NMDA-induced Dopamine Research Articles

How can an inert gas counterbalance a NMDA-induced glutamate release?

Previous neurochemical studies performed in rats have revealed a decrease of striatal dopamine and glutamate induced by inert gas narcosis. We sought to establish the hypothetical role of glutamate and its main receptor, the N-methyl-d-aspartate (NMDA) receptor, in this syndrome. We aimed to counteract the nitrogen narcosis-induced glutamate and dopamine decreases by stimulating the NMDA receptor in the striatum. We used bilateral retrodialysis on awake rats, submitted to nitrogen under pressure (3 MPa). Continuous infusion of 2 mM of NMDA under normobaric conditions (0.01 MPa) (n = 8) significantly increased extracellular average levels of glutamate, aspartate, glutamine, and asparagine by 241.8%, 292.5%, 108.3%, and 195.3%, respectively. The same infusion conducted under nitrogen at 3 MPa (n = 6) revealed significant lower levels of these amino acids (n = 8/6, P > 0.001). In opposition, the NMDA-induced effects on dopamine, dihydrophenylacetic acid (DOPAC), and homovanillic acid (HVA) levels were statistically not affected by the nitrogen at 3 MPa exposure (n = 8/6, P > 0.05). Dopamine was increased by >240% on average. HVA was decreased (down to 40%), and there was no change in DOPAC levels, in both conditions. Results highlight that the NMDA receptor is not directly affected by nitrogen under pressure as indicated by the elevation in NMDA-induced dopamine release under hyperbaric nitrogen. On the other hand, the NMDA-evoked glutamate increase is counteracted by nitrogen narcosis. No improvement in motor and locomotor disturbances was observed with high striatal concentration in dopamine. Further experiments have to be done to specify why the striatal glutamate pathways, in association with the inhibition of its metabolism, only are affected by nitrogen narcosis in this study.

The role of N-methyl-d-aspartate receptors and nitric oxide in cochlear dopamine release

Dopamine (DA) released from lateral olivocochlear (LOC) terminals may have a neuroprotective effect in the cochlea. To explore the role of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) in the modulation of a cochlear DA release, we measured the release of [3H]DA from isolated mouse cochlea in response to the application of NMDA. NMDA at 100 muM significantly increased the electrical-field stimulation-evoked and resting release of DA from the cochlea. The NO donor sodium nitroprusside enhanced the basal outflow of DA but failed to influence the evoked release. The administration of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) alone was ineffective, but it significantly inhibited the initial phase of the NMDA-induced elevation of DA outflow, which suggested the role of NO in the NMDA-induced DA release. The DA uptake inhibitor nomifensine increased the electrically evoked release of DA. Nomifensine failed to change the effect of NMDA on the resting or electrically-evoked DA release, which suggested that the uptake mechanism does not play a role in NMDA-evoked and NO-mediated DA release. In summary, we provide evidence that NO can modulate the release of DA from the cochlea following NMDA receptor activation, but does not affect the uptake of DA.

NMDA modulation of dopamine dynamics is diminished in the aged striatum: An in vivo voltametric study

The technique of in vivo voltametry and a paired recording paradigm were employed to study the age-related changes in N-methyl- d-aspartate (NMDA) function in regulating the striatal dopaminergic transmission in male Sprague–Dawley rats. Microinjection of NMDA (100 pmol) consistently elicited larger striatal dopamine (DA) overflows from young rats (3–4 months old) than from aged rats (27–28 months old). Furthermore, the rate of clearance ( T c) of the NMDA-evoked dopamine release was lower in the aged rats. Local application of dopamine evoked reversible electrochemical signals with similar amplitudes in both young and aged rats. However, T c was reduced and time course parameters were prolonged in the aged rats. While microejection of NMDA (1 pmol) did not induce any dopamine overflow, simultaneous administration of NMDA and K + evoked larger dopamine releases than K + alone in the young striatum. Concomitant application of NMDA did not potentiate the K +-evoked dopamine release in the aged striatum. Taken together, with the reduced dopamine release in response to depolarizing stimuli, our in vivo electrochemical data suggest that age-related changes in NMDA function contribute to the impaired dopaminergic dynamics, including an attenuation of NMDA-evoked dopamine release and a diminished augmentation by K + of NMDA-induced dopamine release during the normal aging process.

Halothane and isoflurane increase spontaneous but reduce the N-methyl-D-aspartate-evoked dopamine release in rat striatal slices: evidence for direct presynaptic effects.

Experimental data suggest that volatile anesthetics induce significant changes in extracellular dopamine concentrations in the striatum, a restricted but functionally important brain area. In the present study, the authors used a superfused slice preparation to examine the effects of halothane and isoflurane on both spontaneous and N-methyl-D-aspartate (NMDA)-evoked dopamine release in the striatum, and whether these effects involved actions of these anesthetics mediated by gamma-aminobutyric acid receptors in this structure. Radioactivity collected from 5-min fractions was compared in the absence (basal release) or presence (evoked release) of NMDA alone and combined with various pharmacologic or anesthetic agents in slices of the dorsolateral striatum and synaptosomes of the whole striatum preloaded with 3H-dopamine and superfused with artificial cerebrospinal fluid. In tetrodotoxin-treated striatal slices, halothane and isoflurane significantly increased dopamine basal release (EC50 = 0.33 mM and 0.41 mM for halothane and isoflurane, respectively). Both agents decreased the NMDA-evoked dopamine release in both the absence (IC50 = 0.15 mM and 0.14 mM for halothane and isoflurane, respectively) and presence (IC50 = 0.15 mM for both halothane and isoflurane) of tetrodotoxin in slices, and in synaptosomes (IC50 = 0.19 mM for both halothane and isoflurane). NMDA-induced dopamine release was significantly enhanced by bicuculline, a gamma-aminobutyric acid receptor antagonist. Halothane and isoflurane inhibitory effects on NMDA-evoked dopamine release were significantly reduced in the presence of bicuculline. These results indicate that halothane and isoflurane decrease the NMDA-evoked dopamine release by acting directly at dopamine terminals in striatal slices. They support the involvement of both depression of presynaptic NMDA receptor-mediated responses and enhancement of gamma-aminobutyric acid receptor-mediated responses in these effects.

Differential regulation of dopamine release by N-methyl- d-aspartate receptors in rat striatum after partial and extreme lesions of the nigro-striatal pathway

The participation of N-methyl- d-aspartate (NMDA) receptors on dopamine (DA) efflux in the striatum of anaesthetized rats, which had their DA nigrostriatal pathway previously lesioned with different doses of 6-hydroxydopamine (6-OH-DA), was assessed by in vivo microdialysis methodology. In addition, the in vivo basal DA and dihydroxy-phenyl-acetic acid (DOPAC) effluxes and the effect of local K +-depolarization on DA release were also evaluated in the striatum of these 6-OH-DA treated rats. Lesioned rats were divided in three groups corresponding to animals with 25–75%, 75–95% and >95% of striatum tissue DA depletion, respectively. Striatal DA tissue depletion between 25–75% occurred in parallel with a 30% reduction in DA extracellular levels, with a moderate 10% increase in basal fractional DA efflux, and with no statistical changes in the fractional DA efflux induced by NMDA (500 μM) receptor stimulation by reverse dialysis. Rats with higher DA tissue depletion (between 75–95%) exhibited a 60% reduction in DA extracellular levels in the striatum and this reduction occurred in parallel with a modest rise in basal fractional DA efflux, but with a striking decrease in the NMDA-induced fractional DA efflux. In rats with extreme or >95% of striatal DA tissue depletion, basal fractional DA efflux in the striatum increased quite substantially along with a recovery in the ability of NMDA receptor stimulation to induce fractional DA release. The >95% striatal DA-depleted rats also exhibited a significant decrease in tissue and extracellular DOPAC/DA ratio when compared to sham and partially DA-depleted rats. In contrast to the previous results, fractional DA efflux induced by reverse dialysis with K + (40 mM) remained the same in the striatum of sham and all groups of DA-tissue depleted rats. The present findings suggest the existence of at least three features associated to the regulation of basal and NMDA-induced extracellular levels of DA in the striatum of rats as a function of striatal tissue DA depletion produced by 6-OH-DA. They also support the view that a differential regulation of basal and NMDA-induced DA extracellular levels occur in partial and extreme DA-depleted striatum after 6-OH-DA treatment. Such findings may have implications as regard to the participation of the NMDA receptor in the compensatory mechanisms associated to the progress of Parkinson's disease, as well as in the therapeutic treatment of this neurological disorder.

Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: Role of ionotropic glutamate receptor-dependent mechanisms

We have investigated the influence of the nitric oxide synthase (NOS) substrate, N G-hydroxy- l-arginine (H-ARG) on dopamine (DA) and glutamate (GLU) efflux in vivo using concentric microdialysis probes implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion of HARG (100 μM, 200 μM, or 1 mM for 120 min) increased DA efflux in a dose-dependent fashion. The facilitatory effect of H-ARG (1 mM) on DA efflux was abolished following pretreatment (80 min) with the constitutive NOS inhibitor 7-nitroindazole (7-NI, 10 μM) but unaffected by l- N G(1-iminoethyl) lysine (100 μM) infusion. As both H-ARG (1 mM) and the NO-generator ( ± )- S-nitroso- N-acetylpenicillamine (1 mM) were observed to increase GLU efflux concurrently with the effect on DA efflux, we evaluated the potential intermediary role of GLU in NO-facilitated DA efflux using ionotropic GLU receptor antagonists. Local infusion of dizocilpine maleate (10 μM) or ( ± )-2-amino-3-[3-(carboxymethoxy)-5-methyl-isoxazol-4-yl] propionic acid (100 μM), attenuated the H-ARG (1 mM)-induced elevation of extracellular DA levels. Conversely, similar treatment with the kainate receptor antagonist d- γ-glutamyl-aminomethanesulfonic acid did not alter H-ARG-induced DA efflux. To evaluate the regulatory influence of striatal NO on NMDA receptor activation, NMDA (100 μM) was co-perfused with either H-ARG (2 mM) or 7-NI (10 μM). While co-perfusion with 7-NI potentiated NMDA-induced DA efflux, similar treatment with H-ARG (2 mM) abolished the effect. These results demonstrate that endogenous NO production, stimulated via H-ARG-dependent activation of type 1 NOS, enhances striatal DA efflux via an increase in glutamatergic tone on ionotropic GLU-receptors. At higher levels of NOS activation (following H-ARG (2 mM) or NMDA infusion), NO may block glutamatergic neurotransmission via inhibition of NMDA receptor function.

Kappa1- and kappa2-opioid receptors mediating presynaptic inhibition of dopamine and acetylcholine release in rat neostriatum.

1. The effects of selective opioid receptor agonists and antagonists on N-methyl-D-aspartate (NMDA, 10 microM)-induced release of [3H]-dopamine and [14C]-acetylcholine (ACh) from superfused neostriatal slices were studied to investigate the possible occurrence of functional kappa-opioid receptor subtypes in rat brain. 2. The kappa receptor agonists (-)-ethylketocyclazocine ((-)-EKC), U69593 and the endogenous opioid peptide dynorphin A1-13 caused a naloxone-reversible inhibition of NMDA-induced [3H]-dopamine release, with pD2 values of about 9, 8.5 and 8.2, respectively, whereas both the mu agonist Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) and the delta agonist D-Pen2-D-Pen5-enkephalin (DPDPE) were ineffective in this respect. The inhibitory effect of submaximally effective concentrations of dynorphin A1-13, U69593 and (-)-EKC on NMDA-induced [3H]-dopamine release were not changed by the delta1/delta2-opioid receptor antagonist naltrindole (up to a concentration of 1 microM, but reversed by the kappa receptor antagonist nor-binaltorphimine (nor-BNI), with an IC50) as low as 0.02 nM, indicating the involvement of U69593-sensitive kappa1-opioid receptors. 3. NMDA-induced [14C]-ACh release was reduced in a naloxone-reversible manner by DPDPE (pD2 about 7.2), dynorphin A1-13 (pD2 6.7) and EKC (pD2 6.2), but not by U69593 and DAMGO. The inhibitory effect of a submaximally effective concentration of DPDPE, unlike those of dynorphin A1-13 and (-)-EKC, on NMDA-induced [14C]-ACh release was antagonized by naltrindole with an IC50 of 1 nM, indicating the involvement of delta-opioid receptors in the inhibitory effect of DPDPE. On the other hand, the inhibitory effects of dynorphin A1-13 and (-)-EKC on [14C]-ACh release were readily antagonized by nor-BNI with an IC50 of about 3 nM. A 100 fold higher concentration of nor-BNI also antagonized the inhibitory effect of DPDPE, indicating the involvement of U69593-insensitive kappa2-opioid receptors in the inhibitory effects of dynorphin A1-13 and (-)-EKC. 4. Although naloxone benzoylhydrazone (NalBzoH), displaying high affinity towards the putative kappa3-opioid receptor, antagonized the inhibitory effects of dynorphin A1-13 and (-)-EKC on [3H]-dopamine and [14C]-ACh release as well as that of U69593 on [3H]-dopamine release, it displayed a low apparent affinity (IC50 about 100 nM) in each case. 5. In conclusion, whereas activation of kappa1-opioid receptors causes presynaptic inhibition of NMDA-induced dopamine release, kappa2 receptor activation results in inhibition of ACh release in rat neostriatum. As such, this study is the first to provide unequivocal in vitro evidence for the existence of functionally distinct kappa-opioid receptor subtypes in the brain.

Nitric oxide regulates NMDA-induced dopamine release in rat striatum.

We investigated the effect of nitric oxide (NO) on N-methyl-D-aspartate (NMDA)-induced changes in levels of dopamine (DA) and its metabolite in the striatum using in vivo microdialysis. Local administration of 1mM NMDA into the striatum significantly augmented DA release in the striatum. Simultaneous administration of -5mM N(G)-nitro-L-arginine methyl ester (-NAME), a NO synthase inhibitor, into the striatum significantly potentiated NMDA-induced DA release. This effect of L-NAME was completely reversed in the presence of 50mM L-arginine (L-Arg). Administration of 1 mM NMDA significantly decreased the levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect of NMDA was not affected by concurrent administration of L-NAME. This study provides in vivo evidence for the involvement of NO in NMDA-induced DA release.

Involvement of Nitric Oxide in Dopaminergic Transmission in Rat Striatum: An In Vivo Electrochemical Study

In vivo electrochemical detection with a Nafion-coated carbon fiber working electrode, which provides information on the spatial and temporal dynamics of dopamine overflow, was used to investigate the involvement of nitric oxide (NO) in the dopaminergic transmission in the striatum of urethane-anesthetized Sprague-Dawley rats. A mixture of N-methyl-D-aspartate (NMDA) and nomifensine, a dopamine uptake blocker, was locally pressure-ejected to elicit a transient dopamine overflow from the dopamine-containing nerve terminals in the striatum. Local application of N omega-nitro-L-arginine methyl ester (L-NAME), which blocks endogenous NO formation, increased the magnitude of dopamine/release evoked by a subsequent NMDA and nomifensine application but resulted in no significant alteration in the time course. Furthermore, microejection of L-arginine, an NO precursor, or sodium nitroprusside (SNP), an NO generator, did not cause detectable changes in dopamine level in the striatal extracellular space. However, NMDA-induced dopamine release was profoundly inhibited with L-arginine or SNP pretreatment. In addition, NO affects dopamine uptake in rat striatum. Exogenous dopamine applied through a micropipette, reversibly and reproducibly, elicited an electrochemical signal. The time course of these signals was significantly prolonged by L-NAME treatment. These data suggest that NO is diversely involved in regulating dopaminergic transmission in rat striatum.

Dynamic analysis of ethanol effects on NMDA-evoked dopamine overflow in rat striatum

This study was undertaken to dynamically examine the effects of ethanol on the striatal dopaminergic transmission, in terms of N-methyl- d-aspartate (NMDA)-evoked dopamine release and dopamine uptake. In the striatum of urethane-anesthetized Sprague-Dawley rats, extracellular dopamine was measured using in vivo electrochemical detection coupled with a nafion-coated carbon fiber working electrode. Micro-ejection of NMDA evoked a transient dopamine release from the dopamine-containing nerve terminals in striatum. Local application of ethanol by pressure ejection did not elicit significant changes in spontaneous dopamine release. However, with ethanol pretreatment, the time course of NMDA-induced dopamine release was markedly prolonged while the magnitude and the rate of clearance were significantly reduced. These effects were compared to those of nomifensine, a dopamine uptake blocker. Nominfensine pretreatment was found to augment the time course of NMDA-evoked dopamine release analogous to those by ethanol pretreatment. Furthermore, pretreatment with ethanol did not increase the time course parameters of dopamine signals if dopamine releases were induced by co-application of NMDA and nomifensine. These data suggest that in addition to the attenuation of NMDA-evoked dopamine release, ethanol inhibits dopamine uptake in a similar fashion to that observed with nomifensine in situ in the striatum. Indeed, ethanol altered the uptake of exogenous dopamine from the extracellular space of striatal cortex. The time course of dopamine signals was prolonged and the rate of clearance was reduced after ethanol treatment. Taken together, our data demonstrate that ethanol simultaneously inhibits NMDA-evoked dopamine release and dopamine uptake in the striatum, suggesting the importance of the interplay between release and uptake in ethanol effects on striatal dopaminergic transmission.

Role of NMDA, AMPA and kainate receptors in mediating glutamate- and 4-AP-induced dopamine and acetylcholine release from rat striatal slices

Striatal slices, preincubated with [ 3H]dopamine and [ 14C]choline, were superfused continuously and subjected to electrical field stimulation (3 Hz) and perfused with amino acid analogues or 4-amino pyridine (4-AP). The released radioactivity was used to monitor release of the neurotransmitters dopamine (DA) and acetylcholine (ACh). Glutamate, NMDA (in the absence of Mg 2+ ), AMPA, kainic acid, domoate and 4-AP all induced DA and ACh release in a concentration-dependent manner. The DA and ACh release induced by NMDA (15 μM) and glutamate (1 mM) was essentially abolished by Mg 2+ (1.15 mM), whereas release induced by AMPA (100 μM), kainic acid (100 μM) or 4-AP (30μM) was not reduced. Tetrodotoxin (1 μM) essentially abolished the effects of NMDA, markedly reduced the effects of glutamate, AMPA and 4-AP, whereas the effect of kainic acid was only modestly affected. MK-801 (30 nM) reduced NMDA-induced DA release by some 70% and ACh release by 30%. MK-801 reduced 4-AP-induced DA release by 40% but not ACh release. CNQX in a concentration (10 μM) that scarcely affected NMDA-induced ACh release, but blocked that induced by AMPA, kainic acid or domoate, reduced the ACh release induced by 4-AP. In summary, DA and ACh release from rat striatum can be stimulated by activation of NMDA and non-NMDA glutamate receptors, and this mechanism is activated by the potassium channel blocker 4-AP.

Role of dynorphin and GABA in the inhibitory regulation of NMDA-induced dopamine release in striosome- and matrix-enriched areas of the rat striatum

Using a new superfusion procedure in vitro, we have previously reported that the NMDA-evoked release of newly synthesized 3H-dopamine (DA) was higher in matrix- than in striosome-enriched areas of the rat striatum. In addition, GABAergic medium-sized spiny neurons were shown to be indirectly involved in this regulation. Since dynorphin and GABA are colocalized in a population of medium-sized spiny neurons, the role of dynorphin-containing neurons in the NMDA-evoked release of 3H-DA has been investigated using the same superfusion procedure on rat striatal slices. (1) The NMDA (50 microM, 25 min application)-evoked release of 3H-DA was increased in the presence of naloxone (1 microM, continuously delivered) in both striatal compartments, the overall response being more elevated in the striosome-enriched area. (2) The TTX (1 microM, continuously delivered)-resistant NMDA-evoked responses were also enhanced in the presence of naloxone, but in this case, the disinhibitory effects of naloxone were similar in striosome- and matrix-enriched areas. (3) The selective kappa-agonist U-50488 (1 microM) totally reversed the naloxone-disinhibitory effect on the NMDA-evoked response in the matrix-enriched area, but only partially in the striosome-enriched area. It also completely prevented the disinhibitory effect of naloxone on the TTX-resistant NMDA-evoked release of 3H-DA in both compartments. (4) The bicuculline (5 microM)- and naloxone (1 microM)-disinhibitory effects on the NMDA-evoked release of 3H-DA were additive in the matrix- but not in the striosome-enriched areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala kindling does not alter the [formula omitted] receptor-channel complex which modulates dopamine release in the rat striatum and amygdala

Kindling is suggested to be critically associated with enhancement of N- methyl- d-aspartate (NMDA) type excitatory amino acid synaptic transmission. The present study examined effects of kindling on NMDA-induced dopamine (DA) efflux from slices of the rat striatum and amygdala. When assayed 5–7 days after the last evoked seizure, no difference was observed between kindled and non-kindled striatum in the ability of NMDA to induce DA release, or in the effect of MK-801 or 7-chlorokynurenic acid to inhibit the amino acid induced transmitter release. The present study revealed that NMDA receptors are also involved in the modulation of DA release in the amygdala. However, no difference was observed between kindled and non-kindled amygdala in the ability of NMDA to induce DA release. These results suggest that amygdala kindling does not alter activity of the NMDA receptor-channel complex modulating DA release in the striatum and amygdala.

In vivo modulation of excitatory amino acid receptors: microdialysis studies on N-methyl- d-aspartate-evoked striatal dopamine release and effects of antagonists

Striatal dopamine (DA) release was measured following intrastriatal (i.s.) administration of N-methyl- d-aspartate (NMDA) to unanesthetized, freely-moving rats. One hour after insertion of a removable microdialysis probe and perfusion with normal Ringer's solution, a modified Ringer's solution containing 100 mM potassium (high-K + Ringer's) was used to standardize the preparation. DA release following i.s. administration of NMDA (12.5 mM in normal Ringer's) was dose-dependent. When NMDA (12.5 mM) was administered in high-K + Ringer's, DA release was greatly potentiated. Administration of the competitive NMDA receptor antagonist aminophosphonovalerate (APV) in normal Ringer's prior to treatment with NMDA in high-K + Ringer's resulted in a significant reduction of DA release compared to control animals. In contrast, administration of APV prior to treatment with NMDA in normal Ringer's resulted in a significantly increased release of DA compared to controls. Administration of the non-competitive NMDA antagonist, dextromethorphan (DXT) prior to treatment with NMDA in normal Ringer's or NMDA in high-K + Ringer's caused significant reductions of DA release compared to controls. Intrastriatal DXT also caused dose-dependent inhibition of high-K + Ringer's-induced DA release. Similarly, administration of the non-specific calcium channel blocker, cadmium, prior to treatment with NMDA resulted in a significant decrease when compared to control values. Results of this study indicate that dose-dependent NMDA-induced striatal DA release is greatly potentiated by potassium suggesting that under physiological conditions in vivo, striatal NMDA receptors are mostly inactivated. The inhibitory effect of cadmium on NMDA-induced DA release suggests that activation of calcium-dependent mechanisms is responsible in large part for the ability of NMDA to release DA. NMDA-induced release of DA in the presence of high-K + Ringer's is blocked by both APV and DXT suggesting specific involvement of NMDA receptors, although the ability of DXT to inhibit both high-K + Ringer's- and NMDA-induced striatal DA release supports the concept that DXT may act as a calcium channel antagonist. Whereas DXT effectively inhibited DA release following administration of NMDA in physiologic Ringer's, APV potentiated DA release suggesting that APV functions as a partial agonist at NMDA receptors or that APV relieves an inhibitory mechanism, mediated through interneurons, on dopaminergic function.