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Biomedical subjects

M Raiteri

Publications and source records attributed to M Raiteri.

At least 181 records · Page 10Linked to original sources
PubMed1989

A novel type of GABA receptor in rat spinal cord?

The depolarization-evoked release of gamma-aminobutyric acid (GABA) and its possible modulation mediated by autoreceptors were studied in nerve endings isolated from rat spinal cord and prelabeled with the radioactive aminoacid. In the presence of the GABA uptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid], used to minimize carrier-mediated homoexchange, exogenous GABA (1-10 mumol/l) decreased in a concentration-dependent way the release of 3H-GABA evoked by 15 mmol/l KCl. The GABAA receptor agonist muscimol (10-100 mumol/l) did not affect the K+ (15 mmol/l)-evoked 3H-GABA release. Similarly ineffective was the GABAB receptor agonist (-)-baclofen (3-100 mumol/l). The effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline,picrotoxin or SR95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Presynaptic regulation of acetylcholine release in the CNS.

The release of ACh appears to be under the control of autoreceptors localized on cholinergic nerve terminals. Moreover, the process can be regulated by transmitters other than ACh or by modulators either through receptor-mediated or carrier-mediated mechanisms. In this chapter we report on our recent results concerning the regulation of the release of ACh by ACh itself, 5-HT and GABA in the rat hippocampus. In particular it will be shown: 1) that the release of the cholinergic transmitter can be inhibited through muscarinic receptors of the M3 subtype; 2) that 5-HT can interact with ACh by depressing ACh release through the activation of receptors of the 5-HT1B subtype; 3) that the release of ACh can be enhanced by GABA by a novel mechanism involving a selective penetration of the amino acid into the cholinergic terminals.

Acetylcholine↗
PubMed1989

Presynaptic mechanisms underlying the gamma-aminobutyric acid-evoked receptor-independent release of [3H]norepinephrine in rat hippocampus.

The effects of gamma-aminobutyric acid (GABA) on the spontaneous efflux of [3H]norepinephrine ([3H]NE) were studied in synaptosomes prepared from rat hippocampus and prelabelled with [3H]NE. It had been observed previously that, when synaptosomes were exposed in superfusion to GABA, the basal release of the tritiated catecholamine was enhanced, apparently with no involvement of the known GABA receptors. The mechanisms underlying this effect have now been investigated. The potency of GABA as a releaser of [3H]NE was decreased by lowering the Na+ content of the superfusion medium, and its effect disappeared at 23 mM Na+. The GABA-induced [3H]NE release was counteracted by the GABA uptake inhibitor N-(4,4-diphenyl-3-butenyl)nipecotic acid (SKF 89976A), but it was unaffected by the NE uptake blockers desmethylimipramine and nisoxetine. The GABA-induced release of [3H]NE was Ca2+-dependent and tetrodotoxin-sensitive. The data support the hypothesis that GABA provoked [3H]NE release by a novel mechanism which involves penetration into the noradrenergic nerve terminals through a GABA carrier located on the NE terminals themselves. This uptake process might be electrogenic and provoke depolarization of the nerve terminals, causing an exocytotic release of [3H]NE.

Animals↗
PubMed1989

Release-regulating autoreceptors of the GABAB-type in human cerebral cortex.

1. The depolarization-evoked release of gamma-aminobutyric acid (GABA) and its modulation mediated by autoreceptors were investigated in superfused synaptosomes prepared from fresh human cerebral cortex. 2. The release of [3H]-GABA provoked by 15 mM K+ from human cortex nerve endings was almost totally (85%) calcium-dependent. 3. In the presence of the GABA uptake inhibitor SK&F 89976A (N-(4,4-diphenyl-3-butenyl)-nipecotic acid), added to prevent carrier-mediated homoexchange, GABA (1-10 microM) decreased in a concentration-dependent manner the K+-evoked release of [3H]-GABA. The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (1-100 microM) but not by the GABAA receptor agonist muscimol (1-100 microM). Moreover, the GABA-induced inhibition of [3H]-GABA release was not affected by two GABAA receptor antagonists, bicuculline or SR 95531 (2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide). 4. (-)-Baclofen also inhibited the depolarization-evoked release of endogenous GABA from human cortical synaptosomes. 5. It is concluded that GABA autoreceptors regulating the release of both newly taken up and endogenous GABA are present in human brain and appear to belong to the GABAB subtype.

Aged↗
PubMed1989

Release of gamma-[3H]aminobutyric acid (GABA) from electrically stimulated rat cortical slices and its modulation by GABAB autoreceptors.

Slices of rat temporo-parietal cortex were prelabeled with gamma-[3H]aminobutyric acid ([3H]GABA), in the presence of the glial GABA uptake inhibitor beta-alanine. The slices were then superfused with a medium containing the GABA transaminase inhibitor aminooxyacetic acid and stimulated electrically (5 min, 2 msec, 36 mA at 5 or 10 Hz), in the presence of the neuronal GABA reuptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and of beta-alanine. Representative experiments showed that the tritium released could be accounted for almost entirely by authentic [3H]GABA. The electrically evoked overflow of [3H]GABA was tetrodotoxin sensitive and largely calcium-dependent. Exogenous GABA, added to the superfusion medium at 3 to 30 microM, reduced in a concentration-dependent manner the electrically evoked (5 Hz) release of [3H]GABA. The GABAB receptor agonist (-)-baclofen, but not the GABAA receptor agonist muscimol, mimicked GABA and produced a concentration-inhibition curve almost superimposable to that of the natural transmitter. The effects of GABA and of (-)-baclofen were much more pronounced at 5 than at 10 Hz. The GABA-induced inhibition of [3H]GABA release was sensitive to the novel GABAB receptor antagonist beta-(p-chlorophenyl)-3-amino propyl phosphonic acid which, by itself, increased the [3H]GABA overflow. The inhibitory effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline or SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide]. The results are compatible with the presence in the rat cerebral cortex of autoreceptors mediating inhibition of GABA release and belonging to the GABAB type. These autoreceptors may be activated tonically under physiological conditions.

Animals↗
PubMed1989

Interaction acetylcholine-glutamate in rat hippocampus: involvement of two subtypes of M-2 muscarinic receptors.

The effects of acetylcholine (ACh) on the release of endogenous glutamic acid (GLU) and of [3H]ACh have been investigated comparatively in superfused rat hippocampal synaptosomes. Exogenous ACh added to the superfusion fluid inhibited the Ca++-dependent K+ (15 mM)-evoked release of GLU in a concentration-dependent manner (the maximal inhibition was about 50%). Carbachol and oxotremorine mimicked, although less potently, the action of ACh. The inhibition of GLU release caused by 10 microM ACh was antagonized by 0.1 microM atropine but not by 10 microM mecamylamine. It also was insensitive to the M-1 receptor antagonists pirenzepine or dicyclomine (both at 1 microM). In contrast, the novel M-2 muscarinic antagonist AF-DX 116 [(11-[(2-[diethylamino]methyl)-1-piperidinyl]acetyl)-5-11-dihydro-6 H-pyrido-[2-3-b][1,4]benzo-diazepine-6-one] was as potent as atropine in blocking the inhibition of GLU release brought about by ACh. The autoreceptor-mediated inhibition of [3H]ACh release observed in presence of ACh (10 microM) was totally antagonized by atropine (0.1 microM). It was insensitive to mecamylamine (10 microM), dicyclomine (1 microM) or pirenzepine (1 microM). However, it was much less sensitive to AF-DX 116 (80-100 times) than the cholinergic inhibition of GLU release. It is concluded that 1) the release of GLU in rat hippocampus can be inhibited through a muscarinic receptor and 2) this novel muscarinic receptor belongs to the M-2 subtype but it seems to differ pharmacologically from the M-2 autoreceptor.

Acetylcholine↗
PubMed1989

Aspartate-releasing nerve terminals in rat striatum possess D-2 dopamine receptors mediating inhibition of release.

The release of endogenous aspartic acid has been investigated using synaptosomes from rat corpus striatum. Exposure in superfusion to a depolarizing concentration of KCl (15 mM) evoked an overflow of aspartate which was almost entirely calcium-dependent. When added to the superfusion medium, dopamine (DA) and the selective DA D-2 receptor agonists quinpirole (LY-171555) and pergolide inhibited the K+ -evoked aspartate release in a concentration-dependent manner. The natural agonist DA was very potent (IC50 = 1 nM). The selective D-1 receptor agonist SK&F 38393 had no effect on the release of aspartate. The selective D-2 receptor antagonist S-sulpiride, but not the R-enantiomer, antagonized the DA-induced inhibition of aspartate release. The DA effect was unaltered by SCH 23390, a selective dopamine D-1 receptor antagonist. The findings that 1) the release of endogenous aspartate evoked by depolarization was calcium-dependent and 2) the release of aspartate was potently modulated through D-2 receptors are compatible with the idea that aspartate is released as a transmitter from striatal axon terminals. The possibility that aspartate and glutamate are coreleased from these terminals is discussed.

Animals↗
PubMed1989

Effect of some quinolizidine derivatives on the release of serotonin, noradrenaline, dopamine and acetylcholine from rat brain synaptosomes.

A set of eleven quinolizidine derivatives together with 10-(quinuclidinyl)phenothiazine, promazine and methixene were tested for their effects on the spontaneous release of serotonin, noradrenaline, dopamine and acetylcholine from rat brain synaptosomes. All tested compounds failed to increase the acetylcholine release, while several of them exhibited rather strong effects on serotonin, noradrenaline and dopamine release at 5-10 microM concentrations. Structure-activity relationships are discussed.

Acetylcholine↗
PubMed1988

Enhancement of endogenous GABA release from rat synaptosomal preparations is mediated by alpha 2-adrenoceptors pharmacologically different from alpha 2-autoreceptors.

The effects of various adrenergic agents on the release of endogenous gamma-aminobutyric acid (GABA) and of [3H]GABA were studied in superfused synaptosomal preparations from rat hippocampus. Noradrenaline (NA) enhanced in a concentration-dependent way the release of endogenous GABA but did not affect the release of the radioactive amino acid. The effect of NA was mimicked by the alpha 2-adrenoceptor agonist, clonidine, but not by the alpha 1-agonist, phenylephrine. Accordingly, NA was antagonized by the alpha 2-adrenoceptor antagonist, yohimbine, but not by the alpha 1-antagonist, prazosin. Both (+)-mianserin and (-)-mianserin, used as alpha 2-adrenoceptor blockers, counteracted the NA-evoked release of endogenous GABA. The results suggest that GABA released from hippocampus crude synaptosomes is modulated by alpha 2-adrenoceptors pharmacologically different from the alpha 2-autoreceptors that modulate NA release and previously found to be blocked by (+)-mianserin but not by the (-) enantiomer (Raiteri et al., 1983).

Animals↗
PubMed1988

In vitro release of somatostatin from cerebral cortical slices: characterization of electrically evoked release.

Calcium-dependent, tetrodotoxin (1 microM)-sensitive release of somatostatin-like immunoreactivity (SRIF-LI) could be evoked by electrical field stimulation of vibratome-cut cerebral cortical slices superfused in vitro. The release of SRIF-LI from cortical slices was frequency-dependent, and showed facilitation between 5 and 25 Hz. Release was also current-dependent and above a threshold of 10 mA increased to plateau at 80 mA. Addition of peptidase inhibitors did not improve the recovery of SRIF-LI, and HPLC analysis of the released material showed that over 95% of SRIF-LI released corresponded to SRIF-14 (SRIF-28).

Animals↗
PubMed1988

Serotonin-glutamate interaction in rat cerebellum: involvement of 5-HT1 and 5-HT2 receptors.

The effects of serotonin (5-HT) on the release of endogenous glutamate (GLU) in rat cerebellum were investigated in slices depolarized with 35 mM K+. The Ca2+-dependent release of GLU was potently inhibited by 5-HT in a concentration-dependent way. Release was also inhibited by the 5-HT1 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The inhibition by 10 nM 5-HT was partly (35-40%) counteracted by the 5-HT2 receptor antagonist ketanserin but was fully blocked by the mixed 5-HT1/5-HT2 receptor antagonist methiothepin. The effect of 8-OH-DPAT was not affected by ketanserin but was totally antagonized by methiothepin, while the effect of DOI was entirely suppressed by ketanserin. Ketanserin or methiothepin themselves increased (by 23 and 55%, respectively, at 10 nM) the K+-evoked release of GLU. In conclusion the release of endogenous GLU in rat cerebellum can be inhibited by 5-HT through receptors of the 5-HT1 and 5-HT2 type. The enhancement of GLU release by ketanserin or methiothepin could suggest a tonic inhibition. The possible localization of the 5-HT receptors involved in the interaction with the GLU systems is discussed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

The activation of phosphatidylinositol turnover is not directly involved in the modulation of neurotransmitter release mediated by presynaptic muscarinic receptors.

In the rat cerebral cortex, the comparative effects of various muscarinic agonists on the release of [3H]dopamine ([3H]DA), [3H]acetylcholine ([3H]ACh), and [3H]5-hydroxytryptamine ([3H]5-HT) from superfused nerve endings and on phosphatidylinositol (PI) turnover were studied. Acetylcholine (ACh) was found to be the most potent among the agonists tested on all three release systems examined, and also on the activation of PI turnover. Oxotremorine and bethanechol were very weak agonists when tested as stimulators of PI turnover. However, oxotremorine was very effective as a release modulator, while bethanechol was completely ineffective. Our data suggest that the activation of PI turnover is not directly involved in the modulation of neurotransmitter release mediated by presynaptic muscarinic receptors.

Acetylcholine↗
PubMed1988

Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers.

The neurochemical and autonomic pharmacological profile of 1,2,3,4,10, 14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c]pyrido[2, 3-c] [2] benzazepine [+/-)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H]noradrenaline ([3H]NA) in vitro was weakly affected by (+/-)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (+/-)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by alpha 2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (-)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosin to alpha 1-adrenoceptors was less potently affected by (+/-)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for alpha 1- and alpha 2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (+/-)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (+/-)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (+/-)Org 3770 (pKi = 6.1) and mianserin (pKi = 6.3). Similar data on tryptamine-D, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.

Animals↗
PubMed1988

Clonidine enhances the release of endogenous gamma-aminobutyric acid through alpha-2 and alpha-1 presynaptic adrenoceptors differentially located in rat cerebral cortex subregions.

UNLABELLED: Clonidine (0.001-1 microM) increased the basal release of endogenous gamma-aminobutyric acid (GABA) in superfused synaptosomes from whole rat cerebral cortex. The effects of 0.1 to 1 microM clonidine were only in part sensitive to the alpha-2 adrenoceptor antagonist yohimbine; a complete antagonism by yohimbine could be seen only with 0.001 microM clonidine. The release of GABA induced by 0.1 to 1 microM clonidine was increasingly sensitive to the alpha-1 adrenoceptor antagonist prazosin. At all the concentrations tested clonidine was antagonized fully by a mixture yohimbine-prazosin (1 microM). The release of GABA was increased by phenylephrine in a concentration-dependent (0.01-1 microM) manner. At 1 microM phenylephrine was antagonized fully by 1 microM prazosin. When synaptosomes prepared from frontal, parietal, temporal and occipital cortex were exposed to clonidine (0.005 microM) or to phenylephrine (0.1 microM), the release of GABA was found to be region specific. Clonidine-induced GABA release could not be seen in temporal and occipital cortex but it was pronounced in parietal and frontal cortex. The effect of phenylephrine did not parallel that of clonidine: for instance, GABA release was most sensitive to phenylephrine in the occipital cortex where clonidine was ineffective. The opposite occurred in parietal cortex synaptosomes, where phenylephrine was much less effective than clonidine. IN CONCLUSION: 1) clonidine stimulates the release of GABA in rat cerebral cortex synaptosomes; 2) the effect is likely to occur by activation of alpha-1 and alpha-2 adrenoceptors possibly situated on GABAergic nerve endings; and 3) a differential distribution of alpha-1 and alpha-2 adrenoceptors regulating GABA release exists within the cortical subregions.

Animals↗
PubMed1988

Release-regulating D-2 dopamine receptors are located on striatal glutamatergic nerve terminals.

The effects of dopamine (DA) and other dopaminergic receptor agonists on the depolarization-evoked release of endogenous glutamic acid (GLU) have been studied using synaptosomes prepared from rat corpus striatum and depolarized in superfusion with 15 mM KCl. DA and the selective D-2 receptor agonists quinpirole (LY-171555, the levorotatory enantiomer of LY-141865) and pergolide inhibited GLU release in a concentration-dependent way. The natural agonist was particularly effective causing 50% inhibition of GLU release at 10 nM. In contrast, the selective D-1 receptor agonist SK&F 38393 did not affect the release of GLU. The inhibitory effect of DA on the K+-evoked release of GLU was antagonized in a concentration-dependent manner by the selective D-2 receptor antagonist S-sulpiride, but not by the R-enantiomer. The data represent a direct demonstration that receptors sensitive to nanomolar concentrations of DA and belonging to the D-2 type are located on GLU axon terminals in the rat corpus striatum where they may modulate the release of GLU from glutamatergic afferents including the cortico-striatal pathway.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗