Iontophoretically administered drugs acting at the N-methyl-D-aspartate receptor modulate burst firing in A9 dopamine neurons in the rat.

Extracellular single-unit recording and iontophoresis were used to examine the effect of N-methyl-D-aspartate (NMDA) and the competitive NMDA antagonist (+/-)-4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) on the firing rate and firing pattern of A9 dopamine (DA) neurons in the rat. Administration of NMDA produced a dose-dependent increase in firing rate (up to nearly 300% of baseline at the highest ejection current), which could be blocked by iontophoretic CPP. Low currents (less than 10 nA) were sufficient to induce apparent depolarisation inactivation in some neurons. In addition to this effect on firing rate, NMDA also caused a dramatic increase in burst firing, which was also dose dependent; cells made more bursts, and each burst consisted of more spikes. The only measured aspect of burst morphology that was not affected was the mean burst interspike interval. All nonbursting cells (n = 10) were converted to burst firing by the drug. CPP administered alone was found to reduce burst firing, without affecting the firing rate. These data suggest that a tonically active excitatory amino acid input to A9 DA neurons is responsible for inducing burst firing in vivo and that this input seems to operate via the NMDA receptor, possibly by virtue of its link to a Ca2+ ionophore.     

Electrophysiological evidence for the existence of NMDA and non-NMDA receptors on rat ventral tegmental dopamine neurons

In vitro extracellular single-unit recordings from rat midbrain slices were used to assess the effects of excitatory amino acid agonists on the activity of A10 dopamine neurons. N-methyl-D-aspartic acid (NMDA), kainic acid (KA), and β-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) elicited dose-dependent increases in firing rates. The relative potencies for the 3 compounds was AMPA > KA > NMDA. None of the excitations was accompained by burst firing, but frequently periods of nonrecordable activity occurred following pronounced stimulation. Concurrent application of the excitatory amino acid antagonist CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) selectively blocked the excitations elicited by NMDA but not by KA or AMPA. Likewise the selective non-NMDA antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline] blocked only the excitatory effects of AMPA and KA but not those elicited by NMDA. NBQX appeared to be less optent at antagonizing KA than AMPA. These results suggest that mesolimbic-mesocortical dopamine neurons possess both NMDA and non-NMDA receptors, and possibly distinct AMPA and KA recognition sites. © 1993 Wiley-Liss, Inc.     

Effects of dizocilpine (MK-801) on rat midbrain dopamine cell activity: differential actions on firing pattern related to anatomical localization

Summary The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) on the firing pattern of midbrain dopamine neurons were studied with single cell recording techniques in male albino rats anaesthetized with chloral hydrate. The extracellularly recorded electrical activity of single, identified dopamine neurons was studied with respect to firing rate, burst firing and regularity of firing. MK-801 (0.01–1.0 mg/kg IV) induced different effects in different subgroups of midbrain dopamine neurons. In the substantia nigra, firing rate was increased while the pattern was regularized and burst firing slightly increased. In the ventral tegmental area, firing rate and regularity of firing was also increased while effects on burst firing were bidirectional. Histological inspections revealed that neurons which responded with an increase in burst firing were mainly located in the nucleus paranigralis subdivision of the ventral tegmental area, while cells responding with a decrease were predominantly found in the nucleus parabrachialis pigmentosus subdivision. The effects of MK-801 were similar to previously described effects of phencyclidine, another non-competitive NMDA antagonist. The present effects of MK-801 might shed some light on the mechanisms involved in psychotic symptoms induced by phencyclidine and other non-competitive NMDA antagonists.     

Kynurenate blocks the acute effects of haloperidol on midbrain dopamine neurons recorded in vivo

Summary The acute effect of systemic administration of the antipsychotic drug haloperidol on the activity of midbrain dopamine (DA) neurons was investigated with extracellular single cell recording in the chloral hydrate anaesthetized male rat. DA cells in the zona compacta-substantia nigra (SN) and ventral tegmental area (VTA) were excited by low doses of haloperidol. This excitation, which included increased firing rate and burst firing, was no longer present after treatment with the excitatory amino acid (EAA) antagonist kynurenate (1 mol ICV). Kynurenate alone profoundly regularized the activity and abolished burst firing in VTA-DA neurons, while SN-DA neuronal activity was unaffected by this treatment. Thus, VTA-DA neurons, but not SN neurons, appear to be dependent on a tonic EAA input for their normal varied, burst-firing activity. The antagonism of haloperidol-induced effects by kynurenate suggests that the acute excitatory action of haloperidol on midbrain DA neurons is executed via EAA neurons, in the case of the VTA probably via a corticofugal EAA pathway from the medial prefrontal cortex.     

Apamin increases NMDA-induced burst-firing of rat mesencephalic dopamine neurons

Intracellular recordings made in vitro from rat midbrain dopamine neurons showed that apamin (100 nM) did not alter the regular spontaneous firing of the neurons, but it increased the occurrence of bursts of action potentials in N-methyl-d-aspartate. Apamin appeared to facilitate burst-firing induced by NMDA because, by blocking an outward calcium-activated potassium current, it increased the depolarizing action of NMDA.     

GABAB-Receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra

Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABA_B-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABA_B-receptor agonist baclofen (1–16 mg/kg) was associated with a dose-dependent regularisation of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16–32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABA_B-receptor antagonist CGP 35348 (200 mg/kg, l.v.). The GABA_A-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a Cecreased regularity. The NMDA receptor antagonist MK 801 (0.4–3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3–10 min) did neither promote nor prevent the regularisation of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABA_B-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst Firing activity on these neurons. © 1993 Wiley-Liss, Inc.     

Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still relatively unknown. A recent study shows that a pharmacologically increased concentration of brain kynurenic acid, an endogenous antagonist at the glycine-site of the NMDA receptor as well as at the alpha7* nicotinic receptor, reverses the excitatory effects of clozapine on ventral tegmental area (VTA) dopamine (DA) neurons into an inhibitory action. In the present in vivo electrophysiological study, we further investigated the mechanisms of action of clozapine on VTA DA neurons. In control rats intravenously administered clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist MK 801 blocked the excitatory action of clozapine. Moreover, in rats pretreated with the antagonist of the glycine-site of the NMDA receptor, L-701,324, the effects of clozapine on VTA DA neurons were converted to purely inhibitory responses, including a decrease in firing rate and burst firing activity. Pretreatment with the alpha7* nicotinic receptor antagonist MLA did not affect the excitatory action of clozapine on VTA DA neurons. The results of the present study suggest that clozapine interacts with the NMDA receptor complex. In this regard, clozapine could affect the glycine site of the NMDA receptor or tentatively inhibit the glycine transporter. The inhibitory action of clozapine on VTA DA neurons may account for its beneficial effects in ameliorating symptoms of schizophrenia and may suggest further studies to investigate a role of the glycine site of the NMDA receptor as a target for novel antipsychotics.     

The effects of selective glutamate receptor antagonists on synchronized firing bursts in layer III of rat visual cortex.

In the rat visual cortex in vitro, single-shock stimulations applied to the border between layer VI and the white matter evoke synchronized burst-firing by units in layer III. We have examined the effects of glutamate receptor antagonists on this activity, with antagonists applied via the bath to allow correlation of effects with concentrations. All synaptically driven components (recorded extracellularly as field potential 'S2' spikes, dipoles 'W1' and 'W2', and coinciding single-unit spikes) were inhibited by greater than 90% in 1.0 mM kynurenic acid and in 3 or 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, which selectively blocks AMPA/kainate receptors). S2 spike amplitudes were reduced by half in 0.7 microM CNQX. 2-Amino-5-phosphonovalerate (APV), a specific blocker of NMDA receptors, did not prevent S2 spike burst or horizontal spread of bursting within layer III. However, APV reduced the duration of synchronized bursts and the slower potentials which followed. In Mg(2+)-free medium, new components appeared which were APV-sensitive: (1) low amplitude spikes, distributed spatially like S2 spike, but recurring more slowly, and (2) slow potentials, distributed spatially like W1 and W2 potentials, but lasting for hundreds of milliseconds. The amplitudes of these spikes were reduced by half in 3 microM D-APV. Our data imply that: (1) glutamate receptors play a major role in mediating local, excitatory neurotransmission in the supragranular layers of neocortex, with NMDA and AMPA/kainate subtypes each subserving somewhat different functions; (2) AMPA/kainate receptors mediate rapid excitatory transmission between layer III neurons, responsible for driving the first 15 ms of synchronized bursts; (3) currents gated by NMDA receptors determine the duration of coherent firing bursts, and drive asynchronous neuronal firing following bursts; and (4) under conditions which circumvent block by extracellular Mg2+, activation of NMDA receptors greatly enhances and prolongs the response to single-shock stimulations. In vivo, activation of layer III neurons is likely to depend significantly upon currents gated by NMDA receptors whenever repetitively firing excitatory inputs summed over several tens of milliseconds provide enough depolarization to lift block by extracellular Mg2+.     

Muscarinic Modulation of Intrinsic Burst Firing in Rat Hippocampal Neurons

Intracellular recordings in rat hippocampal slices were used to examine how exogenous and endogenous cholinergic agonists modulate the firing pattern of intrinsically burst-firing pyramidal cells. About 24% of CA1 pyramidal cells generated all-or-none, high-frequency bursts of fast action potentials in response to intracellular injection of long positive current pulses. Application of carbachol (5 μM) converted burst firing in these neurons into regular trains of independent spikes. Acetylcholine (5 μM) exerted a similar effect, provided acetylcholine esterase activity was blocked with neostigmine (2 μM). Atropine (1 μM) reversed this cholinergic effect, indicating its mediation by muscarinic receptors. Cholinergic agonists also caused mild neuronal depolarization but the block of intrinsic burst firing was independent of this effect. Repetitive stimulation of cholinergic fibres in the presence of neostigmine (2 μM) evoked a slow cholinergic excitatory postsynaptic potential (EPSP) lasting about a minute. During the slow EPSP, burst firing could not be evoked by depolarizing pulses and the neurons fired in regular mode. These effects were prevented by pretreatment with atropine (1 μM). Exogenously applied cholinergic agonists and endogenously released acetylcholine also reduced spike frequency accommodation and suppressed the long-duration afterhyperpolarization in burst-firing pyramidal cells in an atropine-sensitive manner. A membrane-permeable cAMP analogue (8-bromo-cAMP; 1 mM) also reduced frequency accommodation and blocked the long-duration afterhyperpolarization, but did not affect intrinsic burst firing at all. Taken together, the data show that muscarinic receptor stimulation transforms the stereotyped, phasic response of burst-firing neurons into stimulus-graded, tonic discharge.     

Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons

The electrophysiological effects of the non-competitive (NMDA) antagonist (+)-MK801 (MK-801) on nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. MK-801 (0.05–3.2 mg/kg, i.v.) stimulated the firing rates of 14 (74%) of 19 nigrostriatal DA (NSDA) neurons and all 16 mesoaccumbal DA (MADA) neurons tested. Stimulatory effects of the drug were more prominent on MADA neurons. Interspike interval analysis revealed that MK-801 also regularized DA neuronal firing pattern. Acute brain hemitransection between the midbrain and forebrain attenuated the stimulatory effects of MK-801 on firing rate and blocked the effects on firing pattern. Similar to MK-801, hemitransection itself increased NSDA and MADA cell firing rates and regularized firing pattern. Both i.v. and iontophoretic MK-801 blocked the excitatory effects of iontophoretic NMDA but did not effect excitations caused by the non-NMDA glutamatergic receptor agonists quisqualate and kainate. Iontophoretic MK-801 had no effect alone. These results suggest that the excitatory effects of i.v. MK-801 on DA neuronal activity are not due to direct actions on DA neurons. Glutamatergic projections originating anterior to the hemistransection appear to play a role in the effectrs of MK-801 on DA neuronal activity.     

Competitive NMDA receptor antagonists differentially affect dopamine cell firing pattern

Alterations in the firing pattern of mesencephalic dopamine (DA) neurons appear to constitute a physiological mechanism through which these cells modify their effects on target neurons. Several lines of evidence suggest that the activity patterns exhibited by DA cells in vivo are contingent on tonic activation of N-methyl-D-aspartate (NMDA) receptors. In the present series of experiments, extracellular single unit recording techniques were used to assess the effects of the centrally acting, competitive NMDA receptor antagonists CGS-19755, (±)-CPP, NPC-12626 and NPC-17742 on the firing properties of nigral DA neurons in the chloral hydrate-anesthetized rat. Each of the drugs tested produced a modest increase in firing rate accompanied by a significant regularization of neuronal firing pattern. Although the number of bursts and the percentage of spikes in bursts were reduced, the proportion of cells operationally defined as bursting was not appreciably altered. This appeared to be due to the ability of these drugs to reduce the number of spike doublets without affecting the incidence of longer bursts. Although generally consistent with the notion that NMDA receptors modulate DA neuronal firing pattern, the present data do not support the contention that tonic activation of these receptors is solely responsible for the expression of bursting activity in vivo. Synapse 25:234–242, 1997. © 1997 Wiley-Liss, Inc.     

Effects ofl-cysteine-sulphinate andl-aspartate, mixed excitatory amino acid agonists, on the membrane potential of cat caudate neurons

Responses evoked byl-cysteine-sulphinate (l-CSA) andl-aspartate (l-Asp) were recorded with intracellular electrodes from caudate neurons in halothane anesthetized cats.l-CSA andl-Asp were applied microiontophoretically to caudate cells and their effects on membrane and action potentials, as well as on cortically evoked synaptic potentials were evaluated.l-CSA andl-Asp induced depolarizations accompanied by regular firing resembling kainate (KA)- or quisqualate (QUIS)-induced excitation patterns (type 1) in 82% and 72% of the recorded neurons, respectively, and a mixed pattern consisting of aN-methyl-d-aspartate (NMDA)-like excitation (type 2) followed by a regular type 1 pattern in the remaining cells. In about a quarter of the cells the effects ofl-CSA andl-Asp, but not those of KA or QUIS, were partially antagonized by 2-amino-7-phosphonoheptanoate (AP-7), a specific NMDA receptor antagonist. Kynurenate, a broad spectrum excitatory amino acid antagonist, blocked responses elicited by eitherl-CSA or QUIS. The actions ofl-CSA andl-Asp on the firing pattern and membrane potential of cat caudate neurons in situ provide evidence in favor of their mixed agonist nature with respect to NMDA and non-NMDA excitatory amino acid receptors.     

Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex.

BACKGROUND: Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC). METHODS: In freely moving rats, we measured the effects of the positive modulator of mGlu5 receptor 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) alone or in combination with the NMDA antagonist MK801 on 1) spontaneous firing and bursting of medial PFC (mPFC) neurons, and 2) dopamine release as measured by microdialysis in the mPFC and nucleus accumbens (NAc). RESULTS: The predominant effect of CDPPB on mPFC neurons was excitatory, leading to an overall excitatory population response. Pretreatment with CDPPB prevented MK801-induced excessive firing and reduced spontaneous bursting. In contrast, CDPPB had no significant effect on basal dopamine release as compared with control rats and did not alter MK801-induced activation of dopamine release in the mPFC and NAc. CONCLUSIONS: These results show that positive modulation of mGlu5 receptors reverses the effects of noncompetitive NMDA antagonists on cortical neuronal firing without affecting dopamine neurotransmission. Thus, these compounds may be effective in ameliorating PFC mediated behavioral abnormalities that results from NMDA receptor hypofunction.     

Effects of L-cysteine-sulphinate and L-aspartate, mixed excitatory amino acid agonists, on the membrane potential of cat caudate neurons

Responses evoked by L-cysteine-sulphinate (L-CSA) and L-aspartate (L-Asp) were recorded with intracellular electrodes from caudate neurons in halothane anesthetized cats. L-CSA and L-Asp were applied microiontophoretically to caudate cells and their effects on membrane and action potentials, as well as on cortically evoked synaptic potentials were evaluated. L-CSA and L-Asp induced depolarizations accompanied by regular firing resembling kainate (KA)- or quisqualate (QUIS)-induced excitation patterns (type 1) in 82% and 72% of the recorded neurons, respectively, and a mixed pattern consisting of a N-methyl-D-aspartate (NMDA)-like excitation (type 2) followed by a regular type 1 pattern in the remaining cells. In about a quarter of the cells the effects of L-CSA and L-Asp, but not those of KA or QUIS, were partially antagonized by 2-amino-7-phosphonoheptanoate (AP-7), a specific NMDA receptor antagonist. Kynurenate, a broad spectrum excitatory amino acid antagonist, blocked responses elicited by either L-CSA or QUIS. The actions of L-CSA and L-Asp on the firing pattern and membrane potential of cat caudate neurons in situ provide evidence in favor of their mixed agonist nature with respect to NMDA and non-NMDA excitatory amino acid receptors.     

Serotonin Differentially Modulates Responses Mediated by Specific Excitatory Amino Acid Receptors in the Rat Locus Coeruleus

Microiontophoretic application of selective agonists for the three major excitatory amino acid receptors, N -methyl- d -aspartate (NMDA), quisqualate and kainate, increased the discharge rate of noradrenergic locus coeruleus (LC) neurons in vivo. NMDA activation was selectively attenuated by iontophoretic application of 2-amino-5-phosphonopentanoate (AP5), an antagonist at NMDA receptors, whereas kainate- and quisqualate-evoked responses were attenuated by both NMDA and non-NMDA antagonists iontophoresis. NMDA- and quisqualate-evoked responses were significantly decreased by co-iontophoresis of serotonin (5-HT). When the NMDA receptor-mediated component of the response to kainate was blocked with AP5 iontophoresis, 5-HT increased the response of LC neurons to kainate. These results revealed that 5-HT differentially modulates the responsiveness of LC neurons to excitatory amino acids, depending on the receptor subtypes responsible for the neuronal activation.     

The control of firing pattern in nigral dopamine neurons: burst firing

In addition to firing in a single spiking mode, dopamine (DA) cells have been observed to fire in a bursting pattern with consecutive spikes in a burst displaying progressively decreasing amplitude and increasing duration. In vivo intracellular recording demonstrated the bursts to typically ride on a depolarizing wave (5 to 15 mV amplitude). Although the burst-firing frequency of DA cells showed little correlation with the base line firing rate, increases in firing rate were usually associated with an increase in burst firing. Increases in burst firing could also be elicited by intracellular calcium injection and could be prevented by intracellular injection of EGTA, suggesting a calcium involvement in bursting. Blockade of potassium conductances with extracellular iontophoresis of barium or intracellular injection of tetraethylammonium bromide could also trigger an increased degree of burst firing in DA cells. These data suggest that the increased calcium influx accompanying an increased firing rate triggers burst firing, possibly by inactivating a potassium conductance. A switch from a single spiking mode to a burst-firing mode may be important in modulating striatal DA release, as shown for burst firing in other preparations.     

Excitatory amino acid receptors on sustained retinal ganglion cells in the kitten during the critical period of development

Effects of iontophoretically applied excitatory amino acid analogues, kainate, quisqualate and N-methyl-D-aspartate (NMDA) and their receptor antagonists on the sustained class of retinal ganglion cells were studied in the optically intact eye of pentobarbitone-anaesthetized kittens (7-9 weeks of age). These results were compared with the effects obtained in adult cats. All 3 excitatory amino acid agonists had excitatory actions on the majority of On- and Off-sustained ganglion cells in the kitten but at higher current levels than those required for adult cells, suggesting all 3 types of receptors of weaker sensitivity are present on the kitten cells. Whilst the relative potency of kainate, quisqualate and NMDA was 15:3:1 in the adult cells, it was 5:2:1 in the kitten cells. As for other neurones in the CNS, an increase in the potency of kainate receptors and a decrease in that of NMDA receptors appear, therefore, to characterize the postnatal development of the excitatory amino acid receptors on the retinal ganglion cells. In accordance with the agonist results, a broadband receptor antagonist, kynurenate, powerfully antagonised responses of kitten cells as well as those of adult cells. The pure NMDA receptor antagonist, 3((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), however, only suppressed spontaneous firing of kitten cells. Furthermore, in kitten cells, the visually-driven firing was depressed while the level of firing was raised by these excitatory amino acid analogous, and a long period of inhibition of firing followed the agonist-induced excitation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Group I metabotropic glutamate receptor-mediated enhancement of dopamine cell burst firing in rat ventral tegmental area in vitro

Metabotropic glutamate receptor (mGluR) agonist t-ACPD produced concentration-dependent enhancement of NMDA/apamin-induced burst firing and membrane oscillations in dopamine cells, recorded intracellularly from ventral tegmental area in the rat midbrain slice. Such effects were blocked reversibly by mGluR antagonist MCPG, and mimicked by the selective agonist for group I (but not group II and III) mGluRs. Our results point out a selective involvement of group I mGluRs in facilitating burst firing of midbrain dopamine cells.     

The role of putative excitatory amino acid neurotransmitters in the initiation of locomotion in the lamprey spinal cord. I. The effects of excitatory amino acid antagonists

The activation of N-methyl-D-aspartate (NMDA) and kainate receptors will evoke fictive locomotion in the appropriate motor pattern for locomotion in the isolated lamprey spinal cord, but not a selective activation of quisqualate receptors. The present experiments test whether the initiation of locomotion in response to sensory stimulation depends on these types of receptors. An in vitro preparation of the lamprey spinal cord with part of its tailfin left innervated has been used. In this preparation a sequence of fictive locomotion (i.e. alternating bursts in the segmental ventral roots with a rostrocaudal phase lag) can be elicited by continual sensory stimulation of the tailfin. The effects of excitatory amino acid antagonists were studied by recordings from ventral roots (extracellularly) and motoneurones (intracellularly). It was found that the strong initial bursts of each swimming sequence induced by sensory stimulation were depressed by combined NMDA/kainate antagonists (cis-2,3-piperidine dicarboxylate (PDA) and gamma-D-glutamylglycine (gamma-DGG] whereas the less intense burst activity, occurring particularly towards the end of each swimming sequence, was depressed by a selective NMDA antagonist, 2-amino-5-phosphonovalerate (2-APV). This condition could be mimicked in an isolated spinal cord preparation by an application of L-glutamate; the low-level fictive locomotion induced by low doses of L-Glu (less than 100 microM) was depressed by a NMDA antagonist (2-APV), and, if higher doses were applied, the activity was only depressed by PDA/gamma-DGG. The mode and time course of the depression (by excitatory amino acid antagonists) of fictive locomotion, induced by sensory stimulation, shows that the putative excitatory amino acid neurotransmitter directly or indirectly acts at the pattern generating circuitry within the spinal cord.     

Metabotropic glutamate receptor-mediated inhibition and excitation of substantia nigra dopamine neurons

Microiontophoretic drug application and extracellular recording techniques were used to evaluate the effects of the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) on dopamine (DA) neurons in the substantia nigra zona compacta (SNZC) of chloral hydrateanesthetized rats. 1S,3R-ACPD had a biphasic effect on the firing rate of DA cells, initially decreasing, then increasing the firing rate. 1S,3R-ACPD also increased the burst-firing activity of DA neurons. Application of the ionotropic receptor (iGluR) agonists (R,S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) increased the firing rates of neurons which had responded to 1S,3R-ACPD, indicating that mGluRs and iGluRs reside on the same neurons. The initial inhibitory period was not antagonized by systemic haloperidol or iontophoretic bicuculline, indicating a lack of DA or γ-amino-n-butyric acid (GABA) involvement in this effect. Combined application of the AMPA or γ-amino-n-butyric acid (GABA) involvement in this effect. Combined application of the AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), and the NMDA antagonist, (I)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), at currents which antagonized AMPA and NMDA, did not antagonize either the inhibitory or excitatory effects of 1S,3R-ACPD. Application of the metabotropic antagonist (S)-4-carboxy-phenylglycine antagonized both the inhibitory and excitatory effects of 1S-3R-ACPD. These results indicate that mGluRs may play a role in the modulation of dopaminergic activity in the SNZC. Synapse 26:184–193, 1997. © 1997 Wiley-Liss, Inc.