Biomedical subjects
Publications and source records attributed to J Glowinski.
Glycine (5 X 10(-5) M) stimulated the spontaneous release of 3H-DA continuously synthesized from 3H-tyrosine in striatal slices. This effect was calcium-dependent and significantly reduced in the presence of strychnine (10(-5) M). The glycine-evoked release of 3H-DA was no longer seen in the presence of tetrodotoxin (5 X 10(-7) M).
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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.
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"Encéphale isolé" cats were implanted with three push-pull cannulae. The two caudate nuclei (CN) were superfused continuously with 3H-tyrosine to measure the release of 3H-DA in serially collected fractions. Three hours after the beginning of the experiment, d,l-baclofen, d- or l-baclofen or gamma-hydroxybaclofen were introduced for 15 min in the medium used to superfuse the left substantia nigra. d,l-Baclofen (10(-6) M) stimulated 3H-DA release in the ipsilateral as well as in the contralateral CN but the effect was more pronounced in the ipsilateral CN. Similar effects were observed with l-baclofen. d-Baclofen and gamma-hydroxybaclofen were inactive. The results obtained are discussed in the light of effects previously observed during the nigral application of gamma-aminobutyric acid (GABA) and related compounds.
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A new isotopic approach has been developed to study the in vivo release of serotonin (5-HT). 'Encéphale isolé' cats were implanted with a push-pull cannula in the ventrocaudal part of the head of the caudate nucleus to estimate the release of [3H]5-HT continuously synthesized from L-[3H]tryptophan. Both [3H]5-HT and [3H]tryptamine were found in superfusates. Resting steady state in the release of [3H]indoleamines was observed as soon as 20 min after the beginning of the superfusion with L-[3H]tryptophan; the levels of [3H]5-HT in superfusates were 2.5 times those of [3H]tryptamine and about 6 times the blank value. They were markedly enhanced in the presence of fluoxetine (5 x 10(-6)M), a blocker of the 5-HT uptake process. A marked increase in the release of [3H]5-HT was seen during the local depolarization of 5-HT terminals with potassium chloride (60 mM) or batrachotoxin (10(-6)M) or during the stimulation of 5-HT cell bodies in the nucleus raphe dorsalis with L-glutamic acid (5 x 10(-5)M). These treatments did not enhance the efflux of [3H]tryptamine. The potassium-evoked release of [3H]5-HT was reduced by LSD (10(-5)M). LSD added alone in the superfusing fluid was without effect. The batrachotoxin-evoked release of [3H]5-HT was inhibited in the presence of tetrodotoxin (9 x 10(-6)M). The spontaneous release of [3H]5-HT and [3H]tryptamine was markedly reduced in the presence of a calcium-free medium containing cobalt (10 mM). A transient slight reduction in the spontaneous release of [3H]5-HT was observed in the presence of tetrodotoxin (9 x 10(-6)M). The local cooling of 5-HT cell bodies with a cryoelectrode induced a slight reversible decrease in [3H]5-HT release. These last two treatments were without significant effect on [3H]tryptamine efflux in superfusates. These results indicate that the release of [3H]5-HT endogenously formed from [3H]tryptophan is dependent on nerve activity and that this is not the case for [3H]tryptamine. The advantages of the isotopic approach for in vivo studies on the release of 5-HT are discussed.
The effects of electrical foot shock on the activity of the ascending dopaminergic neurons were estimated in the rat by measuring the changes in DOPAC and DA levels in discrete brain areas. DOPAC and DA levels were estimated with a radioenzymatic method in microdiscs of tissues punched out from serial frontal sections of the brain. A marked rise in the ratio of DOPAC/DA levels resulting from an increase of DOPAC and a decrease of DA levels was found in the cerebral frontal cortex at the end of a 20 min stress. The effect was less pronounced in stress of shorter duration from 3 to 10 min and was only related to a reduction of DA levels. Using the DOPAC/DA ratio as an index of the activity of the neurons, the mesocortical dopaminergic neurons were found to be selectively activated under stress since this ratio was increased in the frontal and cingular cortices but not in limbic structures such as the septum, the amygdala and the nucleus accumbens or in the striatum. Finally, pretreatment of the rats with diazepam (5 mg/kg i.p.) or chlordiazepoxide (10 mg/kg i.p.) prevented the increase in the DOPAC/DA ratio in the frontal cerebral cortex of rats submitted to the 20 min stress.
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The effects of the unilateral application of d-amphetamine, benztropine, haloperidol and thioproperazine to one substantia nigra on the release of 3H-dopamine (3H-DA) in the two caudate nuclei were examined in halothane-anesthetized cats. For this purpose animals were implanted with push-pull cannulae and 3H-DA was estimated in superfusates during the continuous delivery of L-3,5-3H-tyrosine. The nigral application of d-amphetamine (10-6 M) or benztropine (10-6 M) reduced the release of 3-H-DA in in the ipsilateral caudate nucleus and induced an opposite effect in the contralateral side. In contrast, the nigral application of haloperidol (10-6 M) or thioproperazine (10-6 M) slightly increased the release of 3H-DA in the ipsilateral caudate nucleus and induced a reduction of 3H-transmitter release in the contralateral side. These results emphasize the role of the dendritic release of DA in the control of the activity of dopaminergic neurons and confirm our previous findings concerning the existence of a reciprocal control in the activity of the two dopaminergic pathways.
A single treatment with a large dose of methiothepin (20 mg/kg, i.p.) induced, as early as the 2nd day after injection, a significant increase (+20--35%) in the number of specific binding sites for 3H-5-HT in forebrain areas, particularly the hippocampus. Experiments with 3H-methiothepin indicated that the drug remained firmly bound to brain membranes thus maintaining a local concentration high enough to effectively block 5-HT receptors for 10--12 h after its peripheral administration. Accordingly, it can be concluded that the occupancy of central 5-HT receptor sites by methiothepin for several hours was sufficient to induce a supersensitivity phenomenon within the two following days. Although 3H-methiothepin was a useful marker for analyzing the disposition and the kinetics of the 5-HT antagonist in brain tissues, it could not be used as a specific ligand of 5-HT receptors in brain since under in vitro as well as in vivo conditions most of 3H-methiothepin bound to non-specific sites, especially to the lipid component of the membranes.
The substance P (SP) content in cat substantia nigra (SN) was estimated by radioimmunoassay in microdiscs punched on successive frontal sections. Only slight differences were seen in the regional distribution of SP within the SN. The highest content was found in the pars reticulata (20.7 pmol/mg protein) which was two times higher than in the pars compacta and pars lateralis. Identical results were found in the right and left part of the SN. Out of this area, as pedunculus cerebri and zona incerta, very low concentrations were detected.
Dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were estimated in the frontal cortex, the nucleus accumbens and the striatum of the rat after electrolytical lesion of the dorsal raphe nucleus. The efficiency of this lesion was tested by measuring the decline in serotonin (5-HT) levels in the striatum. 5-HT levels were reduced by 90% when compared to those of sham-operated rats 11 days after the lesion. As revealed both by the increase in DOPAC levels and in the DOPAC/DA ratio, the rate of DA utilization was markedly increased in the nucleus accumbens, slightly enhanced in the striatum and in contrast remained unaffected in the frontal cerebral cortex 4 days after the lesion. Changes in DOPAC levels in the nucleus accumbens were also seen 11 and 30 days after the lesion but they were less pronounced than those observed at 4 days. These results suggest that neurons originating from the dorsal raphe and projecting to the ventro-tegmental area are regulating the activity of the meso-nucleus accumbens dopaminergic neurons but not that of the meso-cortical dopaminergic neurons.
Push-pull cannuale were implanted into the substantia nigra (SN) and the caudate nucleus (CN) of the cat to study the in vivo release of substance P (SP), using a radioimmunoassay and high pressure liquid chromatography (HPLC) analysis. The spontaneous release of SP could be detected in the SN and the CN. Potassium (50 mM) locally applied stimulated SP release in both structures. Furthermore an important evoked release of SP was observed in the SN during depolarization of striato-nigral SP fibers with potassium (50 mM) applied in the CN.
Acetylcholine (ACh) (10(-5) M) in the presence of eserine (2 . 10(-4) M) stimulated the release of [3H]dopamine (DA) continuously formed from [3H]tyrosine, when delivered to a push-pull cannula implanted in the left caudate nucleus of halothane anaesthetized cats. This effect was transient and followed by a second increase in [3H]DA release after removal of ACh and eserine. These changes in [3H]DA release during and after ACh application were no longer seen during activation of the dopaminergic neurons by continuous delivery of substance P to the ipsilateral substantia nigra (SN). These results indicate that the presynaptic regulation of DA release by ACh is dependent on the rate of firing of nigro-striatal dopaminergic neurons.