A. Nieoullon

Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra in the cat.

The effects of unilateral stimulation of the cerebral motor cortex and of the visual cortical area on the activity of the nigrostriatal dopaminergic neurons were examined in halothane-anesthetized cats. For this purpose, one push-pull cannula was inserted in each caudate nuclei and another one in the substantia nigra ipsilateral to the stimulated side. In all cases, the release of [3H]dopamine ([3H]DA) continuously formed from L-[3,5-3H]tyrosine was estimated in superfusates. Unilateral electrical stimulation of the cerebral motor cortex (area 4) induced a long-lasting and similar activation of [3H]DA release in both caudate nuclei. The activation of [3H]DA release in the contralateral side was selectively abolished after acute transection of the rostral part of the corpus callosum. This transection also suppressed the flexion of the contralateral forelimb induced by the stimulation. The activation of [3H]DA release could be related to the stimulation of corticostriatal neurons which may interact directly or indirectly with dopaminergic terminals in both caudate nuclei. Unilateral electrical stimulation of the visual cortex (areas 18 and 19) markedly stimulated the release of [3H]DA in the ipsilateral caudate nucleus. A slight effect was seen in the contralateral structure 20 min after the stimulation. These results are consistent with the existence of a main ipsilateral pathway originating from the visual cortex and projecting directly to the striatum. Both types of electrical stimulation immediately activated the release of [3H]DA in the ipsilateral substantia nigra. These effects were still seen 20 min after the stimulations. The activation of the dendritic release of [3H]DA could be related to the stimulation of a corticonigral projection. These results further indicate that the nigrostriatal dopaminergic neurons may be involved in sensory motor integration.

Gabaergic processes involved in the control of dopamine release from nigrostriatal dopaminergic neurons in the cat.

Abstract Push-pull cannulae were used to study the release of 3 H-dopamine ( 3 H-DA) continuosly synthetized from L-3,5- 3 H-tyrosine in the caudate nucleus and the substantia nigra of the “encephale isole” cat. GABA (10 −5 M), muscimol (10 −6 M), γ-hydroxybutyrate (GHB, 10 −5 M), GABA-choline (GABA-CH, 10 −5 M) and amino-oxyacetic acid (AOAA, 10 −5 M) stimulated the release of 3 H-DA in the caudate nucleus when introduced for 15 min in the superfusing medium. The initial stimulation of 3 H-DA release was followed by an inhibition of transmitter release when GABA was introduced for a longer time (60 min) into the caudate nucleus. GABA (10 −5 M) had no effect on the release of 3 H-DA in the substantia nigra. However, muscimol (10 −6 M), GHB (10 −5 M) and baclofen (10 −6 M) stimulated the dendritic release of 3 H-DA when each was introduced for 15 min in the substantia nigra. The introduction for 15 min of GABA (10 −5 M), muscimol (10 −6 M), GHB (10 −5 M), GABA-Ch (10 −5 M) or baclofen (10 −6 M) into the substantia nigra simultaneously induced a stimulation of 3 H-DA release in the ipsilateral caudate nucleus. A marked post stimulatory effect was seen with muscimol. When GABA (10 −5 M) was applied for 75 min into the substantia nigra, the initial stimulation of 3 H-DA release (30 min) seen in the caudate nucleus was followed by a short-lasting inhibitory phase (15 min). This inhibition of 3 H-DA release was followed by a second stimulation period. This multiphasic phenomenon was not seen with other compounds. The stimulation of 3 H-DA release in the caudate nucleus induced by a 15 min nigral application of GABA (10 −5 M) was no longer seen when picrotoxin (10 −5 M) was added with GABA in the substantia nigra. On the basis of these results it is proposed that at least two types of GABAergic regulatory processes are involved in the control of the activity of the dopaminergic neurons in the substantia nigra. On the other hand, the interaction of GABA or GABA-related compounds with GABAergic receptors in the striatum may facilitate DA release from dopaminergic terminals through an intrastriatal interneuronal process. The secondary inhibition of 3 H-DA release induced by GABA or GHB could be mediated by a non-GABAergic striato-nigral pathway.

Release of dopamine in both caudate nuclei and both substantia nigrae in response to unilateral stimulation of cerebellar nuclei in the cat

The effects of unilateral focal electrical stimulation of the deep cerebellar nuclei on the activity of the nigrostriatal dopaminergic neurons on both sides of the brain were examined in halothane anaesthetized cats. For this purpose, push-pull cannulae were inserted into both caudate nuclei and both substantia nigrae, and the release of [3H] dopamine ([3H]DA) continuously formed from [3,5-3H]L-tyrosine was estimated in superfusates. The unilateral electrical stimulation of the right cerebellar dentate nucleus induced a long-lasting increase in the release of [3H]DA in the left caudate nucleus and a simultaneous decrease in the release of [3H]transmitter in the right caudate nucleus. These changes were associated with opposite fluctuations in the release of [3H]DA from the corresponding substantia nigrae. Thus, the electrical stimulation of the right dentate nucleus induced a pronounced decrease in the release of the [3H]-amine in the [3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral substantia nigra, whereas the release in the ipsilateral substantia nigra was simultaneously increased. In contrast, the unilateral electrical stimulation of the right cerebellar fastigial nucleus resulted only in an increased release of [3H]DA in the ipsilateral (right) caudate nucleus, associated with a decreased release of the [3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral (left) dopaminergic system was not significantly affected. These results support a direct functional interaction between the cerebellum and the basal ganglia. They also suggest that the release of DA from dopaminergic axonal terminals is inversely correlated to the extent of the transmitter release from dendrites.

Effect of the immunoneutralization of substance P in the cat substantia nigra on the release of dopamine from dendrites and terminals of dopamine-ergic neurons

The substantia nigra (SN) contains the largest concentration of substance P in the brain1,5, 7,1°,11,2°. As revealed by immunohistochemical studies, this undecapeptide is contained in an extensive network of terminals which are mainly distributed in the pars reticulata 6,19. These terminals seem to originate predominantly from cell bodies located in the striatum. However, substance P-positive immunoreactivity was also seen in some pallidal neurones 11. A recent combined biochemical and lesion study suggests that the cell bodies of the striatonigral substance P pathway are distributed in the anterior part of the striatum, whereas the descending GABAergic neurones originate from the posterior part of the structure, as well as from the globus pallidusL As shown in experiments carried out on slices of the rat SN, substance P is released under depolarization by potassium through a calcium-dependent process 9. Furthermore, this potassium-evoked release of substance P can be antagonized by GABA 9. According to microiontophoretic experiments, substance P activates nigral cells 4,21. In a previous study we reported that the application of substance P (10 -s M) in the cat SN induced an activation of dopamine (DA) release in the ipsilateral caudate nucleus a. Furthermore, in the rat, James and Starr 8 observed a contralateral rotatory behaviour associated with an increased concentration of homovanillic acid in the striatum after a microinjection of substance P in the pars reticulata of the homolateral SN. To further explore the role of the descending substance P pathway on the activity of the nigrostriatal dopaminergic neurones, we have examined in the present study the effects of a nigral unilateral application of an anti-substance P rabbit serum on the release of DA f rom nerve terminals and dendrites of the ipsilateral dopaminergic neurones in the cat. Cats of both sexes (2-3 kg) anaesthetized with halothane (Fluothane, ICI-Pharma, France) were each implanted with two push-pull cannulae, one in the left SN and the

Effects of peripheral and local administration of picrotoxin on the release of newly synthesized 3H-dopamine in the caudate nucleus of the cat

SummaryThe release of 3H-DA was estimated in superfusates of a superfusion cannula introduced into the caudate of a superfusion cannula introduced into was continuously formed from l-3,5-3H-tyrosine introduced into the superfusion medium. Injected at the periphery, picrotoxin (2.5 mg/kg, i.p.) markedly enhanced the release of 3H-DA the effect being particularly pronounced 90 min after the drug injection. The effects of the local introduction of picrotoxin into the substantia nigra and into the caudate nucleus on 3H-DA release were also examined to ensure the specificity of the result. Picrotoxin (10−5 M) added into the superfusing medium of a second superfusion cannula introduced into the substantia nigra enhanced by 2 to 5 times the release of 3H-DA during the drug application. No effect could be seen when the tip of the superfusion cannula was not exactly localized into the substantia nigra. Although less pronounced, a stimulation of 3H-DA release was also seen when picrotoxin (10−6 M) was added directly into the superfusion medium of the cannula introduced into the caudate nucleus. These results suggest that some gabaergic neurons are involved in the control of DA release by acting on dopaminergic cell bodies or dendrites into the substantia nigra. Other gabaergic neurons may directly or indirectly act on dopaminergic terminals within the caudate nucleus.

Blockade of the picrotoxin-induced in vivo release of dopamine in the cat caudate nucleus by diazepam.

Abstract The effects of picrotoxin and diazepam on the in vivo release of DA in the caudate nucleus were examined in “encephale isole” cats. A push-pull cannula was introduced into the left caudate nucleus and the structure was continuously superfused with L-3, 5-3H-tyrosine. The 3H-DA endogenously synthesized and released in the superfusates was estimated in successive serial fractions. Picrotoxin (2.5 mg/kg) markedly enhanced the release of 3H-DA, as previously shown. Diazepam (10 mg/kg) had no effect on the spontaneous release of the labelled transmitter, but it did prevent the stimulating effect of picrotoxin.

EFFECTS OF A NIGRAL APPLICATION OF SUBSTANCE P AND OF AN ANTI-SUBSTANCE P SERUM ON DOPAMINE RELEASE FROM DENDRITES AND NERVE TERMINALS OF THE NIGROSTRIATAL DOPAMINERGIC NEURONS IN THE CAT

ABSTRACT Using push-pull cannulae, the release of newly synthesized 3H-DA was estimated in one substantia nigra (SN) and in the ipsilateral caudate nucleus (CN) of halothane anaesthetized cats. Applied into the SN, substance P (10−8M) reduced the dendritic release of 3H-DA but stimulated the release of the 3H-transmitter from nerve terminals in the CN. In contrast, a purified gamma-globulin fraction of a rabbit antiserum against substance P introduced into the SN reduced the release of 3H-DA from dendrites and induced an opposite effect in the CN. These results indicate that the striato-nigral substance P neurons exert an excitatory tonic influence on the nigrostriatal dopaminergic neurons. They are in agreement with the hypothesis of a critical role of the dendritic release of DA in the control of the activity of the dopaminergic neurons.

Role of Gabaergic and Glycinergic Transmissions in the Substantia Nigra in the Regulation of Dopamine Release in the Cat Caudate Nucleus

It is well known that the substantia nigra contains numerous GABAergic terminals (Fonnum et al., 1974; Kataoka et al., 1974; Bak et al., 1975; Ribak et al., 1976). Most of these originate from the striatum (Feltz, 1971; Precht and Yoshida, 1971; Crossman et al., 1973; Fonnum et al., 1974; Kataoka et al.,1974; Bak et al., 1975; Dray et al.,1976) and/or the globus pallidus (Hattori et al.,1973,1975). According to electrophysiological studies, some of the striato-nigral inhibitory neurons projecting into the substantia nigra are involved in the regulation of the activity of an important nigro-thalamic pathway (Albe-Fessard et al., 1975; Deniau et al.,1976). It is also generally assumed that descending GABAergic neurons contribute to the control of the activity of the nigro-striatal dopaminergic neurons. Several electrophysiological (Aghajanian and Bunney, 1975), biochemical (Anden and Stock, 1973; Lloyd et al., 1977) and pharmacological (Tarsy et al., 1975) studies have suggested that these GABAergic neurons exert a direct inhibitory action on the dopaminergic neurons. Besides this direct inhibitory input on dopaminergic neurons, other GABAergic neurons projecting into the pars reticulata could indirectly exert a facilitatory control on dopaminergic neurons by inhibiting nigral inhibitory interneurons (Dray and Straughan, 1976; Fahn, 1976; Cheramy et al., 1977c).