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After injection of 6-hydroxydopamine into the lateral part of the rat substantia nigra, tissue dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced in the corresponding lateral part of the ipsilateral caudate/putamen (CP) complex (13, 40 and 56% of controls, respectively). In this region, tyrosine hydroxylase (TH, the rate limiting enzyme of the DA synthesis) immunoautoradiography decreased by more than 80% as was the case for the binding of tritiated GBR12935 (a specific marker of the DA-carrier protein). In the medial region of the CP, only very moderate reductions of DA, DOPAC and HVA (77, 76 and 84% of controls, respectively) were observed. In this region, TH immunoautoradiography and GBR12935 binding were only reduced by about 20% reflecting weak DA denervation. However, using in vivo voltammetry, extracellular basal DA levels were found to be particularly high in the medial region of CP complex when compared to unoperated animals (up to 235%). In the medial region, TH activity was also significantly increased (161%) but the electrical stimulation of DA fibers produced the same DA overflow in control and lesioned animals. From these results, it may be concluded that elevated basal DA levels in this region cannot be attributed to the reduced DA uptake and/or to an increased ability of DA neurons to release DA in response to impulse flow.

A push-pull cannula supplied with artificial CSF was implanted in the striatum of anaesthetized rats, and the basal extracellular DA and DOPAC was assayed in the superfusates using HPLC and electrochemical detection. Simultaneously, a carbon fibre electrode was implanted in close proximity of the cannula and the evoked DA release was detected by differential pulse amperometry during stimulation of the DA axons. Local treatments with cadmium (100 microM) blocked the evoked DA release (-90%), but substantially increased the basal extracellular DA (+125%). The effects of glutamate agonists NMDA (1 mM) and kainate (0.1 mM), known to increase basal extracellular DA were confirmed (+150% and +60% respectively). It was, however, simultaneously observed that the evoked DA release was inhibited (-80% and -50%, respectively). Amphetamine (1 microM) released DA (+150%) and produced also an increase (+100%) of the evoked DA release. These results, apparently conflicting, show that the two mechanisms releasing dopamine (firing-dependent and not) can be directly and simultaneously observed. These two releasing processes appear to be not strictly antagonist. They are also differently and independently modulated by calcium and by local influences such those conveyed by glutamate.

The release of [3H]DA synthesized from [3H]tyrosine was estimated in the two caudate nuclei (CN) during the unilateral nigral application of glycine and GABA-related compounds in 'encéphale isolé' cats using push-pull cannulae. Glycine (10(-5) M) reduced the release of [3H]DA in both CN and these effects were antagonized by strychnine (10(-5) M). A decrease in [3H]DA release was also seen in both CN during the unilateral nigral application of diazepam (10(-5) M). In contrast, muscimol (10(-6) M) and GABA (10(-5) M) stimulated [3H]DA release on both sides. The effect of GABA was blocked by picrotoxin (10(-5) M). Picrotoxin alone stimulated the release of [3H]DA in the ipsilateral CN and was without effect in the contralateral side. Bicuculline (10(-5) M) stimulated [3H]DA release only in the contralateral CN. A symmetric increase in [3H]DA release in both CN was also observed during the unilateral nigral application of potassium (30 mM). A model involving a facilitatory polysynaptic pathway originating from the substantia nigra (SN) and acting presynaptically on ther terminals of the contralateral DA neurons is proposed to explain the changes in [3H]DA release induced in the contralateral CN in these various situations. The results are discussed taking into account previous data on the reciprocal control of the two dopaminergic pathways induced by the unilateral nigral application of dopaminergic drugs.

In order to study the mechanisms regulating the dopaminergic nigroamygdaloid cells, the release of dopamine was observed in the central nucleus of the amygdaloid complex. Halothane anesthetized rats were implanted, according to the experiment, with one or two push-pull cannulae in the central nuclei of the amygdala (ACE), the substantia nigra (SN) and/or the caudate nucleus (CN). Canulae were supplied with artificial cerebrospinal fluid (CSF) containing tritiated tyrosine, and labeled dopamine [3H]DA was evaluated in successive superfusate fractions. Electrical stimulation of the medial forebrain bundle with an implanted bipolar electrode induced an increase of the [3H]DA release in the ipsi- and contralateral ACE. Electrical stimulation of the SN produced only a very delayed effect in the ipsilateral ACE but an immediate and large increase of [3H]DA release in the contralateral structure. Superfusion of unlabeled DA and alpha-methyl-p-tyrosine in the SN remained ineffective on the [3H]DA release in the ipsilateral ACE. In this structure the release of [3H]DA was, however, decreased by nigral superfusion with gamma-amino-butyric acid (GABA). D-(+)-Amphetamine (1 microM), when superfused in the CN, induced a large enhancement of the [3H]DA release in the ipsilateral ACE simultaneously with the local increase of [3H]DA release. The results presented here are in agreement with the previous studies concerning the anatomical organization of the dopaminergic nigroamygdaloid pathway. The DA cell bodies located in the SN appear insensitive to a local action of DA, perhaps due to a lack of autoreceptors. They are, however, powerfully inhibited by GABA and the relation observed between the [3H]DA release in the CN and ACE support the hypothesis that the SN can act as a relay between the extrapyramidal and limbic systems.

Rats were anesthetized with fluothane and implanted in the caudate nucleus with a push-pull cannula supplied with artificial CSF containing the tritiated precursor of dopamine (DA), [3H]tyrosine. Total DA and dihydroxyphenylacetic acid (DOPAC) were measured in successive 20 min fractions using high performance liquid chromatography and electrochemical detection. Radioisotopic counting of the peaks permitted the calculation of the specific activity of both DA and DOPAC released into the extracellular space. Local applications of potassium (8, 16 and 32 mM) induced a dose-dependent increase of the release of DA with a decrease of its specific activity as evidence of the involvement of a stored DA pool. Base release of DOPAC was increased by repeating potassium applications with a temporary decrease during the applications. Superfusion with alpha-methyl-p-tyrosine produced a decrease of both the [3H]DA and total DA with a simultaneous decrease of its specific activity. This decrease was considered to be an indicator of the involvement by synthesis inhibition of the stored amine, but the simultaneous decrease of the specific activity of DOPAC suggests that this release was intraterminal. These results constitute the first direct observation that DA terminals act with two separate pools (stored and releasable) and suggest that the stored amine is preferentially released intraterminally. Systemic injection of reserpine induced a decrease of the release of DA and DOPAC without alteration of DA-specific activity when the specific activity of DOPAC was lowered. From these results it is concluded that the releasable compartment of the amine is located, in part, in vesicles different in nature from the vesicles containing the stored amine.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of unilateral sensory stimuli on dopamine (DA) release from nerve terminals and dendrites of the two nigrostriatal dopaminergic pathways were estimated in halothane-anaesthetized cats without or with sagittal transections. In control animals, the electrical stimulation of the right forelimb enhanced DA release in the right caudate nucleus (CN) and decreased DA release in the right substantia nigra (SN). Opposite effects were observed in the contralateral structures. Sagittal transections of the corpus callosum and commissura anterior, or of the mesencephalic decussations or of the thalamic massa intermedia were made to investigate mechanisms involved in the reciprocal regulation of the two dopaminergic pathways. These sections were without effect on the spontaneous release of DA from nerve terminals and dendrites. The transection of the thalamic massa intermedia was the only one which interrupted the asymmetric changes in DA release induced by unilateral sensory stimuli; an increased dendritic release of DA was only seen in the left SN but it was significantly less pronounced than that observed in control cats. The other transections did not prevent the asymmetric changes in DA release evoked by the sensory stimulation. However, the mesencephalic sagittal transection significantly reduced the stimulatory effect on DA release induced in the left SN. These results suggest that the thalamus is involved in the transfer of information implicated in the reciprocal regulation of the two dopaminergic pathways. In the light of electrophysiological data, the role of nigrothalamic neurones in this phenomenon is discussed.

The release of dopamine in the substantia nigra and striatum was investigated in halothane anaesthetized rats by means of the push-pull cannula method. Electrical stimulation of the subthalamic nucleus produced a marked enhancement of dopamine release in the ipsilateral substantia nigra. This effect is likely to be mediated by subthalamic efferent neurons since the application of acetylcholine in the subthalamic nucleus produced a similar effect. A later decrease of dopamine release was always observed in the ipsilateral striatum and was attributed to the autoregulation mechanisms of nigro-striatal dopaminergic neurons.

On the basis of histochemical and pharmacological studies, catecholamines have been implicated in central mechanisms controlling respiration. This hypothesis was tested in iontophoretic studies on neurones located in bulbar respiratory centres. Adrenaline and noradrenaline had a predominantly depressant effect on respiratory as well as on closely situated non-respiratory units. These depressions were mimicked by the application of isoproterenol and clonidine; acetylcholine and serotonin had inconsistent effects on these neurones. In control experiments, microinjections, using a Hamilton syringe, were made in the area of bulbar respiratory centres: noradrenaline, but not serotonin, depressed the central respiratory activity reflected in the phrenic nerve discharge. These results suggest that specific adrenergic and noradrenergic depressant mechanisms could affect both respiratory and other physiological centres at the bulbar level.