Excitatory Amino Acid Receptors Research Articles

Cardiovascular responses to microinjection of ATP into the nucleus tractus solitarii of awake rats.

Microinjection of increasing doses of ATP (0.31, 0.62, 1.25, and 2.5 nmol/50 nl) into the nucleus tractus solitarii (NTS) produced a dose-dependent pressor response. Prazosin abolished the pressor response and produced no change in the bradycardic response to ATP. Microinjection of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (0.25 nmol/50 nl), a nonselective P2 receptor antagonist into the NTS, reduced the bradycardic response but had no effect on the pressor response to microinjection of ATP (1.25 nmol/50 nl) into the NTS. Microinjection of suramin (2 nmol/50 nl), another nonselective P2 receptor antagonist, had no effect on the pressor and bradycardic responses to microinjection of ATP (1.25 nmol/50 nl) into the NTS. Antagonism of A1 receptors of adenosine with 1,3-dipropyl-8-cyclopentylxanthine also produced no changes in the cardiovascular responses to microinjection of ATP into the NTS. The involvement of excitatory amino acid (EAA) receptors in the pressor and bradycardic responses to microinjection of ATP into the NTS was also evaluated. Microinjection of kynurenic acid, a nonselective EAA receptor antagonist (10 nmol/50 nl), into the NTS reduced the bradycardic response and had no effect on the pressor response to microinjection of ATP into the NTS. The data show that 1) microinjection of ATP into the NTS of awake rats produced pressor and bradycardic responses by independent mechanisms, 2) the activation of parasympathetic component may involve an interaction of P2 and EAA receptors in the NTS, and 3) the sympathoexcitatory response to microinjection of ATP into the NTS was not affected by the blockade of P2, A1, or EAA receptors.

Rationale for and use of NMDA receptor antagonists in Parkinson's disease

N -Methyl- d -aspartate (NMDA) glutamate receptors are a class of excitatory amino acid receptors, which have several important functions in the motor circuits of the basal ganglia, and are viewed as important targets for the development of new drugs to prevent or treat Parkinson's disease (PD). NMDA receptors are ligand-gated ion channels composed of multiple subunits, each of which has distinct cellular and regional patterns of expression. They have complex regulatory properties, with both agonist and co-agonist binding sites and regulation by phosphorylation and protein-protein interactions. They are found in all of the structures of the basal ganglia, although the subunit composition in the various structures is different. NMDA receptors present in the striatum are crucial for dopamine-glutamate interactions. The abundance, structure, and function of striatal receptors are altered by the dopamine depletion and further modified by the pharmacological treatments used in PD. In animal models, NMDA receptor antagonists are effective antiparkinsonian agents and can reduce the complications of chronic dopaminergic therapy (wearing off and dyskinesias). Use of these agents in humans has been limited because of the adverse effects associated with nonselective blockade of NMDA receptor function, but the development of more potent and selective pharmaceuticals holds the promise of an important new therapeutic approach for PD.

Mechanisms of kainate-induced region-specific neuronal death in immature organotypic hippocampal slice cultures

Excessive activation of excitatory amino acid receptors has been implicated in neuronal death in a number of central nervous system insults. We have here investigated, the time course and mechanisms of kainate (KA)- induced neuronal death in immature organotypic hippocampal slice cultures (OHCs) using Fluoro-Jade B (FJB) staining as a marker of cell death, and immunoblotting, immunocytochemistry, and electron microscopy as methods to clarify the mechanisms. After 6 h KA treatment (5 μM), no significant neuronal death was detected in any hippocampal subregion, whereas the treatment of 12, 24, and 48 h resulted in neuronal death in the CA3 regions, but not in CA1. The 48 h resting period in normal medium after KA-treatment did not rescue the cells but further increased the number of dead neurons in CA3 as compared to the corresponding acute phase. In Western blotting, the expression levels of the active, 17 kDa form of caspase-3, and the 84–85 kDa cleaved fragment of poly(ADP ribose)polymerase (PARP) were not altered from the control levels. Moreover, no active caspase-3 labelled cells were detected in immunocytochemical study 24 h after KA treatment either in the acute or resting groups. Electron microscopy showed non-apoptotic injury in the CA3a/b pyramidal neurons in KA-treated slices. Our results suggest that KA-induced neuronal death in immature OHCs is a strictly region-specific, irreversible, necrotic process.

Electrophysiological characterisations of rat lamina I dorsal horn neurones and the involvement of excitatory amino acid receptors

Lamina I of the spinal cord plays a key role in sensory transmission between afferent activity and the CNS. Studies have shown lamina I neurones to have distinct response properties compared to deep dorsal horn neurones, but little is known regarding excitatory amino acid mechanisms in their responses. Spinal electrophysiological recordings of lamina I neurones confirmed that the majority of these neurones (74%) are nociceptive specific (NS) in their responses, of which 18% can be termed polymodal nociceptive (HPC) (13% of the total population). The remainder (26%) were wide dynamic range. Lamina I neurones had smaller mechanical and heat-evoked responses compared to deeper dorsal horn neurones. The electrically evoked responses were also smaller, with a distinct lack of an NMDA-mediated ‘wind-up’ effect. NBQX (AMPA receptor antagonist, 0.5, 5, 50 μg/50 μl) produced dose-dependent inhibitions of the electrically evoked neuronal responses, but APV (NMDA receptor antagonist, 50, 100, 500 μg/50 μl) had minimal effects on their responses. These results implicate mainly AMPA receptors in the responses of lamina I neurones. Bicuculline (GABA A receptor antagonist, 0.5, 5, 50 μg/50 μl) demonstrated a role exerted by GABA A receptors in the control of A-δ fibre-mediated mechanical responses in lamina I. Overall, this study describes a high threshold, AMPA receptor possessing population of lamina I neurones, which seem to lack functional NMDA receptors, and are partially controlled by GABA A receptor activity.

Modèles de sensibilisation comportementale et troubles psychiques : aspects actuels

Behavioral sensitization is a preclinical model which can be defined as an augmentation in the behavioral effect of a psychostimulant upon re-administration. It has two phases, induction and expression. Induction refers to the transient sequence of events precipitated by psychostimulant administration that leads to the enduring changes in neural functions responsible for behavioral augmentation. Expression corresponds to the enduring neural alterations arising from the induction process that directly mediate the augmented behavorial response. These two processes are not only temporally but also anatomically and biochemically distinct. Induction seems to require the stimulation of dopamine D1 receptors in the ventral tegmental area (VTA) either directly by dopamine (DA) agonists, or indirectly via GABAergic inhibition; the stimulation of excitatory amino acid (EEA) receptor in the VTA, the amygdala and the hippocampus may also have a central role in the induction process. Contrary to its induction the expression of sensitization depends on the stimulation of the DA terminal fields and appears to be D2 mediated, whereas GABA and EEA do not seem to play a role. These processes result in an enhanced DA efflux induced by repeated exposure to stimulants. At least three different subcellular cascades have been involved in the molecular mechanisms of sensitization. Activation of these cascades induce changes in expression of neuritogenesis and synaptogenesis genes and remodelling of neural networks. First used to conceptualize various aspects of the course of affective disorders, behavioral sensitization models have been recently applied to the pathophysiology of schizophrenia, as a consequence of a better understanding of their neurobiologic underpinnings. Other psychiatric syndroms such as anxious disorders and drug addiction have been concerned too. Behavioral sensitization helps understand syndrome progression manifested by either increasing frequency, severity or spontaneity of psychiatric episodes, as well as the deteriorative course of some psychotic illnesses since sensitization, if sustained can lead to potential neurotoxic effects producing structural alterations. This model has found many applications in the psychopharmacological domain. Repeated application of stimulants either parenterally or directly into the brain may also produce a progressive increase in neural excitability, eventually producing major motor seizures in response to a previously subthreshold dose of drug. This could explain why anticonvulsants may be effective in psychiatric disorders in which behavioral sensitization is deemed to be involved. Recent data show that drugs like valproate are not only useful for treating affective illness but are also efficient in schizophrenia and anxious disorders. Contrary to lithium, valproate appears to prevent not only the induction but also the expression of behavioral sensitization in rodents. Drugs like olanzapine have, in addition to their D2 blockade effect, the capacity to block D1 receptors which may be linked to their antimanic and mood stabilising properties, considering the role of D1 receptors in the induction of sensitization phenomena. It is also possible that 5HT2 blockade play a role in this respect, as these receptors have been involved too in the development of behavioral sensitization. Finally the model allows specific predictions about the course of some psychiatric illnesses and particularly regarding the fact that treatment intervention that limit duration and number of psychiatric episodes may prevent progression of brain pathology. However such hypotheses have still to be tested through futures studies.

Integrative neurobiology of the alcohol withdrawal syndrome--from anxiety to seizures.

This article represents the proceedings of a symposium presented at the 2003 Research Society on Alcoholism meeting in Ft. Lauderdale, Florida, organized and chaired by Carl L. Faingold. The presentations were (1) Overview, by Carl L. Faingold; (2) Stress, Multiple Alcohol Withdrawals, and Anxiety, by Darin Knapp; (3) Relationship Between Genetic Differences in Alcohol Drinking and Alcohol Withdrawal, by Julia Chester; (4) Neuronal Mechanisms in the Network for Alcohol Withdrawal Seizures: Modulation by Excitatory Amino Acid Receptors, by Carl L. Faingold; and (5) Treatment of Acute Alcohol Withdrawal and Long-Lasting Alterations in Hippocampal Neuronal Networks, by Larry P. Gonzalez. The presentations emphasized the importance of using intact behaving animals to advance the understanding of the human alcohol withdrawal syndrome. This involves applying and amplifying the neurophysiological and neurotransmitter findings observed in vitro to the network-based neurobiological mechanisms that are involved in several important aspects of the specific behaviors observed clinically. The symposium provided evidence that the organizational aspects of neuronal networks in the intact nervous system add another nexus for the action of alcohol and drugs to treat alcohol withdrawal that may not be readily studied in isolated neural elements used in in vitro approaches.

Intrauterine infection/inflammation during pregnancy and offspring brain damages: Possible mechanisms involved

Intrauterine infection is considered as one of the major maternal insults during pregnancy. Intrauterine infection during pregnancy could lead to brain damage of the developmental fetus and offspring. Effects on the fetal, newborn, and adult central nervous system (CNS) may include signs of neurological problems, developmental abnormalities and delays, and intellectual deficits. However, the mechanisms or pathophysiology that leads to permanent brain damage during development are complex and not fully understood. This damage may affect morphogenic and behavioral phenotypes of the developed offspring, and that mice brain damage could be mediated through a final common pathway, which includes over-stimulation of excitatory amino acid receptor, over-production of vascularization/angiogenesis, pro-inflammatory cytokines, neurotrophic factors and apoptotic-inducing factors.

Excitatory aminoacids and epileptic seizures in immature brain

Data on convulsant and anticonvulsant action of drugs influencing excitatory amino acid receptors in developing rats are reviewed. Agonists of NMDA type of receptors NMDA and homocysteic acid, elicited an age-related seizure pattern--flexion, emprosthotonic seizures--in the first three postnatal weeks of rats. Generalized clonic-tonic seizures appeared only after a longer latency. Kainic acid administration resulted in epileptic automatisms and later in minimal, clonic seizures followed by generalized tonic-clonic seizures. A decrease of sensitivity to convulsant action with age is a general rule for all agonists tested. Different anticonvulsant action of NMDA and nonNMDA antagonists was demonstrated in a model of generalized tonic-clonic seizures induced by pentetrazol, whereas their action against epileptic afterdischarges elicited by electrical stimulation of cerebral cortex was similar. Again, higher efficacy in younger animals was a rule. As far as metabotropic glutamate receptors are concerned, agonists of groups II and III were shown to protect against convulsant action of homocysteic acid in immature rats and an antagonist of group I receptors MPEP suppressed the tonic phase of generalized tonic-clonic seizures induced by pentetrazol more efficiently in younger than in more mature rat pups. Unfortunately, a higher sensitivity to the action of antagonists of ionotropic glutamate receptors was demonstrated also for unwanted side effects (motor functions were compromized). In contrast, glutamate metabotropic receptor antagonist MPEP did not exhibit any serious side effects in rat pups.

Neuropathic pain: drug targets for current and future interventions.

Nociceptive pain alerts the body to potential or actual tissue damage. By contrast, neuropathic pain, which results from injury or damage to the nervous system, persists long after all signs of the original injury have disappeared. This type of maladaptive pain presents a significant clinical problem, as it responds poorly or unpredictably to classical analgesics. There is also no single, uniformly well-tolerated drug that is reliably helpful. Current understanding of the etiology of neuropathic pain reveals seven potential targets for therapeutic intervention. These are: 1) ectopic activity in damaged peripheral nerves; 2) increased excitability in spinal dorsal horn neurons; 3) restoration or augmentation of GABAergic inhibition in the dorsal horn; 4) supraspinal and affective mechanisms; 5) alterations in the sympathetic nervous system; 6) spinal peptidergic mechanisms; and 7) spinal excitatory amino acid receptors. Current therapeutic approaches, using drugs such as gabapentin, anticonvulsants, ketamine or methadone, and potential new approaches are discussed in the context of these seven drug targets.

The neuroactive steroid 3-α-ol-5-β-pregnan-20-one hemisuccinate, a selective NMDA receptor antagonist improves behavioral performance following spinal cord ischemia

The initial response to an ischemic event is the rapid release of excitatory amino acid's followed by the activation of the “ischemic cascade”. It has been suggested that neurosteroids, which act as negative modulators of excitatory amino acid receptors, may improve behavioral functions and promote neuronal survival following ischemia. The present study evaluated the pharmacological effects of 3-α-ol-5-β-pregnan-20-one hemisuccinate (ABHS), a neurosteroid that inhibits excitatory amino acid receptor function, in a rabbit reversible spinal cord ischemia model (RSCIM). ABHS was administered (25 mg/kg) intravenously (i.v.) 5 or 30 min following the start of occlusion to groups of rabbits exposed to ischemia induced by temporary occlusion of the infrarenal aorta. The group P 50 represents the duration of ischemia (min) associated with a 50% probability of resultant permanent paraplegia. Quantal analysis indicated that the P 50 of the control group was 23.44±4.32 min. Using the RSCIM, neuroprotection is observed if a drug significantly prolongs the P 50 compared to the control group. Treatment with ABHS (25 mg/kg) 5 min post-occlusion significantly ( p<0.05) prolonged the P 50 of the group to 49.18±10.44 min, an increase of 110%. The effect of ABHS was not durable following a single injection since a significant difference between the control and ABHS-treated groups was not measurable at 48 h. However, if ABHS was injected 5 min following the start of ischemia and again 24 h after ischemia, there was a persistent effect of the drug at 48 h. Moreover, ABHS also increased the tolerance to ischemia if administered 30 min following the start of occlusion. Our results suggest that neuroactive steroids such as ABHS, which are selective NMDA receptor antagonists, may have substantial therapeutic benefit for the treatment of ischemic injuries including spinal cord neurodegeneration and stroke.

Ionotropic excitatory amino acid receptors in pre-Botzinger complex play a modulatory role in hypoxia-induced gasping in vivo.

Activation of ionotropic excitatory amino acid (EAA) receptors in pre-Bötzinger complex (pre-BötC) not only influences the eupneic pattern of phrenic motor output but also modifies hypoxia-induced gasping in vivo by increasing gasp frequency. Although ionotropic EAA receptor activation in this region appears to be required for the generation of eupneic breathing, it remains to be determined whether similar activation is necessary for the production and/or expression of hypoxia-induced gasping. Therefore, we examined the effects of severe brain hypoxia before and after blockade of ionotropic EAA receptors in the pre-BötC in eight chloralose-anesthetized, deafferented, mechanically ventilated cats. In each experiment, before blockade of ionotropic EAA receptors in the pre-BötC, severe brain hypoxia (6% O2 in a balance of N2 for 3-6 min) produced gasping. Although bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (20-100 mM; 40 nl) into the pre-BötC eliminated basal phrenic nerve discharge, severe brain hypoxia still produced gasping. Under these conditions, however, the onset latency to gasping was increased (P < 0.05), the number of gasps was reduced for the same duration of hypoxic gas exposure (P < 0.05), the duration of gasps was prolonged (P < 0.05), and the duration between gasps was increased (P < 0.05). These findings demonstrate that hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in the pre-BötC, but ionotropic EAA receptor activation in this region may modify the expression of the hypoxia-induced response. The present findings also provide additional support for the pre-BötC as the primary locus of respiratory rhythm generation.

Glutamate and depression: clinical and preclinical studies.

The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical models. Moreover, antidepressant-like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants.

Motor coordination in mice with hotfoot, Lurcher, and double mutations of the Grid2 gene encoding the delta-2 excitatory amino acid receptor

Grid2 ho/ho is a loss of function gene mutation resulting in abnormal dendritic arborizations of Purkinje cells. These mutants were compared in a series of motor coordination tests requiring balance and equilibrium to nonataxic controls ( Grid2 ho/+ ) and to a double mutant ( Grid2 ho/Lc ) with an inserted Lc mutation. The performance of Grid2 ho/ho mutant mice was poorer than that of controls on stationary beam, coat hanger, unsteady platform, and rotorod tests. Grid2 ho/Lc did not differ from Grid2 Lc/+ mice. However, the insertion of the Lc mutation in Grid2 ho/Lc potentiated the deficits found in Grid2 ho/ho in stationary beam, unsteady platform, and rotorod tests. These results indicate a deleterious effect of the Lc mutation on Grid2-deficient mice.

Excitatory amino acid receptors in the dorsomedial hypothalamus mediate prostaglandin-evoked thermogenesis in brown adipose tissue.

We determined whether the dorsomedial hypothalamus (DMH) plays a role in the thermogenic, metabolic, and cardiovascular effects evoked by centrally administered PGE2. Microinjection of PGE2 (170 pmol/60 nl) into the medial preoptic area of the hypothalamus in urethane-chloralose-anesthetized, artificially ventilated rats increased brown adipose tissue (BAT) sympathetic nerve activity (SNA; +207 +/- 18% of control), BAT temperature (1.5 +/- 0.2 degrees C), expired CO2 (0.9 +/- 0.1%), heart rate (HR; 106 +/- 12 beats/min), and mean arterial pressure (22 +/- 4 mmHg). Within 5 min of subsequent bilateral microinjections of the GABAA receptor agonist muscimol (120 pmol.60 nl-1.side-1) or the ionotropic excitatory amino acid antagonist kynurenate (6 nmol.60 nl-1.side-1) into the DMH, the PGE2-evoked increases were, respectively, attenuated by 91 +/- 3% and 108 +/- 7% for BAT SNA, by 73 +/- 12% and 102 +/- 28% for BAT temperature, by 100 +/- 4% and 125 +/- 21% for expired CO2, by 72 +/- 11% and 70 +/- 16% for HR, and by 84 +/- 19% and 113 +/- 16% for mean arterial pressure. Microinjections outside the DMH within the dorsal hypothalamic area adjacent to the mamillothalamic tracts or within the ventromedial hypothalamus were less effective for attenuating the PGE2-evoked thermogenic, metabolic, and cardiovascular responses. These results demonstrate that activation of excitatory amino acid receptors within the DMH is necessary for the thermogenic, metabolic, and cardiovascular responses evoked by microinjection of PGE2 into the medial preoptic area.

Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis

To investigate the role of excitatory amino acid neurotransmission within the rostral raphe pallidus area (RPa) in thermogenic and cardiovascular responses, changes in sympathetic nerve activity to brown adipose tissue (BAT), BAT temperature, expired CO 2, arterial pressure, and heart rate were recorded after microinjection of excitatory amino acid (EAA) receptor agonists into the RPa in urethan-chloralose-anesthetized, ventilated rats. To determine whether EAA neurotransmission within the RPa is necessary for the responses evoked by disinhibition of the RPa or by prostaglandin E 2 acting within the medial preoptic area, BAT sympathetic nerve activity, BAT temperature, expired CO 2, arterial pressure, and heart rate were measured during these treatments both before and after blockade of EAA receptors within the RPa. Microinjection of EAA receptor agonists into the RPa resulted in significant increases in all measured variables; these increases were attenuated by prior microinjection of the respective EAA receptor antagonists into the RPa. Microinjection of prostaglandin E 2 into the medial preoptic area or microinjection of bicuculline into the RPa resulted in respective significant increases in BAT sympathetic nerve activity (+approximately 190% and +approximately 235% of resting levels), in BAT temperature (approximately 1.8 °C and approximately 2 °C), in expired CO 2 (approximately 1.1% and approximately 1.1%), and in heart rate (approximately 97 beats per minute (bpm) and approximately 100 bpm). Blockade of ionotropic EAA receptors within the RPa by microinjection of kynurenate completely reversed the prostaglandin E 2 or bicuculline-evoked increases in all of the measured variables. Blockade of either N-methyl- d-aspartate (NMDA) receptors or non-NMDA receptors alone resulted in marked attenuations of the prostaglandin E 2-evoked effects on all of the measured variables. These data demonstrate that activation of an EAA input to the RPa is necessary for the BAT thermogenic and the cardiovascular effects resulting from the actions of prostaglandin E 2 within the medial preoptic area or from the disinhibition of local neurons in the RPa.

MGluRs: a target for pharmacotherapy in Parkinson disease

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled excitatory amino acid (glutamate) receptors and are abundantly expressed in basal ganglia nuclei. We used behavioral, regional glucose uptake metabolic mapping, and FOS protein expression to examine the effects of stimulating striatal and subthalamic mGluRs in rats. Stimulation of striatal Group I mGluRs produced behavioral effects mediated by polysynaptic activation of subthalamic neurons. Stimulation of subthalamic Group II mGluRs produced similar effects. Excessive activity of subthalamic neurons is a key feature of parkinsonism. mGluR Group I or Group II antagonists may prove to be useful for symptomatic treatment of parkinsonism. Stimulation of Group III mGluRs produced behavioral effects in only 6-hydroxydopamine-lesioned animals. Regional glucose uptake metabolic mapping and FOS expression studies suggested that striatal dopamine denervation produced increased sensitivity of Group III mGluRs. Agents active at Group III mGluRs may also be useful for treatment of parkinsonism.

Epileptiform synchronization in the human dysplastic cortex

Taylor's focal cortical dysplasia corresponds to a localized disruption of the normal cortical lamination with an excess of large, aberrant cells. Sustained epileptic discharges originate from the dysplastic neocortex and this tissue retains sufficient connectivity for expressing seizure abnormalities. In this brief review, we summarize the findings obtained by analyzing surgicallyresected human tissue with focal cortical dysplasia that was maintained in vitro in a brain slice preparation. These data have been compared with those obtained from human cortex with normal structural organization; such tissue was available from patients undergoing surgery for a variety of neurological disorders, most often for mesial temporal lobe epilepsy. These studies have shown that: (i) slices obtained from focal cortical dysplastic tissue have an intrinsic ability to generate ictal‐like epileptiform events when challenged with the convulsant drug 4‐aminopyridine; (ii) 4‐aminopyridine‐induced ictal discharges are not seen in neocortical slices obtained from neocortical samples with no or minimal structural lesion; (iii) these ictal discharges are caused by the activation of excitatory amino acid receptors, and in particular those of the N‐methyl‐D aspartate type; (iv) focal cortical dysplastic tissue also generates synchronous potentials that are mainly contributed by GABA A receptormediated conductances.

Effect of systemic administration of L-kynurenine on corticocerebral blood flow under normal and ischemic conditions of the brain in conscious rabbits.

Kynurenic acid, the only known endogenous antagonist of the excitatory amino acid receptors, exerts neuroprotective effect in focal cerebral ischemia. Kynurenic acid poorly while its bioprecursor, l-kynurenine (L-KYN) completely crosses the blood-brain barrier. The aim of our study was to investigate the effect of intravenous l-KYN (0.3, 1, and 3 mg/kg) on the normal and the unilateral carotid artery occlusion induced ischemic corticocerebral blood flow (cCBF) measured by hydrogen polarography in conscious rabbits. Administration of l-KYN produced a significant increase in the normal cCBF; the peak values were recorded at the dose of 1 mg/kg (187% at 120 and 150 mins. respectively). The cCBF-improving effect of l-KYN was immediate and highly pronounced also in rabbits with carotid occlusion (peak value was 192% at 120 mins. at the dose of 1 mg/kg). Pretreatment with either atropine or Nomega-nitro-L-arginine-methyl-ester (L-NAME) prevented the l-KYN induced enhancement of the normal and the ischemic cCBF alike. It is suggested that the cCBF-increasing effect of l-KYN might be mediated by activation of cholinergic and nitric oxide pathways.

Effect of excitatory amino acid receptor agonists on penile erection after administration into paraventricular nucleus of hypothalamus in the rat

ObjectivesTo investigate whether the excitatory amino acid receptor agonists can activate the paraventricular nucleus of the hypothalamus (PVN) and induce penile erections in the rat. MethodsMale adult Sprague-Dawley rats were used. A 26-gauge needle was inserted into the corpus cavernosum to monitor the intracavernous pressure (ICP) simultaneously with the systemic arterial pressure and heart rate. The study was divided into seven parts: stereotaxic delivery of N-methyl-d-aspartic acid (NMDA) (50 ng/500 nL) into the PVN; administration of the NMDA noncompetitive antagonist MK-801 (100 ng/250 nL) and NMDA (50 ng/250 nL) into the PVN; administration of the NMDA competitive antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 100 ng/250 nL) and NMDA (50 ng/250 nL) into the PVN; microinjection of (±)-α-(amino)-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA; 100 ng/500 nL) into the PVN; microinjection of trans-(±)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD; 100 ng/500 nL) into the PVN; saline 500 nL into the PVN; and intracavernous administration of NMDA (50 ng/100 μL). ResultsOn administration of NMDA into the PVN, a significant increase occurred in the ICP from a resting 8.3 ± 1.8 mm Hg to a peak at 59.0 ± 8.4 mm Hg. No change occurred in the resting ICP after administration of either the mixture of MK-801 and NMDA or CPP and NMDA into the PVN. Microinjection of AMPA, ACPD, or saline into the PVN and intracavernous administration of NMDA were all ineffective to induce an increase in ICP. ConclusionsThe results of this study suggest that ionotropic excitatory amino acid (NMDA) may have an effect on inducing penile erection through activation of the PVN in the rat.

Sympathoexcitation by PVN-injected bicuculline requires activation of excitatory amino acid receptors.

Acute blockade of gamma-aminobutyric acid (GABA)-A receptors in the hypothalamic paraventricular nucleus (PVN) increases mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). However, the underlying neural mechanisms have not been fully determined. We tested the hypothesis that responses to GABA-A receptor blockade in the PVN require activation of local ionotropic excitatory amino acid (EAA) receptors. MAP, HR, and renal SNA responses to unilateral PVN microinjection of bicuculline methobromide (BIC, 0.1 nmol) were recorded before and after ipsilateral PVN injection of either vehicle (saline), the nonselective ionotropic EAA receptor antagonist kynurenate (KYN), the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5), or the non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX). Responses to PVN-injected BIC were unaltered by vehicle injection. In contrast, injection of KYN (7.2 nmol; n=4) nearly abolished ABP and renal SNA responses to BIC (P<0.01) and significantly attenuated (P<0.05) HR responses as well. Similarly, graded doses of AP5 (0.6, 3, and 6 nmol) and NBQX (0.26, 1.3, and 2.6 nmol) reduced responses to PVN-injected BIC in a dose-related manner, with the 3 nmol (n=7) and 1.3 nmol (n=6) doses producing maximal effects (P<0.05). KYN, AP5, and NBQX did not affect baseline parameters. Effects of a cocktail containing AP5 (3 nmol) and NBQX (1.3 nmol) were greater (P<0.01) than either antagonist alone and were not statistically different from KYN. These data indicate that cardiovascular and renal sympathetic responses to acute GABA-A receptor blockade in the PVN require local actions of EAAs at both NMDA and non-NMDA receptors.