Effects of hypomagnesia on histamine H1 receptor-mediated facilitation of NMDA responses.

1. The ability of histamine to facilitate the N-methyl-D-aspartate (NMDA) induced depolarization of cortical projection neurones was examined by use of grease-gap recording. 2. Histamine (1 to 15 microM) reversibly facilitated the NMDA-induced depolarization yielding a bellshaped concentration-response relationship. The peak enhancement was 167% above the control at 10 microM histamine. Desensitization was present in 4 out of 5 slices on second exposure 40 min following the first exposure. 3. Histamine did not alter the depolarization induced by 10 microM kainate. 4. The histamine-induced facilitation persisted in the presence of tetrodotoxin, but was reduced in a concentration-dependent manner by diphenhydramine (IC50 = 7.6 nM). Cyproheptadine (10 nM) also reduced the facilitation, whereas ranitidine (200 nM) and thioperamide (10 nM) were ineffective in this regard. 5. Histamine (10 microM) facilitated the NMDA (25 microM)-induced depolarization in nominally Mg(2+)-free medium. The magnitude of the facilitation was smaller than that observed in Mg(2+)-containing medium (17% above the control) and desensitization was not observed. This facilitation was not reduced by cyproheptadine (10 nM) or diphenhydramine (1 microM). 6. We conclude that histamine facilitates the NMDA depolarization at cortical neurones via two distinct mechanisms. One mechanism involves activation of the histamine H1 receptor and is sensitive to Mg2+. The second mechanism is independent of histamine cell surface receptor activation and may reflect a direct action of histamine at the NMDA receptor.

Fictive oesophageal peristalsis evoked by activation of muscarinic acetylcholine receptors in rat nucleus tractus solitarii.

The aim of the present study was to determine if muscarinic acetylcholine receptor-mediated peristaltic rhythmogenesis in the rat oesophagus is a central motor program that can be generated without peripheral sensory support. In anaesthetized male Sprague-Dawley rats, pressure-ejection of glutamate (10-20 pmol) and muscarine (5-10 pmol) in the sub-nucleus centralis of the nucleus tractus solitarii (NTSC) evoked monophasic pressure waves and rhythmic oesophageal peristalsis, respectively, but did not change mean arterial blood pressure or respiration. Application of muscarine (50-100 pmol) to the NTS extraventricular surface evoked rhythmic multi-unit burst discharges in the compact formation of the nucleus ambiguus (AMBC) that led to oesophageal peristalsis in a phase-locked manner. Evoked rhythmic AMBC activity persisted during neuromuscular blockade with curare, although the peak frequency of individual bursts was decreased. In a brainstem slice preparation, intracellular and whole cell patch recordings from AMBC neurones during focal stimulation of the NTSC region with muscarine revealed rhythmic depolarizing waves that showed a pattern similar to that of rhythmic oesophageal peristalsis. The present findings support the concept that medullary circuits comprising premotor neurones of the NTSC are intrinsically capable of generating rhythmic oesophagomotor output, but are subject to a powerful modulation by peripheral sensory feedback.

Action of 5-hydroxytryptamine in facilitating N-methyl-D-aspartate depolarization of cortical neurones mimicked by calcimycin, cyclopiazonic acid and thapsigargin.

1. The ability of calcimycin, cyclopiazonic acid and thapsigargin to facilitate the N-methyl-D-aspartate (NMDA)-mediated depolarization of cortical projection neurones was investigated by use of grease-gap recording and the results compared with the facilitation that results from activation of 5-hydroxytryptamine2A receptors. 2. Calcimycin (0.25 to 3 microM), cyclopiazonic acid (5 to 30 microM), and thapsigargin (10 to 300 nM) reversibly facilitated the NMDA (50 microM)-induced depolarization in the presence of tetrodotoxin. The concentration-response relationships were bell-shaped with a mean enhancement of 550% for calcimycin (1 microM) and approximately 400% for cyclopiazonic acid (20 microM) and thapsigargin (100 nM). At the highest concentration of each agent tested, no facilitation was observed. 3. Chlorpromazine (1 microM) partially restored a facilitation at 3 microM calcimycin and 300 nM thapsigargin. Myo-inositol (10 mM) and 100 nM staurosporine were both ineffective in this regard. 4. The depolarization elicited by 10 microM quisqualate or 5 microM kainate was not facilitated by 10 microM cyclopiazonic acid. 5. Calcimycin (0.5 microM), cyclopiazonic acid (20 microM), and thapsigargin (100 nM) elicited a significant facilitation in the presence of an antagonist cocktail consisting of D,L-2-amino-3-phosphonopropionic acid, prazosin, ritanserin, and scopolamine, although the magnitude of the facilitation was reduced. 6. Facilitation of the NMDA depolarization elicited by both 30 microM 5-hydroxytryptamine and 10 microM phenylephrine was eliminated in nominally Mg(2+)-free medium. In contrast, the facilitation induced by 0.5 microM calcimycin remained intact. 7. Bis-(o-aminophenoxy)-ethane-N,N,N,N, tetraacetic acid aminoethoxy (50 microM) or perfusion with nominally Ca(2+)-free medium eliminated facilitation of the NMDA depolarization induced by 30 microM 5-hydroxytryptamine and 100 nM thapsigargin. 8. The facilitation induced by both 30 microM 5-hydroxytryptamine and 1 microM calcimycin was reduced in a concentration-dependent manner by nifedipine (1 to 10 microM). 9. Calcimycin, cyclopiazonic acid and thapsigargin facilitate the NMDA depolarization in a manner which closely mimics the facilitation induced by 5-hydroxytryptamine. It is concluded that enhancement of the NMDA depolarization at cortical projection neurones results from an elevation of Ca2+ in the cytosol and that several sources of Ca2+ contribute to the facilitation.

Characterization of metabotropic glutamate receptor-mediated facilitation of N-methyl-D-aspartate depolarization of neocortical neurones.

1. Facilitation of the N-methyl-D-aspartate (NMDA) receptor-mediated depolarization of cortical neurones induced by metabotropic glutamate receptor (mGluR) agonists in the presence of tetrodotoxin has been examined by use of grease-gap recording. 2. Quisqualate (1-2 microM) and 10 to 100 microM 1S,3R-I-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) facilitated the NMDA-, but not the kainate-induced depolarization with an EC50 of 16 microM for 1S,3R-ACPD. The facilitation induced by quisqualate was reduced, but not blocked, by 4 microM 6-cyano-7-nitroquinoxaline-2,3-dione. 3. D,L-2-Amino-3-phosphonopropionic acid and D,L-2-amino-4-phosphonobutyric acid antagonized the 1S,3R-ACPD facilitation in a non-competitive manner with IC50 values of 0.24 microM and 4.4 microM respectively. 4. Homologous desensitization of the 1S,3R-ACPD induced facilitation was not observed. The facilitation was not altered by 10 nM staurosporine or 3 microM phorbol diacetate. 5. Substitution of 20 microM 8-bromo-cyclic adenosine monophosphate, 20 microM 8-bromo-cyclic guanosine monophosphate, or 10 microM arachidonic acid for 1S,3R-ACPD did not induce facilitation of the NMDA response. However, the 1S,3R-ACPD facilitation was potentiated by 10 mM myo-inositol and exhibited heterologous desensitization following exposure to 100 microM 5-hydroxytryptamine. 6. The 1S,3R-ACPD-induced facilitation persisted in both 10 microM nifedipine and nominally Ca(2+)-free medium and was only gradually eliminated following addition of 100 microM bis-(-o-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid in Ca(2+)-free medium. Facilitation of the NMDA response induced by carbachol, but not phenylephrine, was also observed in nominally Ca(2+)-free medium. Perfusing 50 microM bis-(-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid aminoethoxy eliminated the 1S,3R-ACPD facilitation. 7. These experiments have shown that mGluR agonists selectively facilitate the NMDA depolarization of cortical wedges, most likely by activating one or more mGluR subtypes that couple to phospholipase C. We conclude the facilitation results from a Ca(2+)-sensitive mechanism dependent on activation of phospholipase C and release of internal Ca2+. The facilitation is not contingent on activation of protein kinase C or entry of Ca2+ through nifedipine-sensitive Ca2+ channels.

Ca2+ mobilizing agents mimic serotonin 5-HT2A facilitation of N-methyl-D-aspartate depolarization.

Serotonin activation of 5-HT2A receptors facilitates depolarization of neocortical neurons by N-methyl-D-aspartate (NMDA). Using grease-gap recordings from an in vitro cortical wedge preparation we have examined whether agents which raise the concentration of intracellular Ca2+ mimic the facilitation. Perfusing A23187, cyclopiazonic acid or thapsigargin selectively facilitate the NMDA depolarization of cortical neurons in a concentration-dependent manner. Buffering intracellular Ca2+ by perfusing BAPTA-AM eliminates the serotonin, cyclopiazonic acid and thapsigargin induced facilitation. We conclude that a rise in intracellular Ca2+ is both necessary and sufficient to account for facilitating the NMDA depolarization following activation of 5-HT2A receptors.

Loss of cortical serotonin2A signal transduction in senescent rats: reversal following inhibition of protein kinase C.

Using grease gap recordings, age-related changes in serotonin2A receptors were assessed in sensorimotor regions of the cortex by examining serotonin-induced facilitation of the N-methyl-D-aspartate depolarization in cortical wedges prepared from young adult (3-6 months) and senescent (22-34 months) Fisher 344 rats. Serotonin (10-100 microM) facilitated the N-methyl-D-aspartate depolarization in wedges from young adult rats in a concentration-dependent manner, whereas no facilitation was observed in wedges from senescent rats. Similar results were obtained when +/- 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, a mixed serotonin2A and serotonin2C receptor agonist, was substituted for serotonin. In contrast, agonists at alpha 1A-adrenoceptors, metabotropic glutamate receptors and muscarinic cholinoceptors facilitated the N-methyl-D-aspartate depolarization in wedges from both young adult and senescent rats. Chelerythrine and staurosporine, inhibitors of protein kinase C, but not concanavalin A, myo-inositol or calmodulin antagonists, restored the serotonin facilitation in wedges from senescent animals. In situ hybridization histochemistry revealed that serotonin2A receptor messenger RNA was present in layers II-VI of the cortex, with the highest density of silver grains located in layers III and V of both young adult and senescent rats. Detailed examination of layer V showed that silver grains were significantly higher than background only over pyramidal cells. We conclude that serotonin2A receptors are expressed by pyramidal cells in both young adult and senescent rats and that serotonin acts directly on these receptors to facilitate the N-methyl-D-aspartate depolarization. Moreover, in senescent rats, signal transduction at cortical serotonin2A receptors involved with facilitation of the N-methyl-D-aspartate response is compromised as a result of protein kinase C activation.

[Morphine blocked the exitatory amino acid mediated membrane current in ambigual motoneurons of the rat].

Excitatory postsynaptic potentials (EPSPs) and responses of neurons in the compact formation of the neucleus ambiguus (AMBc) to pressure-ejected or bath-applied test substances were recorded intracellularly from sagittal slices of Sprague-Dawley rat medulla containing subnucleus centralis of solitary complex (NTSc), AMBc and solitarioambigual pathway. In 5 cells, recorded spontaneous EPSPs could be blocked by morphine (3-5 pmol) to AMBc. Electrical stimulation of NTSc evoked EPSPs in AMBc neurons, the amplitude of which were decreased to 71.1 +/- 6.2% (P < 0.001) with the addition to morphine. The morphine effect could be abolished by bath-applied naloxone (50 nmol/L). The amplitude of membrane depolarization induced by pressure-ejected N-methyl-D-aspartate (NMDA, 0.5-1.0 pmol), acetylcholine (3 pmol) and quisqualate (0.1-0.5 pmol) to NTSc could also be decreased by bath-applied morphine (10 mumol/L) respectively to 38.1 +/- 5.7% (P < 0.001), 32.8 +/- 5.5% (P < 0.01) and 29.6 +/- 7.1% (P < 0.05). The above results suggest that morphine is capable of block by NMDA, ACh and non-NMDA receptors, increaseing the M-current and decreasing the permeability of Na+ and Ca2+.

Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization.

The effect of myo-inositol was examined on 5-HT2 receptor mediated facilitation of NMDA depolarization of rat neocortical neurons in vitro. Myo-inositol (1-10 mM) potentiated the 5-HT facilitation, the potentiation increasing linearly with log 5-HT concentration. Myo-inositol also eliminated 5-HT induced heterologous desensitization of muscarinic and alpha 1-adrenergic receptor mediated facilitation. Our findings suggest that 5-HT induced homologous and heterologous desensitization results in part from depleting phosphoinositide substrate.

Multiple mechanisms of serotonin 5-HT2 receptor desensitization.

Desensitization of serotonin 5-HT2 receptor-mediated enhancement of the N-methyl-D-aspartate (NMDA) depolarization was studied in rat cortical neurons. Serotonin and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced long term desensitization. Staurosporine, a nonspecific protein kinase C inhibitor, potentiated the serotonin and DOI facilitation, suggesting acute desensitization was operative. In the case of DOI, long term desensitization was prevented by staurosporine. Activators of protein kinase C abolished the serotonin facilitation, an action prevented by staurosporine. Concanavalin A potentiated the facilitation at 100 microM, but not 30 microM serotonin, suggesting these receptors undergo dose dependent internalization. Calmodulin antagonists prevent long term desensitization induced by serotonin. The depolarization induced by NMDA alone was not altered by staurosporine, protein kinase C activators, concanavalin A or calmodulin antagonists. Serotonin at 100 microM, but not 30 microM, induced heterologous desensitization of phenylephrine and carbachol induced facilitation of the NMDA depolarization. We conclude that serotonin 5-HT2 receptors both induce and undergo several forms of desensitization.

Somatostatin regulates excitatory amino acid receptor-mediated fast excitatory postsynaptic potential components in vagal motoneurons.

Somatostatin is considered to be a brain neurotransmitter/neuromodulator; however, there is little concrete information on how this peptide contributes to generation of synaptic potentials in the mammalian central nervous tissue. Recently, a well-defined somatostatin-containing pathway has been traced from the subnucleus centralis of the solitarial complex to the compact formation of the nucleus ambiguus. Moreover, we have demonstrated both in vivo and in vitro that somatostatin enhances glutamate but inhibits acetylcholine excitation of ambigual motoneurons, suggesting involvement of this peptide in central oesophagomotor transmission. The availability of a brainstem slice containing this pathway has allowed us to characterize an excitatory amino acid receptor-mediated excitatory postsynaptic potential in compact formation neurons. This excitatory postsynaptic potential is unusual because its rising phase involves activation of N-methyl-D-aspartate receptors. Here we report that somatostatin participates in ambigual excitatory postsynaptic potential generation by permitting expression of the N-methyl-D-aspartate receptor-mediated component, thereby regulating fast information transfer in this pathway.

Activation of 5-HT2 receptors facilitates depolarization of neocortical neurons by N-methyl-D-aspartate.

The interaction between serotonin and excitatory amino acid agonists at rat neocortical neurons was investigated using the grease-gap recording method. Depolarization evoked by 50 microM N-methyl-D-aspartate was dose dependently facilitated by serotonin (5-HT) (1 to 100 microM) giving a bell-shaped dose-response curve with maximum enhancement at 30 microM. In contrast, quisqualate and kainate depolarizations were not enhanced. Subnanomolar concentrations of methysergide, ritanserin and spiperone, but not ICS 205-930, attenuated the 5-HT enhancement, compatible with 5-HT2, but not 5-HT1 or 5-HT3 receptor subtype involvement. Enhancement was observed with 5-HT2 receptor agonists, whereas 5-HT1 receptor subtype agonists had either no effect (1B and 1C) or reduced (1A) the N-methyl-D-aspartate depolarization. Scopolamine and prazosin reduced the N-methyl-D-aspartate depolarization and blocked facilitation induced by carbachol and phenylephrine, but not that due to 5-HT. Tetrodotoxin reduced the N-methyl-D-aspartate depolarization, but the facilitation by 5-HT persisted. Activators of protein kinase C (phorbol diacetate and 1-oleoyl-2-acetyl-sn-glycerol) did not mimic the serotonin facilitation. We conclude that serotonin enhances N-methyl-D-aspartate depolarization of rat cortical neurons through activation of 5-HT2 receptors, however the cellular mechanism underlying the facilitation remains to be established.

Nicotinic cholinoceptor-mediated excitatory postsynaptic potentials in rat nucleus ambiguus.

In rat brainstem slice preparations, intracellular recording from neurons (n = 39) in the compact formation of the nucleus ambiguus (AMBc) revealed spontaneous and miniature excitatory postsynaptic potentials (EPSPs; n = 11) that, along with acetylcholine-induced depolarization, were enhanced by physostigmine (10 microM; n = 2) and blocked by dihydro-beta-erythroidine 1-5 pmol (n = 4). Retrograde neuronal tracing combined with choline acetyltransferase immunocytochemistry demonstrated that the AMBc receives a projection from a subpopulation of cholinergic neurons in the zona intermedialis reticularis parvicellularis. Electrical stimulation of this region in slices evoked fast EPSPs in AMBc neurons (n = 23) that were inhibited by dihydro-beta-erythroidine 2-5 pmol (n = 8), but not by methscopolamine 1 pmol (n = 2). The present findings strongly support the existence of a cholinergic nicotinic synapse mediating fast transmission in brainstem vagal motoneurons.

Serotonin (5-HT2) receptor mediated enhancement of cortical unit activity.

Simultaneous single-unit and intracortical activity were recorded from neocortical neurons in urethane-anaesthetized rats to investigate the role of serotonin (5-HT) in modifying cortical excitability. Units, at a depth of 775-1100 microns from the pial surface, discharged in a burst-pause pattern that was correlated with slow wave activity. Application of noxious somatic stimulation resulted in cortical desynchronization and altered the pattern of unit activity such that firing was continuous, i.e., the pauses were eliminated. Intravenous administration of the mixed 5-HT1C/5-HT2 antagonists (cinanserin, cyproheptadine, ketanserin, and ritanserin) prevented both desynchronization and the change in unit activity induced by noxious stimulation within 2.5-15 min of the injection. The basic pattern of burst-pause activity remained intact, but the number of spikes per burst was typically reduced, whereas interburst intervals were increased. Iontophoretic application of these antagonists onto cortical neurons resulted in actions similar to those observed following systemic administration. Intravenous and iontophoretic application of m-trifluomethylphenylpiperazine (5-HT1C agonist, 5-HT2 antagonist) resulted in actions indistinguishable from those observed with the above antagonists, from which we conclude 5-HT2 and not 5-HT1C receptors mediate the alteration in unit activity observed with noxious stimulation. The results are discussed with respect to an interaction between N-methyl-D-aspartate and 5-HT2 receptors leading to the enhanced unit activity observed with noxious stimulation.

Activation of NMDA receptors is necessary for fast information transfer at brainstem vagal motoneurons.

The involvement of N-methyl-D-aspartate (NMDA) excitatory amino acid subtype receptors in synaptically driven excitatory responses of ambigual motoneurons was investigated in vivo and in vitro. In urethane-anaesthetized rats, fictive oesophageal peristalsis evoked by topical application of muscarine (0.05-0.5 nmol) to the dorsal surface of the solitarial complex (NTS) was reversibly blocked by ipsilateral intraambigual injection of DL-2-amino-7-phosphonoheptanoic acid (AP-7, 0.5-1.5 nM) and (+-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 0.5-1.5 nM). In brainstem sagittal slices, post-synaptic potentials were recorded from neurons of the compact formation of the nucleus ambiguus (AMBc). Stimulation of presumptive NTS afferents elicited a complex excitatory postsynaptic potential (EPSP) which usually consisted of both a high-threshold fast (HTF) and a low-threshold slow (LTS) component. Bath perfusion with AP-7 (30-50 microM) and CPP (50 microM) selectively blocked the HTF without affecting the LTS component, while kynurenate (1 mM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5-10 microM) nonselectively suppressed both components. With sufficient stimulus strength, the EPSP generated a single spike arising from the HTF component. AP-7 (50 microM) either blocked the spike or increased the firing threshold. Furthermore, at the resting membrane potential, bath-applied NMDA induced a net inward current (269 +/- 189 pA) which had a negative slope in the range of -95 to -35 mV. In conclusion, NMDA receptors participate in solitario-ambigual synaptic transmission under physiological conditions and activation of these receptors is necessary for functional information transfer in this pathway.

Alteration of neocortical activity in response to noxious stimulation: participation of the dorsal raphe.

Noxious stimulation induces cortical desynchronization which in turn can suppress epileptic seizures in humans and epileptiform activity in laboratory animals. Recent evidence indicates that serotonin mediates both atropine-resistant cortical desynchronization and the suppression of focal epileptiform activity induced by noxious stimulation. As a large forebrain projection of serotonergic fibres originates from the dorsal raphe nucleus, involvement of this nucleus in altering cortical activity was investigated. Agents known to inhibit serotonergic unit activity including serotonin, (+/-)-8-hydroxy-dipropylaminotetralin, fluoxetine and baclofen, when pressure ejected in the vicinity of the dorsal raphe, prevented cortical desynchronization as well as the suppression of focal epileptiform activity in response to noxious stimulation. From these observations it is concluded that serotonergic neurones of the dorsal raphe can profoundly influence neocortical excitability and this action may underlie the clinical effectiveness of strong or noxious stimuli in suppressing epileptic seizures.

Somatostatin inhibits nicotinic cholinoceptor mediated-excitation in rat ambigual motoneurons in vitro.

The interaction between somatostatin and acetylcholine, two putative transmitters in the nucleus ambiguus, was investigated on single ambigual neurons in a brainstem slice preparation. Somatostatin reversibly inhibited the nicotinic cholinoceptor-mediated depolarization and inward current induced by acetylcholine. This inhibition persisted in the presence of tetrodotoxin (TTX) or Mn2+. In contrast, somatostatin enhanced both the glutamate-evoked depolarization and spiking discharges generated by current injection. These results suggest that somatostatin exerts a differential action in modulating excitatory inputs to the nucleus ambiguus at the level of postsynaptic receptors.

Nicotinic cholinoceptor-mediated excitation in ambigual motoneurons of the rat.

The purpose of this study was to determine if ambigual oesophageal motoneurons of the rat possess functional nicotinic cholinoceptors. In urethane anaesthetized rats, acetylcholine (20-50 pmol) delivered micropneumophoretically from multibarrelled pipettes to the compact formation of the nucleus ambiguus produced either synchronous or propulsive oesophageal contractions which were fully and reversibly blocked by dihydro-beta-erythroidine (8-10 pmol) but were resistant to D-tubocurarine and hexamethonium (10-20 pmol). 1,1-Dimethyl-4-phenyl-piperazinium but not muscarine (8 pmol) exerted an analogous agonist action. Ejection of glutamate at the same sites produced similar oesophageal responses which were, however, resistant to dihydro-beta-erythroidine. Acetylcholine applied 5-15 s prior to glutamate transiently facilitated the glutamate-evoked response. The facilitatory effect of acetylcholine was replicated by 1,1-dimethyl-4-phenyl-piperazinium but not muscarine and inhibited by dihydro-beta-erythroidine. Physostigmine, applied either intra-ambigually (10-20 pmol) or by intravenous injection (0.15-0.3 mumol/kg), enhanced both acetylcholine and glutamate-evoked responses. In brainstem transverse slices, application of acetylcholine and glutamate to quiescent ambigual neurons of the compact formation resulted in a rapid membrane depolarization associated with an increased membrane conductance and spiking. Under voltage clamp, both acetylcholine and glutamate elicited a net inward current. The depolarizing response of these neurons to acetylcholine was blocked by dihydro-beta-erythroidine (0.5-2 pmol), hexamethonium (0.2 mM) and D-tubocurarine (10 microM) and persisted in the presence of tetrodotoxin (10(-6) M) or Mn2+ (5 mM) in the bathing medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin mediates suppression of focal epileptiform activity induced by noxious stimulation.

Noxious stimulation can suppress epileptic seizures in humans and epileptiform activity in laboratory animals. Using as a model system the focal epileptiform activity (FEA) induced by the pneumophoresis of penicillin, the role of 5-hydroxytryptamine (5HT) in suppression of this activity by noxious stimulation was investigated. Drugs known to depress dorsal raphe unit activity, (+/-)-8-hydroxydipropylaminotetralin (DPAT), imipramine, and fluoxetine prevented suppression of FEA induced by noxious stimulation. Desimipramine, which depresses locus ceruleus but not dorsal raphe unit activity, was ineffective in blocking the suppression. Quipazine, an agonist at 5-HT receptors, in part restored the suppression that had been blocked by DPAT or imipramine. Several serotonin antagonists effective at 5-HT1 and 5-HT2 receptors blocked suppression, but an unequivocal determination of the serotonin receptor subtype mediating suppression could not be made. We conclude that 5-HT mediates suppression of FEA induced by noxious stimulation.

Endogenous and network bursts induced by N-methyl-D-aspartate and magnesium free medium in the CA3 region of the hippocampal slice.

The epileptogenic properties of N-methyl-D-aspartate and magnesium-free medium were investigated in the CA3 region of the hippocampal slice preparation in the rat. Bath application of N-methyl-D-aspartate (5-10 microM) or magnesium-free medium induced both spontaneous and stimulus-evoked bursts. Both endogenous and network bursts were generated, the former always preceding the latter. The paroxysmal depolarizing shift underlying the network bursts generated by N-methyl-D-aspartate and magnesium-free medium resembled a giant excitatory postsynaptic potential with a reversal potential near 0 mV and a synaptic input in the apical dendrites above the mossy fibre zone. In the presence of N-methyl-D-aspartate or magnesium-free medium, population bursts were synchronized by activating single CA3 neurons. N-methyl-D-aspartate receptor antagonists prevented the development of N-methyl-D-aspartate-induced spontaneous and stimulus-evoked bursts. However, the only N-methyl-D-aspartate receptor antagonist effective in preventing such bursts in magnesium-free medium was DL-3-[(+/-)-2-carboxypiperazin-4-yl-]-propyl-1-phosphonic acid. Endogenous bursting in the CA3 region has not been observed with other convulsants and thus may reflect the novel voltage dependence of the N-methyl-D-aspartate receptor gated ionic channel. N-methyl-D-aspartate receptors may also partially contribute to the excitatory interaction between CA3 neurons and thereby account for the synchronization of the population observed when activating single CA3 neurons.

Antagonism of spontaneous and evoked bursts by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the CA3 region of the in vitro hippocampus.

Superfusion of hippocampal slices with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) antagonized kainate-induced bursts and bursts of unknown origin in the CA3 region. CNQX also increased the latency of and eventually blocked evoked bursts which persist following kainate washout. In contrast, D-(-)-2-amino-7-phosphonoheptanoic acid did not alter burst latency or block bursts unless applied subsequent to CNQX. We conclude that the quisqualate type receptor has a prominent role in burst generation with a smaller contribution from N-methyl-D-aspartate receptors.