased GnRH release by APOA-MBH in vitro during sexual maturation. Nevertheless, while NMDA administration only increased serum LH levels, kainate showed only an effect on increasing FSH concentrations. These differential effects of NMDA and non-NMDA subtypes of EAA receptors on LH and FSH could probably explain some aspects of the differential modifications of LH and FSH observed in different physiological circumstances.

The role of mesoprefrontal dopamine neurons in stress.

While several catecholaminergic systems are activated by stressful stimuli, the mesoprefrontal dopamine (DA) system appears to be particularly vulnerable to stress. Low intensity stressors that do not produce detectable effects in most ascending catecholaminergic systems activate mesoprefrontal DA neurons. Mesoprefrontal DA neurons are unique in that they lack or have decreased densities of specific autoreceptors affecting autoregulatory capabilities, which could contribute to the fact that mesoprefrontal DA neurons exhibit increased rates of burst firing and DA turnover relative to other midbrain dopaminergic projections. In addition, mesoprefrontal DA neurons are uniquely modulated by a number of chemically distinct afferent influences including gamma-aminobutyric acid (GABA), serotonin, excitatory amino acid, substance P, opiate, and noradrenergic systems. Any or all of these factors could contribute to the selective activation of mesoprefrontal DA neurons following exposure to low intensity stressors. The present review summarizes the possible mechanisms by which mesoprefrontal DA neurons are preferentially activated by stress. The operational significance of this unique neurochemical response to stress is discussed in terms of a possible coping versus anxiety function. Also discussed are the ramifications of a dysfunction of this system with respect to stress-related or exacerbated disorders such as post-traumatic stress disorder and schizophrenia.

The GABAergic control of gonadotropin-releasing hormone secretion in male rats during sexual maturation involves effects on hypothalamic excitatory and inhibitory amino acid systems.

In order to evaluate the possible participation of the hypothalamic excitatory and inhibitory amino acid neurotransmitter systems in the GnRH release response to GABAergic drugs, hypothalami (preoptic and mediobasal area) of immature (26 days of age) and adult male rats were perifused with GABA-A and -B agonists and antagonists. GnRH and amino acid neurotransmitter concentrations (glutamate, taurine, GABA) were measured in perfusate samples collected every 15 min during 150 min. In immature rats, muscimol and baclofen (GABA-A and GABA-B agonists, respectively) increased GnRH, glutamate and GABA release and decreased taurine output, while in adults these agonists showed opposite effects on GnRH and glutamate release, and increased GABA and taurine output. On the other hand, in immature rats bicuculline and phaclofen (GABA-A and GABA-B antagonists, respectively) decreased GnRH, glutamate and GABA release, increasing taurine outflow. In adult animals, these antagonists enhanced GnRH and glutamate release, decreasing taurine and GABA outflow. These results indicate that GABA stimulates GnRH release in immature male rats and confirm the inhibitory role of this amino acid neurotransmitter in adult animals. This effect might be associated, at least partially, with the modifications observed in the excitatory and inhibitory amino acid release. On the other hand, in immature rats, stimulation of GABA-A and GABA-B receptors increased GABA release. Although ultrastructural studies have not produced any evidence of GABA-GABA neurointeractions, our results suggest the existence of a positive feedback mechanism of GABA autoregulation active during the prepubertal stage. Participation of this mechanism in the onset of puberty cannot be discarded.

Hypothalamic excitatory amino acid system during sexual maturation in female rats.

The present results indicate that during sexual maturation the APOA-MBH from rats of 30 days of age released significantly higher quantities of GnRH than the tissue from 16-day-old rats (P < 0.01). The addition of NMDA, an agonist of the excitatory amino acids system (EAAs), to the medium after 30 min of incubation significantly increased (P < 0.01) the GnRH release in normal rats of both ages and this increase was significantly (P < 0.01) higher in 30-day-old rats (to 661%) than in rats of 16 days of age (to 273%). The administration of estrogen-progesterone (EP) to rats of 16 days of age did not modify the GnRH release response to NMDA. On the contrary, at 30 days of age EP administration significantly potentiated the GnRH release response to NMDA since while in the control group NMDA increased the GnRH release to 630%, in the EP-pretreated group this was to around 4700% (P < 0.01). EP pretreatment of prepubertal rats decreases the hypothalamic release of aspartate and glutamate, the excitatory amino acids involved in NMDA neurotransmission and glycine but increases EAAs release in peripubertal rats. On the basis of these results it is proposed that the increase in EAAs release by the hypothalamus is directly connected with the onset of puberty and that the maturation of the positive feedback effect of ovarian hormones on gonadotropin secretion is related to the maturation of the capacity of EP to increase hypothalamic EAAs. Before this maturational event EP inhibits EAAs release as well as gonadotropin release (prepubertal rats). NMDA receptor stimulation leads to a positive mechanism which increases the release of Asp and Glu from APOA-MBH both in prepubertal and peripubertal rats, but EP potentiates this mechanism only in peripubertal rats. This could be an additional neuroendocrine mechanism involved in the increase of gonadotropin during sexual maturation which induces the onset of puberty and the preovulatory discharge of these pituitary hormones.

Anxiogenic-like effect of glycine and d-serine microinjected into dorsal periaqueductal gray matter of rats

The glutamatergic system of the dorsal periaqueductal gray matter (DPAG) has been implicated in anxiety. This study shows that microinjections of glycine (GLY) or d-serine ( d-SER), into the DPAG of rats, dose-dependently reduced the number of entries and the time spent on open arms of an elevated plus-maze (EPM), an established animal model for measuring anxiety-related behavior. This anxiogenic-like effect was greatest following DPAG application of either 80 nmol GLY or 160 and 320 nmol d-SER. Microinjections of these same amino acid doses outside the DPAG, or of l-serine (320 nmol) inside the DPAG, produced neither of these pro-anxiety effects. The current results suggest that, in vivo, the GLY modulatory site of N-methyl- d-aspartate receptors is not fully saturated, and further substantiate a role for the DPAG excitatory amino acid system in anxiety.

An animal model of hypoxia-induced perinatal seizures.

Clinically, neonatal hypoxic encephalopathy is commonly associated with seizure activity. Here we describe a rodent model of cerebral hypoxia in which there is are age dependent effects of hypoxia, with hypoxia inducing seizure activity in the immature rat, but not in the adult. Global hypoxia (3-4% O2) induced acute seizure activity during a window of development between postnatal day (P5-17), peaking at P10-12. Animals which had been rendered hypoxic between P10-12 had long term decreases in seizure threshold, while animals exposed at younger (P5) or older (P60) ages did not. Antagonists of excitatory amino acid (EAA) transmission appear to be superior to benzodiazepines in suppressing the acute and long term effects of perinatal hypoxia, suggesting involvement of the EAA system in these phenomena. No significant histologic damage occurs in this model, suggesting that functional alterations take place in neurons when exposed to an hypoxic insult at a critical developmental stage. Future work is directed at evaluating molecular and cellular events underlying the permanent increase in seizure susceptibility produced by this model.

Effect of ovarian hormones on the hypothalamic excitatory amino acids system during sexual maturation in female rats.

The present experiments were designed to study in female rats during sexual maturation: (1) the hypothalamic release of aspartate (Asp), glutamate (Glu) and glycine (Gly) which are the excitatory amino acids (EAAs) involved in NMDA neurotransmission and of taurine (Tau), a putative inhibitory amino acid of GnRH secretion; (2) the relationships between the effect of estrogen-progesterone (EP) on the release of these EAAs and the secretion of gonadotropins, and (3) the effect of hypothalamic NMDA receptor stimulation on EAAs release by the hypothalamus as well as the effect of EP on this release. The release of EAAs by the anterior preoptic and medial-basal hypothalamic areas (APOA-MBH) is significantly higher in peripubertal than in prepubertal rats (p < 0.01). EP treatment in prepubertal rats (16 days of age) decreased LH and FSH plasmatic levels and also the in vitro release of Asp, Glu, Gly and Tau. Contrary to the observations in prepubertal rats, in 30-day-old peripubertal rats the ovarian hormones significantly (p < 0.01) increased the levels of LH and FSH as well as the release to the medium of these amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)