L. Barbeito

Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo

When applied locally to the caudate nucleus of the halothane-anaesthetized cat, riluzole (10(-5) M) markedly reduced (-57%) the spontaneous release of glutamate. This effect seems to be specific, since the efflux of the other amino acids, including aspartate was not affected. Indicating further its selective inhibitory effect on the spontaneous release of glutamate, the prolonged (90 min) application of riluzole (10(-5) M) enhanced the size of the potassium-releasable pool of glutamate, but not that of aspartate. This effect of riluzole was not noticed with classical anti-glutamatergic drugs, tested in the same conditions.

Substance P and neurokinin A regulate by different mechanisms dopamine release from dendrites and nerve terminals of the nigrostriatal dopaminergic neurons

Numerous striatal neurons innervating the substantia nigra contain substance P and/or neurokinin A. In contrast to substance P or neurokinin A, little neurokinin B is found in the substantia nigra. This led us to compare the effects of nigral application of these tachykinins on the release of dopamine from dendrites and nerve terminals of nigrostriatal dopaminergic neurons. Experiments were made in halothane-anesthetized cats implanted with one push-pull cannula in the substantia nigra and another in the ipsilateral caudate nucleus [3H]Tyrosine was delivered continuously to each push-pull cannula and the release of newly synthesized [3H]dopamine measured in the superfusate. Unlike substance P or neurokinin A, neurokinin B (10(-8) M) applied for 30 min into the pars compacta of the substantia nigra was without effect on the release of [3H]dopamine from nerve terminals or dendrites. When either substance P (10(-8) M) or neurokinin A (10(-8) M) was applied into the pars compacta, the release of [3H]dopamine from nerve terminals was enhanced. While neurokinin A also stimulated the dendritic release of [3H]dopamine, this was reduced by substance P. At a lower concentration (10(-9) M), neurokinin A induced similar effects to those observed at 10(-8) M whereas substance P (10(-9) M) stimulated moderately [3H]dopamine release from nerve terminals but did not affect the dendritic release of the [3H]amine. When superfused into the pars reticulata, substance P (10(-8) M) still stimulated [3H]dopamine release from nerve terminals but not from dendrites while neurokinin A (10(-8) M) was without effect either in the caudate nucleus or the substantia nigra. Additional experiments were made to determine whether or not substance P (10(-8) M) or neurokinin A (10(-8) M) act directly on nigral dopaminergic neurons when applied into the pars compacta. The effects of substance P on [3H]dopamine release from nerve terminals and dendrites were prevented when 2-amino-6-trifluoromethoxy benzothiazole (10(-5) M), an antagonist of glutamatergic transmission, was applied continuously into the caudate nucleus. In contrast, the stimulatory effects of neurokinin A on [3H]dopamine release from nerve terminals and dendrites were insensitive to 2-amino-6-trifluoromethoxy benzothiazole (10(-5) M). These results suggest that neurokinin A, but not substance P, acts directly on dopaminergic cells. In the light of previous observations, we propose that the effects of substance P on dopaminergic transmission are mediated by a nigro-thalamo-cortico-striatal loop.(ABSTRACT TRUNCATED AT 400 WORDS)

Presynaptic regulation of dopaminergic transmission in the striatum

Summary1.In vitro studies have indicated that several transmitters present in the striatum can regulate presynaptically the release of dopamine (DA) from nerve terminals of the nigrostriatal DA neurons.2.The receptors involved in these local regulatory processes are located or not located on DA nerve terminals.3.Recentin vivo investigations have demonstrated that the corticostriatal glutamatergic neurons facilitate presynaptically the release of DA and have allowed the analysis of the respective roles of presynaptic events and nerve activity in the control of DA transmission.

Glutamate Receptors of a Quisqualate‐Kainate Subtype are Involved in the Presynaptic Regulation of Dopamine Release in the Cat Caudate Nucleus in vivo

Experiments were conducted with halothane‐anesthetized cats implanted with a push‐pull cannula in the caudate nucleus in order to estimate the effects of glutamate (GLU) agonists on the release of 3H‐dopamine continuously synthesized from 3H‐tyrosine. In the presence of tetrodotoxin (TTX), glutamate (10−8 M, 10−4 M) and kainate (KAI) (10−5 M) stimulated the release of 3H‐dopamine while quisqualate (10−5 M) and N‐methyl‐D‐aspartate (NMDA) (10−5 M) were without effect. The stimulatory effect of kainate (10−5 M) on 3H‐dopamine release did not seem to be mediated by glutamate released from corticostriatal fibers, as not only kainate, but also quisqualate (QUI) and N‐methyl‐D‐aspartate enhanced the efflux of glutamate through a tetrodotoxin‐resistant process. Riluzole (10−5 M), gamma‐D‐glutamyl‐glycine (GDGG) (10−5 M) and glutamine‐diethyl‐ester (10−5 M) prevented the stimulatory effect of kainate (10−5 M) while 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione (CNQX) (10−5 M), kynurenate (10−5 M) and 2‐amino‐5‐phosphonovalerate (APV) (10−5 M) were without effect. In the presence of concanavalin A (CONA) (10−7 M), a lectin which is known to prevent the quisqualate‐evoked desensitization of glutamate receptors, quisqualate (10−5 M) stimulated the release of 3H‐dopamine. In addition, in the absence of concanavalin A, quisqualate (10−5 M) blocked the stimulatory effects of kainate (10−5 M) or glutamate (10−4 M) on 3H‐dopamine release. These results suggest the involvement of receptors of the quisqualate/kainate subtype in the direct glutamate‐induced presynaptic facilitation of dopamine release. In contrast to what was observed in the presence of tetrodotoxin, in the absence of the neurotoxin, high concentrations of glutamate (10−4 M) and kainate (10−5 M) reduced rather than stimulated the release of 3H‐dopamine. A weak inhibitory effect was also observed with quisqualate (10−5 M) while N‐methyl‐D‐aspartate (10−5 M) was without effect. In the light of previous studies, these latter observations suggest that glutamate can also exert an indirect inhibitory presynaptic influence on the release of dopamine from nerve terminals of the nigrostriatal dopaminergic neurons by acting on receptors of the quisqualate/kainate subtype located on striatal GABAergic neurons.

Activation of the bilateral corticostriatal glutamatergic projection by infusion of GABA into thalamic motor nuclei in the cat: An in vivo release study

The unilateral application of GABA (10(-5) M; 30 min) into thalamic motor nuclei of the cat increases the release of dopamine in both caudate nuclei. This effect has been suggested to be related to an activation of the bilateral corticostriatal glutamatergic projection, glutamate exerting a presynaptic facilitatory influence on dopamine release. To explore this hypothesis further, halothane-anesthetized cats implanted with push-pull cannulae were used in order to examine the effects of such a GABA application on the release of glutamate in both caudate nuclei. Aspartate, alanine, glutamine, serine and tyrosine were also measured in the superfusates. The unilateral application of GABA (10(-5) M; 30 min) into thalamic motor nuclei increased the release of glutamate bilaterally. Although less pronounced, ipsi- or bilateral increases in the efflux of alanine, glutamine and tyrosine were also observed. Contralateral changes in the efflux of glutamate, alanine and tyrosine were prevented following acute section of the corpus callosum. In addition, when applied continuously into one caudate nucleus, 2-amino-5-phosphonovaleric acid, a blocker of N-methyl-D-aspartate receptors, prevented the GABA-induced increase in alanine or tyrosine efflux but did not affect the enhanced release of glutamate. These results confirm that the unilateral application of GABA in thalamic motor nuclei activates a thalamo-cortico-striatal neuronal loop leading to the stimulation of glutamate release in both caudate nuclei. Changes in the efflux of other amino acids could be linked to increased metabolic activity of striatal target cells resulting from the increased release of glutamate and from its effect on N-methyl-D-aspartate receptors.

Specific role of n-acetyl-aspartyl-glutamate in the in vivo regulation of dopamine release from dendrites and nerve terminals of nigrostriatal dopaminergic neurons in the cat

Levels of N-acetyl-aspartyl-glutamate measured by high-pressure liquid chromatography were found to be very high in the cat substantia nigra, particularly in the pars compacta, while those in the caudate nucleus were much lower. In halothane-anaesthetized cats implanted with push-pull cannulae, N-acetyl-aspartyl-glutamate (10(-8) M) induced a marked and prolonged release of newly synthesized [3H]dopamine, when infused into the posterior but not into the anterior part of the caudate nucleus. In contrast, in the presence of tetrodotoxin (10(-6) M), N-acetyl-aspartyl-glutamate (10(-8) M) reduced the residual release of [3H]dopamine; this effect was also more pronounced in the posterior than in the anterior part. In the conditions used, as indicated by experiments with [3H]N-acetyl-aspartyl-glutamate no glutamate was formed from the infused N-acetyl-aspartyl-glutamate. Ibotenate (10(-5) M) induced changes in [3H]dopamine release in both the absence and presence of tetrodotoxin, which were closely similar to those observed with N-acetyl-aspartyl-glutamate. Responses induced by either N-acetyl-aspartyl-glutamate or ibotenate were not mediated by N-methyl-D-aspartate receptors since N-methyl-D-aspartate stimulated the release of [3H]dopamine only when used in a high concentration (10(-4) M) and applied in a magnesium-free superfusion medium in both the presence of glycine (10(-6) M) and strychnine (10(-6) M). In addition, the stimulatory effect of N-methyl-D-aspartate persisted in the presence of tetrodotoxin; it was of similar amplitude in both parts of the caudate nucleus and of shorter duration than that evoked by either N-acetyl-aspartyl-glutamate or ibotenate alone. N-Acetyl-aspartyl-glutamate interacted with dopaminergic neurons not only presynaptically in the caudate nucleus but also in the substantia nigra since a marked increase in [3H]dopamine release was observed both from local dendrites and from nerve terminals in the ipsilateral caudate nucleus when N-acetyl-aspartyl-glutamate (10(-7) M) was infused locally into the substantia nigra pars compacta. No effect could be seen in contralateral structures. The isomer of natural N-acetyl-aspartyl-glutamate, beta-N-acetyl-aspartyl-glutamate (10(-7) M), had no effect on [3H]dopamine release when applied similarly in the substantia nigra, thus confirming the specificity of the action of N-acetyl-aspartyl-glutamate.

Respective contributions of neuronal activity and presynaptic mechanisms in the control of the in vivo release of dopamine

Studies performed in several in vivo and in vitro conditions have demonstrated that the release of dopamine from nerve terminals of the nigrostriatal dopaminergic neurons depends not only on the activity of dopaminergic cells but also on presynaptic regulations by heterologous fibers. The presynaptic facilitation of dopamine release by the cortico-striatal glutamatergic neurons has been particularly investigated. A quisqualate/kainate receptor subtype is involved in the direct (tetrodotoxine-resistant) presynaptic regulation of dopamine release by glutamate. The respective roles of presynaptic events and nerve activity in the control of dopaminergic transmission are discussed.

Depolarization-evoked release of N-acetyl-L-aspartlyl-L-glutamate from rat brain synaptosomes

Depolarization by potassium and veratridine stimulated the release of N-acetyl-L-aspartyl-L-glutamate from crude synaptosomes prepared from the rat mesencephalon and diencephalon. The potassium-evoked release of N-acetyl-L-aspartyl-L-glutamate was calcium-dependent and the stimulatory effect of veratridine was prevented by tetrodotoxin.

Cholecystokinin: Corelease with dopamine from nigrostriatal neurons in the cat.

Halothane‐anaesthetized cats were implanted with push‐pull cannulae to demonstrate the in vivo release of cholecystokinin‐like immunoreactivity (CCK‐LI) in the substantia nigra and the ipsilateral caudate nucleus. The spontaneous and the calcium‐dependent potassium‐evoked release of CCK‐LI were observed in both structures. In addition, the local application of tetrodotoxin (10−6 M) reduced the spontaneous release of the peptide. 6‐OHDA lesions made in the substantia nigra pars compacta led to a complete destruction of nigrostriatal dopaminergic neurons. CCK‐LI levels were not affected in the caudate nucleus but were reduced substantially in the substantia nigra. The activation of dopaminergic cells induced by the nigral application of alpha‐methyl‐para‐tyrosine (10−4 M) stimulated the release of CCK‐LI and dopamine in the ipsilateral caudate nucleus, whilst opposite effects were seen in the substantia nigra. Similar results were obtained when dopaminergic transmission was blocked in the caudate nucleus suggesting that the evoked release of CCK‐LI by the alpha‐methyl‐para‐tyrosine treatment originates from dopaminergic nerve terminals and not from other CCK‐LI containing fibres in response to released dopamine. Dopamine (10−7 M) as well as the D1 agonist SKF 38393 (10−5 M) stimulated CCK‐LI release when applied into the caudate nucleus while the D2 agonist, LY 171555 (10−6 M) slightly reduced peptide release. The local application of cholecystokinin‐8 sulfate (CCK‐8S) (10−8 M, for 30 min) into the substantia nigra pars compacta increased the firing rate of dopaminergic cells and stimulated the release of newly synthesized 3H‐dopamine from dendrites and nerve terminals.

Role of excitatory amino acids in the direct and indirect presynaptic regulation of dopamine release from nerve terminals of nigrostriatal dopaminergic neurons

SummaryIn vivo experiments carried out in halothane-anaesthetized cats implanted with push-pull cannulae demonstrated that glutamate (GLU) released from corticostriatal fibers triggers the release of dopamine (DA), even in the absence of activity in nigral DA cells. As shown in vitro, using rat striatal slices or synaptosomes or in vivo in the cat, both NMDA and AMPA receptors subtypes are involved in the GLU-induced release of DA. Beside this direct regulation, GLU also exert several indirect facilitatory and inhibitory controls on DA release, particularly through cholinergic and GABAergic striatal neurons. Indeed, as shown by numerous authors, the GLU-evoked release of DA is markedly reduced in the presence of tetrodotoxin, bicuculline or atropine or by previous kainate- or ibotenate-induced lesion of striatum. Differences in the presynaptic regulation of DA release in striosomal and matrix compartments have also been found with NMDA and acetylcholine. The effect of acetylcholine was of shorter duration in the matrix than in the striosomal-enriched areas. Two opposite indirect regulations of DA release could be demonstrated: one is facilitatory and involves nicotinic receptors, the other is inhibitory, involves muscarinic receptors and mediated, at least in the matrix by dynorphin containing neurons. The NMDA-evoked responses are of larger amplitude and more sensitive to tetrodotoxin in the matrix than in the striosomes. In conclusion, GLU released from corticostriatal fibers, is able to control the release of DA from terminals of nigrostriatal neurons through direct facilitatory mechanisms (NMDA and AMPA receptors), but also through indirect facilitatory and inhibitory local circuits involving cholinergic and GABAergic neurons.