An inverse correlation between the apparent rate of dopamine clearance and tonic autoinhibition in subdomains of the rat striatum: a possible role of transporter-mediated dopamine efflux

The dopaminergic terminal field in the rat striatum is compartmentalized into sub-domains that exhibit distinct dynamics of electrically evoked dopamine release. The fast striatal domains, where dopamine release is predominantly vesicular, exhibit conventional dopaminergic activity. However, vesicular dopamine release is tonically autoinhibited in the slow domains, which suggests that dopamine reaches the autoreceptors via a non-vesicular route. Hence, it appears that the domains use distinct mechanisms to regulate the basal dopamine concentration available to activate, or not, pre-synaptic autoinhibitory receptors. However, direct detection of local variations in tonic extracellular dopamine concentrations is not yet possible. So, the present study employed voltammetry to test the hypothesis that the apparent rate of dopamine clearance from the extracellular space should be domain-dependent. The apparent rate of dopamine clearance is equal to the difference in the rates of dopamine release and uptake that determine extracellular dopamine concentrations. This study confirms that the apparent rate of dopamine clearance is slower in the slow striatal domains where vesicular dopamine release is tonically autoinhibited. These findings support the view that the basal concentration in slow domains is maintained by a non-vesicular release process, possibly transporter-mediated efflux.     

Cortical Regulation of Subcortical Dopamine Release: Mediation via the Ventral Tegmental Area

Abstract: In vivo microdialysis was used to determine the extent to which ionotropic glutamate receptors in the ventral tegmental area (VTA) regulate dopamine release in the nucleus accumbens. Coapplication of 2-amino-5-phosphonopentanoic acid (AP5; 200 µ M ) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 µ M ) to the VTA via reverse dialysis decreased extracellular concentrations of dopamine in the nucleus accumbens by ∼30%. In accordance with previous results, electrical stimulation of the prefrontal cortex increased dopamine release by 60%. Application of AP5 and CNQX to the VTA during cortical stimulation blocked the effect of stimulation on dopamine release. These results indicate that ionotropic glutamate receptors in the VTA are critically involved in basal and evoked dopamine release in the nucleus accumbens and suggest that a glutamatergic projection from the prefrontal cortex regulates the activity of dopaminergic neurons in the VTA.     

Chronic nicotine causes functional upregulation of ionotropic glutamate receptors mediating hippocampal noradrenaline and striatal dopamine release

It has been proposed that (-)-nicotine can activate release-stimulating presynaptic nicotinic acetylcholine receptors (nAChRs) on glutamatergic nerve terminals to release glutamate, which in turn stimulates the release of noradrenaline (NA) and dopamine (DA) via presynaptic ionotropic glutamate receptors on catecholaminergic terminals. The objective of this study was to compare the function of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazide-4-propionic acid (AMPA) glutamate receptors in synaptosomes of rat hippocampus and striatum following acute and chronic (-)-nicotine administration. In hippocampal synaptosomes, prelabeled with [3H]NA, both the NMDA- and AMPA-evoked releases were higher in (-)-nicotine-treated (10 days) than in (-)-nicotine-treated (1 day) or vehicle-treated (1 or 10 days) rats. In striatal synaptosomes prelabeled with [3H]DA, the NMDA-evoked, but not the AMPA-evoked, release of [3H]DA was higher in (-)-nicotine-treated (10 days) than in nicotine-treated (1 day) or vehicle-treated (1 or 10 days) animals. Chronic (-)-nicotine did not affect catecholamine uptake, basal release and release evoked by high-K+ depolarization. Thus, chronic exposure to nicotine enhances the function of ionotropic glutamate receptors mediating noradrenaline release in the hippocampus and dopamine release in the striatum.     

Functional striatal hypodopaminergic activity in mice lacking adenosine A(2A) receptors.

Adenosine and caffeine modulate locomotor activity and striatal gene expression, partially through the activation and blockade of striatal A(2A) receptors, respectively. The elucidation of the roles of these receptors benefits from the construction of A(2A) receptor-deficient mice (A(2A)-R(-/-)). These mice presented alterations in locomotor behaviour and striatal expression of genes studied so far, which are unexpected regarding the specific expression of A(2A) receptor by striatopallidal neurones. To clarify the functions of A(2A) receptors in the striatum and to identify the mechanisms leading to these unexpected modifications, we studied the basal expression of immediate early and constitutive genes as well as dopamine and glutamate neurotransmission in the striatum. Basal zif268 and arc mRNAs expression was reduced in mutant mice by 60-80%, not only in the striatum but also widespread in the cerebral cortex and hippocampus. Striatal expression of substance P and enkephalin mRNAs was reduced by about 50% and 30%, respectively, whereas the expression of GAD67 and GAD65 mRNAs was slightly increased and unaltered, respectively. In vivo microdialysis in the striatum revealed a 45% decrease in the extracellular dopamine concentration and three-fold increase in extracellular glutamate concentration. This was associated with an up-regulation of D(1) and D(2) dopamine receptors expression but not with changes in ionotropic glutamate receptors. The levels of tyrosine hydroxylase and of striatal and cortical glial glutamate transporters as well as adenosine A(1) receptors expression were indistinguishable between A(2A)-R(-/-) and wild-type mice. Altogether these results pointed out that the lack of A(2A) receptors leads to a functional hypodopaminergic state and demonstrated that A(2A) receptors are necessary to maintain a basal level in immediate early and constitutive genes expression in the striatum and cerebral cortex, possibly via their control of dopamine pathways.     

Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum

Summary We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, usingin vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-a-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DAsynthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DArelease. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.     

GABA and glutamate signaling: homeostatic control of adult forebrain neurogenesis

The neurotransmitter GABA exerts a strong negative influence on the production of adult-born olfactory bulb interneurons via tightly regulated, non-synaptic GABAergic signaling. After discussing some findings on GABAergic signaling in the neurogenic subventricular zone (SVZ), we provide data suggesting ambient GABA clearance via two GABA transporter subtypes and further support for a non-vesicular mechanism of GABA release from neuroblasts. While GABA works in cooperation with the neurotransmitter glutamate during embryonic cortical development, the role of glutamate in adult forebrain neurogenesis remains obscure. Only one of the eight metabotropic glutamate receptors (mGluRs), mGluR5, has been reported to tonically increase the number of proliferative SVZ cells in vivo, suggesting a local source of glutamate in the SVZ. We show here that glutamate antibodies strongly label subventricular zone (SVZ) astrocytes, some of which are stem cells. We also show that some SVZ neuroblasts express one of the ionotropic glutamate receptors, AMPA/kainate receptors, earlier than previously thought. Collectively, these findings suggest that neuroblast-to-astrocyte GABAergic signaling may cooperate with astrocyte-to-neuroblast glutamatergic signaling to provide strong homeostatic control on the production of adult-born olfactory bulb interneurons. An erratum to this article can be found at     

Blockade of Striatal 5-Hydroxytryptmine2 Receptors Reduces the Increase in Extracellullar Concentrations of Dopamine Produced by the Amphhetamine analogue 3,4-Methylenedioxymethamphetamine

Abstract: 5-Hydroxytryptamine₂ (5-HT₂) receptor antagonists have been shown to interfere with the stimulation of striatal dopamine synthesis and release produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). To localize the receptors responsible for the attenuation of MDMA-induced release, 5-HT₂ receptor antagonists were infused via the microdialysis probe directly into the brains of awake, freely moving rats before the systemic administration of MDMA. Intrastriatal infusions of the selective 5-HT₂ antagonist MDL 100, 907 produced a concentration-dependent inhibition of MDMA-induced dopamine release. Similar results were observed with intrastriatal infusions of the 5-HT₂ antagonist amperozide. In contrast, infusion of MDL 100, 907 into the midbrain region near the dopaminergic cell bodies was with out effect on the MDMA-induced elevation of extracellular dopamine in the ipsilateral striatum. Neither antagonist attenuated basal transmitter efflux nor the MDMA-stimulated release of [³H]dopamine from striatal slices in vitro indicating that the in vivo effect of the antagonists was not due to inhibition of the dopamine uptake carrier. Intrastriatal infusion of tetrodotoxin reduced both basal and MDMA-stimulated dopamine efflux and eliminated the effect of intrastriatal MDL 100, 907. The results indicate that 5-HT₂ receptors located in the striatum augment the release of dopamine produced by high doses of MDMA. Furthermore, these 5-HT₂ receptors appear to be located on nondopaminergic elements of the striatum.     

In vivo modulation of α7 nicotinic receptors on striatal glutamate release induced by anatoxin-A

In vitro studies suggest that α7 nicotinic receptors located on striatal glutamatergic terminals stimulate the release of glutamate which in turn acts at ionotropic glutamate receptors on dopaminergic terminals to increase dopamine release. However, this mechanism has never been observed in in vivo studies. In the present work, the effect of the nicotinic receptors agonist, anatoxin-a, on striatal glutamate and dopamine release has been studied. Using in vivo microdialysis technique, our results have shown that anatoxin-a evokes glutamate release in a dependent way of activation α7 nicotinic receptors. The increase of glutamate is followed by an increase on dopamine levels. These results represent a clear in vivo evidence of the striatal modulation of dopamine by means of glutamate release through α7 nicotinic receptors.     

Endogenous interaction of glutamate and dopamine in the basal ganglia of the awake rat during aging

The interaction of glutamate and dopamine in the basal ganglia of fully conscious rat during the normal process of aging is reviewed. Using a novel approach, that of blocking the reuptake of glutamate, the effects of increasing concentrations of endogenous glutamate on the extracellular concentrations of dopamine in striatum and nucleus accumbens in the young rat were investigated. It was found that increasing concentrations of glutamate correlated significantly with increasing concentrations of dopamine in striatum and nucleus accumbens. Moreover the increase of dopamine in both structures was significantly reduced after blockade of NMDA and AMPA/kainate glutamate receptors, suggesting that the increase of dopamine was mediated by glutamate. The interaction glutamate/dopamine expressed by its ratio showed a significant age-related decrease in nucleus accumbens but not in striatum, so that to a given amount of glutamate less increase of dopamine is produced. It is suggested that the interaction glutamate-dopamine represents a balanced input to the GABA neuron in the basal ganglia and that during aging this balance is disrupted. In addition, we also speculate on the significance of this glutamate-dopamine disruption in relation to the changes in motor behavior found with age.     

Extracellular Striatal Dopamine and Glutamate After Decortication and Kainate Receptor Stimulation, as Measured by Microdialysis

Abstract: Disruption of corticostriatal glutamate input in the striatum decreased significantly extracellular striatal glutamate and dopamine levels. Local administration of 300 µ M concentration of excitatory receptor agonist kainic acid increased significantly extracellular striatal dopamine in intact freely moving rats. These findings support the hypothesis that glutamate exerts a tonic facilitatory effect on striatal dopamine release. The effect of kainic acid on extracellular striatal glutamate concentration in intact rats was a biphasic increase. The first glutamate increase can be explained by stimulation of presynaptic kainate receptors present on corticostriatal glutamatergic nerve terminals; the second increase is probably the result of a continuous interaction of the different striatal neurotransmitters after disturbance of their balance. Release of dopamine and glutamate was modulated differently in the intact striatum and in the striatum deprived of corticostriatal input. Dopamine release in the denervated striatum after kainate receptor stimulation was significantly lower than in intact striatum, confirming the so-called cooperativity between glutamate and kainic acid. Loss of presynaptic kainate receptors on the glutamatergic nerve terminals after decortication resulted in a loss of effect of kainic acid on glutamate release in denervated striatum. Aspartate showed no significant changes in this study.     

Glutamatergic Regulation of Basal and Stimulus-Activated Dopamine Release in the Prefrontal Cortex

Abstract: The present study was undertaken to determine whether basal and stimulus-activated dopamine release in the prefrontal cortex (PFC) is regulated by glutamatergic afferents to the PFC or the ventral tegmental area (VTA), the primary source of dopamine neurons that innervate the rodent PFC. In awake rats, blockade of NMDA or α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in the VTA, or blockade of AMPA receptors in the PFC, profoundly reduced dopamine release in the PFC, suggesting that the basal output of dopamine neurons projecting to the PFC is under a tonic excitatory control of NMDA and AMPA receptors in the VTA, and AMPA receptors in the PFC. Consistent with previous reports, blockade of cortical NMDA receptors increased dopamine release, suggesting that NMDA receptors in the PFC exert a tonic inhibitory control on dopamine release. Blockade of NMDA or AMPA receptors in the VTA as well as blockade of AMPA receptors in the PFC reduced the dopaminergic response to mild handling, suggesting that activation of glutamate neurotransmission also regulates stimulus-induced increase of dopamine release in the PFC. In the context of brain disorders that may involve cortical dopamine dysfunction, the present findings suggest that abnormal basal or stimulus-activated dopamine neurotransmission in the PFC may be secondary to glutamatergic dysregulation.     

Endogenous Dopamine Increases Extracellular Concentrations of Glutamate and GABA in Striatum of the Freely Moving Rat: Involvement of D1 and D2 Dopamine Receptors

Interactions between endogenous dopamine, glutamate, GABA, and taurine were investigated in striatum of the freely moving rat by using microdialysis. Intrastriatal infusions of the selective dopamine uptake inhibitor nomifensine (NMF) were used to increase the endogenous extracellular dopamine. NMF produced a dose-related increase in extracellular dopamine and also increased extracellular concentrations of glutamate, GABA, and taurine. Extracellular increases of dopamine were significantly correlated with extracellular increases of glutamate and GABA, but not taurine. To investigate whether the increased extracelular dopamine produced by NMF was responsible for the concomitant increase of glutamate and GABA, D1, and D2 receptor antagonists were used. Dopamine receptor antagonists D1 (SCH23390) and D2 (sulpiride) significantly attenuated the increases of glutamate and GABA produced by NMF. These data suggest that endogenous dopamine, through both D1 and D2 dopamine receptors, plays a role in releasing glutamate and GABA in striatum of the freely moving rat.     

Limited regulation of somatodendritic dopamine release by voltage-sensitive Ca channels contrasted with strong regulation of axonal dopamine release

The mechanism underlying somatodendritic release of dopamine (DA) appears to differ from that of axon-terminal release. Specifically, somatodendritic DA release in the substantia nigra pars compacta (SNc) persists in low extracellular Ca2+ concentrations that are insufficient to support axonal release in striatum, suggesting that limited Ca2+ entry is necessary to trigger somatodendritic release. Here, we compared the role of voltage-dependent Ca2+ channels in mediating DA release in striatum versus SNc using specific blockers of N-, P/Q-, T-, R- and L-type Ca2+ channels individually and in combination. Release of DA evoked by a single stimulus pulse in the dorsal striatum and SNc of guinea-pig brain slices was monitored in real time using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Single-pulse evoked DA release was shown to be independent of regulation by concurrently released glutamate or GABA acting at ionotropic receptors in both regions. Under these conditions, striatal DA release was completely prevented by an N-type channel blocker, omega-conotoxin GVIA (100 nm), and was decreased by 75% by the P/Q-type channel blocker omega-agatoxin IVA (200 nm). Blockade of T-type channels with Ni2+ (100 microm) or R-type channels with SNX-482 (100 nm) decreased axonal release in striatum by 25%, whereas inhibition of L-type channels with nifedipine (20 microm) had no effect. By contrast, none of these Ca2+-channel blockers altered the amplitude of somatodendritic DA release in the SNc. Even a cocktail of all blockers tested did not alter release-signal amplitude in the SNc, although the duration of the release response was curtailed. The limited involvement of voltage-dependent Ca2+ channels in somatodendritic DA release provides further evidence that minimal Ca2+ entry is required to trigger the release process, compared with that required for axon-terminal release.     

Vesicular and nonvesicular glutamate release in the nucleus accumbens during a forced switch in behavioral strategy

By means of in vivo microdialysis combined with HPLC analysis, we have shown that glutamate extracellular level in the rat n. accumbens increases during a forced switch in behavioral strategy. When infused in the n. accumbens, a Na+ channel blocker tetrodotoxin (TTX, 1 microM) completely prevents this increase whereas a potent cystine/glutamate exchanger blocker (S)-4-carboxyphenylglycine ((S)-4-CPG, 5 microM) has no effect. In contrast, TT (1 microM), infused in the n. accumbens, fails to significantly alter basal level of extracellular glutamate in this region whereas (S)-4-CPG (5 microM) produced a significant decrease. Our data suggest that basal and factional glutamate releases in the n. accumbens are differently regulated. The source of basal glutamate release is a non-vesicular release via cystine/glutamate exchanger. Functional glutamate release observed during a forced switch in behavioral strategy derives from vesicular synaptic pool.     

Presynaptic glutamate receptors: physiological functions and mechanisms of action

Glutamate acts on postsynaptic glutamate receptors to mediate excitatory communication between neurons. The discovery that additional presynaptic glutamate receptors can modulate neurotransmitter release has added complexity to the way we view glutamatergic synaptic transmission. Here we review evidence of a physiological role for presynaptic glutamate receptors in neurotransmitter release. We compare the physiological roles of ionotropic and metabotropic glutamate receptors in short- and long-term regulation of synaptic transmission. Furthermore, we discuss the physiological conditions that are necessary for their activation, the source of the glutamate that activates them, their mechanisms of action and their involvement in higher brain function.     

Effects of Endogenous Glutamate on Extracellular Concentrations of GABA, Dopamine, and Dopamine Metabolites in the Prefrontal Cortex of the Freely Moving Rat: Involvement of NMDA and AMPA/KA Receptors

Using microdialysis, interactions between endogenous glutamate, dopamine, and GABA were investigated in the medial prefrontal cortex of the freely moving rat. Interactions between glutamate and other neurotransmitters in the prefrontal cortex had already been studied using pharmacological agonists or antagonists of glutamate receptors. This research investigated whether glutamate itself, through the increase of its endogenous extracellular concentration, is able to modulate the extracellular concentrations of GABA and dopamine in the prefrontal cortex. Intracortical infusions of the selective glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) were used to increase the endogenous extracellular glutamate. PDC (0.5, 2, 8, 16 and 32 mM) produced a dose-related increase in dialysate glutamate in a range of 1–36 M. At the dose of 16 mM, PDC increased dialysate glutamate from 1.25 to 28 M. PDC also increased extracellular GABA and taurine, but not dopamine; and decreased extracellular concentrations of the dopamine metabolites DOPAC and HVA. NMDA and AMPA/KA receptor antagonists were used to investigate whether the increases of extracellular glutamate were responsible for the changes in the release of GABA, and dopamine metabolites. The NMDA antagonist had no effect on the increase of extracellular GABA, but blocked the decreases of extracellular DOPAC and HVA, produced by PDC. In contrast, the AMPA/KA antagonist blocked the increases of extracellular GABA without affecting the decreases of extracellular DOPAC and HVA produced by PDC. These results suggest that endogenous glutamate acts preferentially through NMDA receptors to decrease dopamine metabolism, and through AMPA/KA receptors to increase GABAergic activity in the medial prefrontal cortex of the awake rat.     

Characterization of Basal and Morphine-Induced Uridine Release in the Striatum: An In Vivo Microdialysis Study in Mice

Uridine, a pyrimidine nucleoside, has been proposed to be a potential signaling molecule in the central nervous system. The understanding of uridine release in the brain is therefore of fundamental importance. The present study was performed to determine the characteristics of basal and morphine-induced uridine release in the striatum of freely moving mice by using the microdialysis technique. To ascertain whether extracellular uridine was derived from neuronal release, the following criteria were applied: sensitivity to (a) K⁺ depolarization, (b) Na⁺ channel blockade and (c) removal of extracellular Ca²⁺. Uridine levels were not greatly affected by infusion of tetrodotoxin (TTX) and were unaffected by either Ca²⁺-free medium or in the presence of EGTA (a calcium chelator), suggesting that basal extracellular uridine levels were maintained mainly by non-vesicular release mechanisms. In addition, both systemic and local application of morphine increased striatal uridine release. The morphine-induced release was reversed by naloxone pretreatment, but was unaffected by TTX or EGTA infusion. Moreover, co-administration of morphine and nitrobenzylthioinosine (NBTI, an inhibitor of nucleotide transporter) produced increases of uridine levels similar to that produced by NBTI or morphine alone, suggesting a nucleotide transporter mechanism involved. Taken together, these findings suggest that morphine produces a μ-opioid receptor-mediated uridine release via nucleoside transporters in a TTX- and calcium-independent manner.     

Intraplantar injection of glutamate evokes peripheral adenosine release in the rat hind paw: involvement of peripheral ionotropic glutamate receptors and capsaicin-sensitive sensory afferents

Glutamate receptors have been identified on the peripheral terminals of both primary sensory afferents and sympathetic post-ganglionic neurons, and activation of these receptors produces peripheral sensitization and enhances nociception. Adenosine is an endogenous agent that has a regulatory effect on pain. In brain and spinal cord, adenosine release can be promoted by excitatory amino acids. In the present study, we used in vivo microdialysis to determine whether glutamate also can release adenosine in peripheral tissues. Rats were anesthetized with pentobarbital and microdialysis probes were implanted into the subcutaneous tissue of the plantar aspect of the rat hind paw. Subcutaneous injection of glutamate (50 microL, 0.3-100 micromol) evoked a short-lasting adenosine release immediately following drug injection. Co-administration of either the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocipine maleate (MK-801, 1 nmol) or the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline (CNQX, 10 nmol) with glutamate blocked such release, suggesting an involvement of peripheral ionotropic glutamate receptors in this response. Systemic pre-treatment with capsaicin, a neurotoxin selective for unmyelinated sensory afferents, significantly reduced glutamate-evoked peripheral adenosine release, but release was not affected by systemic pre-treatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic nerve efferents. Neither MK-801 nor CNQX blocked 5% formalin-evoked adenosine release, suggesting adenosine release by formalin is not secondary to ionotropic glutamate receptor activation. We conclude that administration of glutamate evokes peripheral adenosine release, and that peripheral ionotropic glutamate receptors on unmyelinated sensory afferents are involved in such release. The released adenosine may provide a negative feedback control on nociception.     

Influence of local administration of apomorphine on citrulline extracellular level in the striatum: participation of the dopamine D1 and D2 receptors

By means of in vivo microdialysis combined with HPLC analysis, we have shown that local infusions of 1 mM N-nitro-L-arginine (NO-synthase inhibitors) in the rat striatum reduced, and infusions of 100 microM apomorphine (agonists of the dopamine receptors) increased the level of citrulline (a NO co-product) in extracellular space of this structure. The apomorphine-induced increase in citrulline extracellular levels in the striatum was completely prevented by infusions of N-nitro-L-arginine in this structure, and 10 microM raclopride (dopamine D2 receptor blocker), but not by infusions of 50 microM SCH-23390 (dopamine D1 receptor blocker). The data obtained suggest that the increase in citrulline extracellular levels in striatum resulted from local activation of NO-synthase, and this effect is mediated by D2 rather than D1 dopamine receptors.     

Effects of endogenous glutamate on extracellular concentrations of taurine in striatum and nucleus accumbens of the awake rat: Involvement of NMDA and AMPA/kainate receptors

Summary. Using microdialysis, the effects of endogenous glutamate on extracellular concentrations of taurine in striatum and nucleus accumbens of the awake rat were investigated. The glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) was used to increase the extracellular concentration of glutamate. PDC (1, 2 and 4 mM) produced a dose-related increase of extracellular concentrations of glutamate and taurine in striatum and nucleus accumbens. Increases of extracellular taurine were significantly correlated with increases of extracellular glutamate, but not with PDC doses, which suggests that endogenous glutamate produced the observed increases of extracellular taurine in striatum and nucleus accumbens. The role of ionotropic glutamate receptors on the increases of taurine was also studied. In striatum, perfusion of the antagonists of NMDA and AMPA/kainate glutamate receptors attenuated the increases of extracellular taurine. AMPA/kainate, but not NMDA receptors, also reduced the increases of extracellular taurine in nucleus accumbens. These results suggest that glutamate-taurine interactions exist in striatum and nucleus accumbens of the awake rat. Received March 5, 1999/Accepted September 22, 1999