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E Fedele

Publications and source records attributed to E Fedele.

At least 37 records · Page 2Linked to original sources
PubMed1997

Activation of brain nitric oxide synthase in depolarized human temporal cortex slices: differential role of voltage-sensitive calcium channels.

1. Nitric oxide (NO) synthase activity was studied in slices of human temporal cortex samples obtained in neurosurgery by measuring the conversion of L-[3H]-arginine to L-[3H]-citrulline. 2. Elevation of extracellular K+ to 20, 35 or 60 mM concentration-dependently augmented L-[3H]-citrulline production. The response to 35 mM KCl was abolished by N(G)-nitro-L-arginine (100 microM) demonstrating NO synthase specific conversion of L-arginine to L-citrulline. Increasing extracellular MgCl2 concentration up to 10 mM also prevented the K+ (35 mM)-induced NO synthase activation, suggesting the absolute requirement of external calcium ions for enzyme activity. 3. However, the effect of high K+ (35 mM) on citrulline synthesis was insensitive to the antagonists of ionotropic and metabotropic glutamate receptors dizocilpine (MK-801), 6-nitro-7-sulphamoylbenzo(f)-quinoxaline-2-3-dione (NBQX) or L-2-amino-3-phosphonopropionic acid (L-AP3) as well as to the nicotinic receptor antagonist, mecamylamine. 4. The 35 mM K+ response was insensitive to omega-conotoxin GVIA (1 microM) and nifedipine (100 microM), but could be prevented in part by omega-agatoxin IVA (0.1 and 1 microM). The inhibition caused by 0.1 microM omega-agatoxin IVA (approximately 30%) was enhanced by adding omega-conotoxin GVIA (1 microM) or nifedipine (100 microM). Further inhibition (up to above 70%) could be observed when the three Ca2+ channel blockers were added together. Similarly, synthetic FTX 3.3 arginine polyamine (sFTX) prevented (50% at 100 microM) the K+-evoked NO synthase activation. This effect of sFTX was further enhanced (up to 70%) by adding 1 microM omega-conotoxin GVIA plus 100 microM nifedipine. No further inhibition could be observed upon addition of MK-801 or/and NBQX. 5. It was concluded that elevation of extracellular [K+] causes NO synthase activation by external Ca2+ entering cells mainly through channels of the P/Q-type. Other Ca2+ channels (L- and N-type) appear to contribute when P/Q-channels are blocked.

Alanine↗
PubMed1996

Ectocellular in vitro and in vivo metabolism of cADP-ribose in cerebellum.

CD38, a type II transmembrane glycoprotein predominantly expressed in blood cells, is a bifunctional ectoenzyme directly involved in the metabolism of cADP-ribose (cADPR). This is a potent Ca2+ mobilizer in several types of cells. The relationship between the ectocellular site of cADPR production and its intracellular calcium-related functions is poorly understood. Cultured rat cerebellar granule cells showed both enzymic activities of CD38, ADP-ribosyl cyclase and cADPR hydrolase, at a ratio of 16 to 1 respectively, and were immunostained by the anti-(human CD38) monoclonal antibody IB4. In these cells externally added cADPR and beta-NAD+ (the precursor of cADPR), but not alpha-NAD+ or ADP-ribose, enhanced the peak of the depolarization-induced rise in intracellular Ca2+ concentration. This effect was inhibited by 1 microM ryanodine, suggesting a potentiation of calcium-induced calcium release by cADPR. CD38 ectoenzyme activities, ADP-ribosyl cyclase and cADPR hydrolase, were also demonstrated in vivo by microdialysis of adult rat cerebellum, where IB4 bound to granule neurons selectively. Trace amounts (11.5 +/- 3.8 nM) of NAD+ were detected by microdialysis sampling and sensitive assays in the basal interstitial fluid of the cerebellum. These results provide a link between ectocellular cADPR turnover and intracellular calcium mobilization in cerebellum.

ADP-ribosyl Cyclase↗
PubMed1996

In vivo microdialysis study of a specific inhibitor of soluble guanylyl cyclase on the glutamate receptor/nitric oxide/cyclic GMP pathway.

1. Nitric oxide (NO) is known to stimulate soluble guanylyl cyclase, thereby eliciting an elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) in target cells. Recently, a selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), has been identified and characterized in vitro. We have investigated the in vivo effects of ODQ on the glutamate receptor/NO/ cyclic GMP pathway by monitoring extracellular cyclic GMP during microdialysis of the cerebellum or the hippocampus of freely-moving adult rats. 2. Intracerebellar administration of ODQ (1-100 microM) via the microdialysis probe inhibited, in a concentration-dependent manner, the basal extracellular level of cyclic GMP. The maximal inhibition, measured after a 20 min perfusion with 100 microM ODQ, amounted to 80% and persisted unchanged as long as ODQ was perfused. When ODQ was removed from the perfusion stream after 20 min, the levels of cyclic GMP started to recover, suggesting reversibility of guanylyl cyclase inhibition by ODQ. 3. The cyclic GMP response evoked in the cerebellum by NMDA (200 microM) or by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 100 microM) was largely attenuated by 100 microM ODQ. The pattern of the inhibition curves suggests competition for guanylyl cyclase between ODQ and the NO generated by NMDA or AMPA receptor activation. 4. ODQ (100 microM) prevented the elevation of extracellular cyclic GMP levels provoked by intracerebellar infusion of the NO generator S-nitroso-N-acetylpenicillamine (SNAP; 1 mM). The inhibition of the SNAP effect was rapidly relieved when ODQ was removed from the perfusion fluid. However, ODQ (100 microM) was unable to affect the cyclic GMP response elicited by 5 mM SNAP, in keeping with the proposed idea that ODQ binds to the "NO receptor' in a reversible and competitive manner. 5. Infusion of ODQ (10, 100 or 300 microM) into the hippocampus of freely-moving rats diminished the basal extracellular level of cyclic GMP. The maximal inhibition amounted to 50% and was produced by 100 microM ODQ. 6. The cyclic GMP response observed when 1 mM SNAP was perfused in the hippocampus, similar in percentage terms to that seen in cerebellum, was dramatically reduced during co-infusion of 100 microM ODQ. 7. ODQ appears to act in vivo as a selective, reversible and possibly competitive inhibitor of the soluble guanylyl cyclase targeted by NO. This enzyme may generate most (about 80%) of the cyclic GMP found under basal conditions in the extracellular space of the cerebellum. In the hippocampus, about 50% of the basal cyclic GMP does not seem to originate from the ODQ-sensitive soluble guanylyl cyclase.

Animals↗
PubMed1996

Desensitization of AMPA receptors and AMPA-NMDA receptor interaction: an in vivo cyclic GMP microdialysis study in rat cerebellum.

1. Desensitization is an important characteristic of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type. 2. Stimulation of N-methyl-D-aspartate (NMDA) or AMPA receptors in cerebellum results in increased production of cyclic GMP. We have investigated AMPA receptor desensitization in vivo by monitoring extracellular cyclic GMP during intracerebellar microdialysis in conscious unrestrained adult rats. 3. Local infusion of AMPA (10 to 100 microM) caused dose-related elevations of cyclic GMP levels. The effect of AMPA was prevented by the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NOARG). 4. In the absence of AMPA, DNQX lowered the basal levels of cyclic GMP whereas the NMDA receptor channel antagonist dizocilpine (MK-801) was ineffective. 5. Cyclothiazide, a blocker of AMPA receptor desensitization, potentiated the cyclic GMP response to exogenous AMPA. Moreover, cyclothiazide (100-300 microM) produced on its own dose-dependent elevations of extracellular cyclic GMP. The cyclothiazide-induced response was prevented not only by DNQX but also by MK-801. 6. While the cyclic GMP response elicited by AMPA was totally insensitive to MK-801, the response produced by AMPA (10 microM) plus cyclothiazide (30 microM) was strongly attenuated by the NMDA receptor antagonist (30 microM). 7. The results suggest that (a) AMPA receptors linked to the NO-cyclic GMP pathway in the cerebellum can undergo desensitization in vivo during exposure to exogenous AMPA; cyclothiazide inhibits such desensitization; (b) AMPA receptors (but not NMDA receptors) are 'tonically' activated and kept in a partly desensitized state by endogenous glutamate; (c) if cyclothiazide is present, activation of AMPA receptors may permit endogenous activation of NMDA receptors.

Animals↗
PubMed1995

Transmitter release associated with long-term synaptic depression in rat corticostriatal slices.

Using a corticostriatal slice preparation, we have recently shown that tetanic stimulation of the corticostriatal pathway produces long-term depression (LTD) of striatal excitatory synaptic transmission. In the present study we have analysed the relationship between LTD and the striatal release of different endogenous transmitters. Samples of perfusate were collected via a small cannula placed just above the surface of the striatal slice close to the recording electrode, and were analysed by HPLC. The high-frequency stimulation (100 Hz, three trains, 3 s duration, 20 s interval) used to induce LTd caused a significant but transient increase in the release of both excitatory (aspartate and glutamate) and inhibitory (glycine and GABA) amino acid transmitters. Tetanic stimulation also produced a significant, but transient increase in the release of endogenous dopamine. We conclude that the tetanic stimulation of the corticostriatal pathway is able to induce a large but transient release of excitatory amino acids and of dopamine, whose participation in the induction of striatal LTD has been demonstrated previously. Moreover, the maintenance of this form of synaptic plasticity does not seem to require a sustained change in transmitter release.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

Heterocarrier-mediated reciprocal modulation of glutamate and glycine release in rat cerebral cortex and spinal cord synaptosomes.

The effects of glutamic acid (Glu) and glycine (Gly) on each others release were studied using rat brain cortex and spinal cord synaptosomes. Previously taken up [3H]Gly and [3H]D-aspartic acid ([3H]D-Asp) was employed as markers for Gly and Glu/Asp release, respectively. Glu enhanced the release of [3H]Gly (EC50 = 8.4 microM) from cortical synaptosomes. The effect of Glu was not mimicked by the glutamate receptor agonists N-methyl-D-aspartic acid (NMDA), kainic or quisqualic acid. The Glu effect was abolished by the Glu/Asp uptake inhibitor D-threo-hydroxy-aspartic acid and it was Na+ sensitive. D-Asp also increased [3H]Gly release (EC50 = 9.9 microM) and the effect was blocked by the Glu/Asp uptake inhibitor. In contrast to its effect in the cortex, Glu failed to increase the release of [3H]Gly from spinal cord synaptosomes. Gly enhanced the outflow of [3H]D-Asp from rat cerebral cortex and spinal cord synaptosomes (EC50 = 75.0 and 99.5 microM, respectively). Gly was much more potent a releaser of [3H]D-Asp in the spinal cord than in the cortex. The Gly effects were insensitive to strychnine or to 7-Cl-kynurenic acid, antagonists at the two known Gly receptors, but they were strongly Na+ dependent. Our results are compatible with the idea that high-affinity uptake systems specific for Glu/Asp or Gly are colocalized on the same nerve terminal in rat spinal cord and cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Evaluation of the mechanisms underlying the kainate-induced impairment of [3H]dopamine release in the rat striatum.

Kainic acid caused a marked decrease of the electrically evoked release of [3H]dopamine from rat striatal slices 4 days after its injection (10 nmol/microliters) into the corpus striatum. This damage was prevented by the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) when co-injected with kainic acid into the striatum. Prior systemic administration of the NMDA selective antagonists (cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), dizocilpine (MK-801) and ketamine did not alter the kainate effect. Previous destruction of the cortico-striatal pathway abolished the kainate-induced decrease of [3H]dopamine release. When injected into the striatum, domoic acid or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mimicked kainic acid and damaged the dopaminergic nigro-striatal afferents. The [3H]dopamine release evoked by electrical stimulation of slices of frontal cortex was unaffected following local injections of kainic acid. Taken together, the results indicate that AMPA/kainate receptors play a key role in the impairment of [3H]dopamine release caused by kainate in the striatum. However, the kainic acid effect is probably indirect since it appears to require the availability of endogenous glutamate originating from cortico-striatal afferents.

Animals↗
PubMed1993

Autoradiographical evaluation of [3H]glycine uptake in rat forebrain: cellular localization in the hippocampus.

The cellular elements responsible for the uptake of [3H]glycine into rat hippocampal slices were investigated. The diffuse laminar distribution of labelling observed under control conditions was greatly reduced seven days after intrahippocampal injection of a neurotoxic dose of quinolinic acid, suggesting a neuronal localization. Glycine was also taken up into glial cells, since dense clusters of silver grains were present on small sized cells throughout the hippocampus which were apparently increased in number after the lesion. The pattern of [3H]glycine uptake into rat cerebral cortex and cerebellar slices was also consistent with both neuronal and glial localization. These glycine transport sites may be strategically located to control excitatory neurotransmission mediated by the N-methyl-D-aspartate sub-type of glutamate receptors.

Animals↗
PubMed1993

Age-related decrease of the NMDA receptor-mediated noradrenaline release in rat hippocampus and partial restoration by D-cycloserine.

The release of [3H]noradrenaline ([3H]NA) evoked by N-methyl-D-aspartate (NMDA) from superfused rat hippocampus synaptosomes was monitored during aging. The maximal effects of NMDA decreased with age from 50% (1.5 months) to 10% enhancement (24 months). Quisqualic acid (100 microM) also enhanced [3H]NA release. Its effect decreased with age with a pattern partly different from that of NMDA. Glycine (1 microM) potentiated the [3H]NA releasing effect of 100 microM NMDA. Unexpectedly, the potentiation which amounted to 50% at 1.5 months, reached almost 200% and 300% in the 18- and 24-month-old rats, respectively, thus compensating in part for the age-related loss of the NMDA-induced effect. Concentration-response relationships for glycine at 3 vs. 24 months suggest that the glycine receptor is superresponsive in the aged brain. This may be due to more efficient glycine removal or/and to impaired release since uptake of the amino acid was increased by 350% in 24- vs. 3-month-old rats, while the K(+)-evoked tritium release from synaptosomes prelabeled with [3H]glycine was decreased. D-Cycloserine, although about 10 times less potent than glycine, strongly enhanced the NMDA-evoked [3H]NA release and may prove useful in cognitive deficits associated with aging and dementia.

Aging↗
PubMed1993

An evaluation of the role of extracellular amino acids in the delayed neurodegeneration induced by quinolinic acid in the rat striatum.

The effect of the N-methyl-D-aspartate receptor agonist quinolinic acid on extracellular levels of striatal amino acids, following its injection directly into the rat striatum, has been investigated using intracerebral dialysis in the attempt to elucidate the cellular mechanisms underlying delayed neurodegeneration. A neurotoxic dose (200 nmol) of quinolinic acid caused an elevation in the levels of aspartate (x 6), glutamate (x 2), asparagine (x 2), serine (x 2.5), glycine (x 3), and threonine (x 2) which peaked in the fractions 20-40 min after the injection and achieved statistical significance for aspartate and asparagine. The dialysate content of these amino acids returned to basal values within 1 h and no further changes were observed in the following 4 h. Injection of an equivalent dose of nicotinic acid did not mimic the effect of quinolinate, indicating that osmotic and/or mechanical damage was not responsible for the observed phenomena. Pretreatment with the N-methyl-D-aspartate receptor channel blocker dizocilpine (MK-801) completely blocked the quinolinate-induced increase of the amino acids, thus confirming that N-methyl-D-aspartate receptor activation is required for this effect to occur. Seven days after the injection of quinolinate, histological analysis showed an extensive loss of neuronal elements in the injected striatum, which was completely prevented in the dizocilpine-treated animals. Sections from striata of animals injected with nicotinic acid showed normal-appearing neurons and no differences were detectable from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1993

Glutamic acid and gamma-aminobutyric acid modulate each other's release through heterocarriers sited on the axon terminals of rat brain.

The effects of gamma-aminobutyric acid (GABA) on the spontaneous release of endogenous glutamic acid (Glu) or aspartic acid (Asp) and the effects of Glu on the release of endogenous GABA or [3H]GABA were studied in superfused rat cerebral cortex synaptosomes. GABA increased the outflow of Glu (EC50 17.2 microM) and Asp (EC50 18.4 microM). GABA was not antagonized by bicuculline or picrotoxin. Neither muscimol nor (-)-baclofen mimicked GABA. The effects of GABA were prevented by GABA uptake inhibitors and were Na+ dependent. Glu enhanced the release of [3H]GABA (EC50 11.5 microM) from cortical synaptosomes. Glu was not mimicked by the glutamate receptor agonists N-methyl-D-aspartic, kainic, or quisqualic acid. The Glu effect was decreased by the Glu uptake inhibitor D-threo-hydroxyaspartic acid (THA) and it was Na+ sensitive. Similarly to Glu, D-Asp increased [3H]GABA release (EC50 9.9 microM), an effect blocked by THA. Glu also increased the release of endogenous GABA from cortex synaptosomes. In this case the effect was in part blocked by the (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, whereas the 6-cyano-7-nitroquinoxaline-2,3-dione-insensitive portion of the effect was prevented by THA. GABA increased the [3H]D-Asp outflow (EC50 13.7 microM) from hippocampal synaptosomes in a muscimol-, (-)-baclofen-, bicuculline-, and picrotoxin-insensitive manner. The GABA effect was abolished by blocking GABA uptake and was Na+ dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Transport System X-AG↗
PubMed1993

Release-regulating dopamine autoreceptors in human cerebral cortex.

Slices from fresh specimens of human neocortex which had to be removed during neurosurgery to reach subcortical tumours were labelled with [3H]-dopamine and stimulated electrically. Quinpirole, a selective dopamine D2 receptor agonist, inhibited the stimulated tritium overflow (EC50 = 25 nM; maximal inhibition: about 80% at 10 microM). The selective D1 receptor agonist, SKF 38393, was inactive up to 10 microM. Quinpirole was antagonized by the D2 receptor antagonist (-)-sulpiride (apparent pA2 = 8.26). Thus dopaminergic axon terminals in the human mesocortical pathway possess autoreceptors of the D2 type.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Dopamine release and dopaminergic inhibition of acetylcholine release in rat striatal slices after nigro-striatal hemitransection and parenteral ganglioside administration.

Hemitransection of the nigro-striatal bundle in adult rats reduced [3H]dopamine ([3H]DA) uptake into striatal slices from the lesioned side to about 20% of that in the contralateral side 5 days after surgery. Spontaneous recovery of [3H]DA uptake was observed at days 8 and 15 post-lesion (42 and 67% of the unoperated side, respectively). After a short treatment (3 days) with the GM1 ganglioside inner ester (AGF2, 30 mg/kg i.p., daily, starting on day 2 after surgery) [3H]DA uptake amounted to 52% of that in the unoperated side. The electrically evoked fractional overflow of [3H]DA was increased by 500% in slices prepared from the lesioned side 5 days after injury, largely due to the reduced re-uptake by the DA axon terminals. The increase on day 5 was only about 350% in AGF2-treated animals. The DA D2 receptor antagonist, (-)-sulpiride, potentiated the stimulus-evoked overflow of [14C]acetylcholine in slices from the unoperated side prelabelled with [14C]choline. The effect of (-)-sulpiride was much reduced (by about 80%) in the lesioned striata at days 5 and 8 after surgery. Partial recovery was seen at day 15. The lesion did not modify the (-)-sulpiride effect in animals treated with AGF2 from the 2nd to the 5th day post-lesion. Thus early ganglioside administration slows the loss of endogenous dopaminergic control of acetylcholine release caused by partial hemitransection of the nigro-striatal bundle.

Acetylcholine↗
PubMed1992

[3H]glycine uptake in rat hippocampus: kinetic analysis and autoradiographic localization.

The uptake of [3H]glycine by rat hippocampal tissue in vitro has been characterized. [3H]Glycine transport into a crude synaptosomal (P2) fraction was resolved into two components. The high affinity component (Km = 21 +/- 5.4 microM, Vmax = 490 +/- 234 pmol/3 min/mg protein) was almost completely sodium dependent whereas the low affinity component (Km = 2.214 +/- 0.958 mM, Vmax = 13.9 +/- 0.5 nmol/3 min/mg protein) was partially dependent on sodium ions. Amongst a range of amino acids, only L-serine, L-glutamate, L-proline, histidine and glycine itself inhibited [3H]glycine uptake at 1 mM. The autoradiographic localization of [3H]glycine uptake in rat hippocampal slices revealed a general pattern of labeling in dendritic regions with a sparing of pyramidal and granule neuron cell bodies. However, a laminar distribution was apparent since the amino acid was preferentially accumulated in the hilus of the dentate gyrus, in the stratum lacunosum-moleculare, in the alveus and in the molecular layer of the lower blade of the dentate gyrus. A diffuse pattern of accumulation was apparent in these areas along with dense clusters of silver grains. The clusters were associated with small cell bodies and might represent glycine uptake into astrocytes. Glycine transport mechanisms may influence the modulatory effects of this amino acid on N-methyl-D-aspartate receptor-mediated neurotransmission in the hippocampus.

Animals↗
PubMed1991

Cholinergic modulation of [3H]dopamine release from dendrosomes of rat substantia nigra.

Dendrosomes prepared from substantia nigra are able to take up and release [3H]dopamine in a CA(2+)-dependent manner. The Vmax values of [3H]dopamine uptake in substantia nigra dendrosomes was about 5 times lower than that in caudate putamen synaptosomes. The pattern of the K(+)-dependency of the [3H]dopamine release in substantia nigra dendrosomes was significantly different from that found in caudate putamen synaptosomes. The release of [3H]dopamine evoked by 15 mmol/l KCl from superfused dendrosomes was increased in a concentration-dependent manner by acetylcholine. The maximal potentiation produced by acetylcholine was about 40%. The potentiation of [3H]dopamine release by 10 mumol/l acetylcholine was insensitive to mecamylamine but antagonized by atropine and by pirenzepine. The effects of acetylcholine on the release of [3H]acetylcholine from substantia nigra nerve endings was also studied. Exogenous acetylcholine added to the superfusion medium decreased in a concentration-dependent manner the release of acetylcholine. This effect was not antagonized by mecamylamine or pirenzepine but fully antagonized by atropine. The data suggest the existence, in the substantia nigra of the rat, of two distinct muscarinic receptor subtypes regulating respectively dopamine release from dopamine dendrites and acetylcholine release from cholinergic nerve terminals.

Acetylcholine↗
PubMed1991

gamma-Aminobutyric acid (GABA) stimulates somatostatin release following activation of a GABA uptake carrier located on somatostatin nerve endings of rat cerebral cortex.

The effect of gamma-aminobutyric acid (GABA) on the release of somatostatin-like immunoreactivity (SRIF-LI) was studied in synaptosomes prepared from rat cerebral cortex and exposed in superfusion to the amino acid. GABA (1-300 microM) increased the spontaneous outflow of SRIF-LI in a concentration-dependent manner. The effect of GABA was not prevented by the GABAA receptor antagonists bicuculline or picrotoxin. The GABAA receptor agonist muscimol (10-100 microM) did not affect SRIF-LI release. Similarly ineffective was the GABAB receptor agonist (-)-baclofen (100 microM). The GABA-induced SRIF-LI release was counteracted by the GABA uptake inhibitors N-(4,4-diphenyl-3-butenyl)-nipecotic acid (SK&F 89976A) and nipecotic acid. When used as a GABA carrier substrate, nipecotic acid mimicked GABA and increased SRIF-LI release; its effect was antagonized by SK&F 89976A. The mechanism involved appears to be selective for GABA inasmuch as neutral amino acids such as leucine, alpha-aminobutyric acid or valine, tested at 100 microM, had little or no effect on the release of SRIF-LI. Neither GABA (100 microM) nor nipecotic acid (300 microM) enhanced the release of cholecystokinin-like immunoreactivity. The GABA-evoked somatostatin release was calcium-dependent and tetrodotoxin-insensitive. It is concluded that a carrier for the uptake of GABA exists on somatostatin-releasing terminals of rat cerebral cortex and that GABA uptake may regulate somatostatin release. This conclusion would be compatible with the reported coexistence of GABA and somatostatin in cerebrocortical neurons.

Amino Acids↗
PubMed1991

gamma-Aminobutyric acidB receptors mediate inhibition of somatostatin release from cerebrocortex nerve terminals.

The effects of gamma-aminobutyric acid (GABA) and of various GABA receptor agonists and antagonists on the calcium-dependent depolarization-evoked release of somatostatin (SRIF) from rat cerebrocortex synaptosomes have been studied by a superfusion technique. GABA (0.3-30 microM) decreased the K+ (15 mM)-evoked overflow of SRIF-like immunoreactivity (SRIF-LI) in a concentration-dependent manner (EC50 = 1.3 microM; maximal inhibition, 45% reached at 10 microM GABA). The effect of the amino acid was insensitive to the GABAA receptor antagonist bicuculline. Accordingly, the K(+)-evoked SRIF-LI release was not affected by muscimol, a GABAA receptor agonist, up to 100 microM. The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (EC50 = 1.2 microM; maximal effect, about 45% reached at 10 microM). The effect of baclofen was stereoselective, the (+)-enantiomer being inactive up to 100 microM. The inhibition of SRIF-LI release brought about by GABA was sensitive to the GABAB receptor antagonists 2-hydroxy-saclofen and CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid]. Also, the effect of (-)-baclofen was antagonized by CGP 35348 (IC50 = 4.8 microM). It is concluded that GABA can inhibit the depolarization-evoked release of SRIF by activating receptors which are located on SRIF-releasing nerve terminals and belong to the GABAB type.

Animals↗