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M Morari

Publications and source records attributed to M Morari.

34 records · Page 2Linked to original sources
PubMed1995

AMPA receptor activation regulates the glutamate metabotropic receptor stimulated phosphatidylinositol turnover in human cerebral cortex slices.

The effect of excitatory amino acids (EAA) on phosphatidylinositol (PI) turnover in human cerebral cortical slices was investigated. Trans-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) increased inositol phosphate (IP) formation in the 1-1000 microM range. Quisqualic acid (QA) was maximally effective at 10-100 microM, showing an inverse correlation between concentration and effect in the 100-1000 microM range. The glutamate metabotropic receptor antagonist 2-amino-3-phosphonopropionic acid (AP3), the ionotropic non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the NMDA channel blocker dizolcipine (MK-801) failed to prevent the PI response to ACPD (1000 microM). However, CNQX (100 microM) modified the concentration-response curve of QA reducing the effect of QA 10 microM by approx. 50% and enhancing that of QA 1000 microM by 2-fold. In addition, CNQX (100 microM) together with MK-801 (100 microM) unmasked the ability of L-glutamate (L-GLU) 3000 microM to stimulate PI turnover. The effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on the EAA-induced PI turnover was also studied. AMPA (0.1-1 microM) potentiated the response to submaximal (30 microM) ACPD and (1 microM) QA concentrations. However, higher AMPA concentrations (10 microM) failed to synergize with ACPD 30 microM and, in addition, inhibited the PI turnover maximally stimulated by QA 10 microM. These results further support the presence of the glutamate metabotropic receptor in the human neocortex. In addition, they show the occurrence of a concentration-related dual interaction between AMPA and glutamate metabotropic receptor activation in the IP formation in this brain area.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

5-Hydroxytryptamine-mediated effects of nicotine on endogenous GABA efflux from guinea-pig cortical slices.

1. The effect of nicotine on endogenous basal GABA outflow was studied in guinea-pig cerebral cortex slices. 2. Nicotine 1.86-18.6 mumol l-1 significantly decreased the basal, tetrodotoxin-sensitive GABA efflux, whereas at higher concentrations (186-620 mumol l-1) nicotine increased it. The inhibition was prevented by mecamylamine while the facilitation was blocked by mecamylamine, (+)-tubocurarine and tetrodotoxin. 3. The effect of nicotine was due to an indirect 5-hydroxytryptaminergic action. In fact, MDL 72222 (1 mumol l-1) completely prevented the alkaloid inhibition and methysergide (1 mumol l-1) reversed the facilitation into inhibition; concomitant treatment with methysergide and MDL 72222 antagonized the effect of nicotine at 186 mumol l-1 4. Lower concentrations of 5-HT (3-10 mumol l-1) decreased, whereas higher concentrations (30-100 mumol l-1) increased, spontaneous GABA outflow. The inhibition of GABA efflux was prevented by MDL 72222 whereas the facilitation was reversed by methysergide (1 mumol l-1) into inhibition, and prevented by MDL 72222 1 mumol l-11. 5. These results suggest that, by activating nicotinic receptors present on 5-hydroxytryptaminergic terminals, nicotine releases 5-HT which, in turn, inhibits or increases the secretory activity of cortical GABA interneurones via 5-HT3 and methysergide-sensitive receptors, respectively.

Animals↗
PubMed1994

Dopamine D1 and D2 receptor antagonism differentially modulates stimulation of striatal neurotransmitter levels by N-methyl-D-aspartic acid.

The effects of local perfusion with the dopamine D1 receptor antagonist SCH 23390 and the dopamine D2 receptor antagonist raclopride on basal and N-methyl-D-aspartate (NMDA) stimulated dopamine, gamma-aminobutyric acid (GABA) and glutamate levels in the dorsolateral striatum were monitored using in vivo microdialysis in the halothane anaesthetized rat. Local perfusion (90 min) with SCH 23390 and raclopride (1 and 10 microM) dose dependently increased basal striatal dopamine release whereas GABA and glutamate dialysate levels were unaffected. Local perfusion (10 min) with the 1 mM concentration of NMDA increased striatal dopamine, GABA and glutamate outflow. However, when perfused together with SCH 23390 (1 microM) NMDA inhibited glutamate efflux. Moreover, in the presence of SCH 23390 (10 microM) the NMDA induced rise in dopamine and GABA levels was partly prevented. On the other hand, raclopride 1 microM enhanced the NMDA stimulated GABA efflux while at 10 microM it partly counteracted the NMDA induced dopamine release. These data demonstrate that NMDA induced changes in striatal neurotransmitter outflow are effectively modified by dopamine D1 and D2 receptor blockade.

Animals↗
PubMed1994

Excitatory amino acids (EAAs) stimulate phosphatidylinositol turnover in adult rat striatal slices: interaction between NMDA and EAA metabotropic receptors.

The effect of excitatory amino acids (EAAs) on phosphatidylinositol (PI) turnover in adult rat striatal slices was investigated. Quisqualic acid (QA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), ibotenic acid (IBO) and N-methyl-D-aspartic acid (NMDA) maximally increased inositol phosphate (IP) formation at 10 microM while trans-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) was maximally effective at 100 microM. The NMDA channel blocker dizolcipine (MK-801) counteracted the effect of NMDA 10 microM and IBO 10 microM while it potentiated that of IBO 100 microM and IBO 1000 microM. Conversely, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prevented the effect of AMPA and KA and reduced that of QA (all at 10 microM). Lowering extracellular Ca2+ concentrations ([Ca2+]0) differentially affected the PI response to EAAs. The ACPD 30 microM effect was unchanged at low [Ca2+]0 (but abolished when EGTA 2 mM was added), while that of ACPD 100 microM was halved in 0.1 mM and almost abolished in a nominally free Ca2+ medium. NMDA 10 microM and AMPA 10 microM were ineffective at low [Ca2+]0 while NMDA 100 microM, ineffective in a 1.2 mM Ca2+ medium, strongly stimulated IP formation in 0.1 mM Ca2+ but not in a nominally free Ca2+ medium. The effect of NMDA on EAA metabotropic receptor agonist stimulated PI turnover was also studied. NMDA 10 microM potentiated the effect of ACPD 30 microM. This positive cooperation persisted at low [Ca2+]0 but not in the presence of EGTA. Conversely, NMDA 100 microM prevented the effect of ACPD 100 microM. This negative interference was reversed when Ca2+ was omitted from the medium. This study shows that in the adult rat striatum both EAA metabotropic and ionotropic receptor activation increases IP formation. A positive and negative interaction between NMDA and metabotropic receptor activation was also found to regulate PI turnover. The role of [Ca2+]0 in subserving the PI response to EAAs was made evident.

Amino Acids↗
PubMed1993

N-methyl-D-aspartic acid differentially regulates extracellular dopamine, GABA, and glutamate levels in the dorsolateral neostriatum of the halothane-anesthetized rat: an in vivo microdialysis study.

The effects of local perfusion with the glutamate receptor agonist NMDA and the noncompetitive NMDA receptor antagonist dizolcipine (MK-801) on extracellular dopamine (DA), GABA, and glutamate (Glu) levels in the dorsolateral striatum were monitored using in vivo microdialysis in the halothane-anesthetized rat. In addition, the sensitivity of both the basal and NMDA-induced increases in levels of these neurotransmitter substances to perfusion with tetrodotoxin (TTX: 10(-5) M) and a low Ca2+ concentration (0.1 mM) was studied. The results show that the local perfusion (10 min) with both the 10(-3) and 10(-4) M dose of NMDA increased striatal DA and GABA outflow, whereas only the (10(-3) M) dose of NMDA was associated with a small and delayed increase in extracellular Glu levels. The NMDA-induced effects were dose-dependently counteracted by simultaneous perfusion with MK-801 (10(-6) and 10(-5) M). Both the basal and NMDA (10(-3) M)-induced increase in extracellular striatal DA content was reduced in the presence of TTX and a low Ca2+ concentration, whereas both basal and NMDA-stimulated GABA levels were unaffected by these treatments. Both the basal and NMDA-stimulated Glu levels were enhanced following TTX treatment, whereas perfusion with a low Ca2+ concentration reduced basal Glu levels and enhanced and prolonged the NMDA-induced stimulation. These data support the view that NMDA receptor stimulation plays a role in the regulation of extracellular DA, GABA, and Glu levels in the dorso-lateral neostriatum and provide evidence for a differential effect of NMDA receptor stimulation on these three striatal neurotransmitter systems, possibly reflecting direct and indirect actions mediated via striatal NMDA receptors.

Anesthesia↗
PubMed1992

Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.

Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Comparison of [3H]choline and D-[3H]aspartate efflux from guinea pig and human neocortex.

The outflow of [3H]choline ([3H]Ch) evoked by electrical field stimulation and the efflux of D-[3H]Asp induced by 35 mM KCl and 1-10 microM ouabain were studied in human and guinea pig cortical slices, kept under identical experimental conditions. [3H]Ch outflow was significantly lower whereas D-[3H]Asp efflux was significantly higher in humans than in guinea pigs. This suggests a different proportion of the two neuronal systems in these two species. Blockade of muscarinic autoreceptors with atropine increased, whereas stimulation of alpha 2 receptors with norepinephrine (NE) reduced, the evoked [3H]Ch outflow to the same extent in human and guinea pig cortical slices. Conversely, NE did not affect ouabain-induced D-[3H]Asp efflux, suggesting that an alpha 2-mediated control is not operative in the glutamatergic cortical structures. Desmethylimipramine, 2-5 microM, was able to increase [3H]Ch outflow through atropine-like mechanisms only in the human. This drug at 20-50 microM inhibited [3H]Ch and D-[3H]Asp efflux in both species, through mechanisms unrelated to its monoamine reuptake blocking properties. Thus, similarities and differences can be detected between humans and guinea pigs with regard to (a) the relative potency of the cholinergic and acidic amino acidergic signals and (b) the modulation of neurotransmitter outflow by drugs acting on auto- and the heteroreceptors.

Animals↗
PubMed1991

Inhibitory effect of NMDA receptor activation on quisqualate-stimulated phosphatidylinositol turnover in the human cerebral cortex.

The effect of excitatory amino acids (EAA) on the phosphatidylinositol (PI) turnover in human cerebral cortical slices was investigated. Quisqualic acid (QA) and, to lesser extent, ibotenic acid (IBO) at 10(-5)-10(-3) M increased inositol phosphate (IP) accumulation. L-Glutamic acid (L-glu), kainic acid (KA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartic acid (NMDA) were ineffective. NMDA dose-dependently antagonized the QA facilitatory effect. Such inhibition was prevented by the NMDA receptor complex antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine (MK-801) and by 3[+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid. The effect of IBO (but not that of QA) was greatly potentiated by MK-801. These data suggest that the EAA metabotropic receptor described in the rodent brain is also present in human cerebral cortex and is negatively modulated by the NMDA receptor.

Amino Acids↗
PubMed1991

Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs.

The effects of excitatory amino acid antagonists on increased cortical acetylcholine release and behavioral hyperactivity induced by naloxone in morphine tolerant guinea pigs and mice were studied. The results show that the N-methyl-D-aspartic acid (NMDA) antagonist MK-801 (0.1-1 mg/kg, i.p.) injected 30 min before naloxone (3 mg/kg, s.c.) dose-dependently prevented the neurochemical and behavioral signs of morphine withdrawal in guinea pigs and mice. The non-selective antagonist glutamic acid diethylester only at 100 mg/kg i.p. reduced the naloxone-induced increase of cortical acetylcholine release without affecting the behavioral changes. These findings indicate that the activation of excitatory amino acid receptors, mainly the NMDA receptors, plays a relevant role in the expression of opiate abstinence.

Acetylcholine↗
PubMed1991

Synthesis and structure-activity relationships of deltorphin analogues.

In order to study the structure-activity relationships of natural opioid deltorphins (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 and H-Tyr-D-Ala-Phe-Asp [or Glu]-Val-Val-Gly-NH2), 15 analogues were synthesized by the solution method. Their activities were determined in binding studies based on displacement of mu- and delta-receptor selective radiolabels from rat brain membranes and in two bioassays, using guinea pig ileum and mouse vas deferens. The obtained data indicate that the high delta-selectivity of deltorphins can be due to the constitution/conformation of the C-terminal part and, at least in part, to preselection by charge.

Amino Acid Sequence↗
PubMed1991

Effect of acute and subchronic nicotine treatment on cortical efflux of [3H]-D-aspartate and endogenous GABA in freely moving guinea-pigs.

1. The [3H]-D-aspartate preloading of the parietal cortex of freely moving guinea-pigs equipped with epidural cups makes it possible to investigate drug effects on the efflux of this radiolabel, assumed as a marker of the glutamatergic structures underlying the cup. In the same model, the efflux of [3H]-gamma-aminobutyric acid ([3H]-GABA) and endogenous GABA can be measured. 2. Nicotine, 0.9-3.6 mg kg-1, s.c., or 3-5 micrograms, i.c.v., increased the efflux of [3H]-D-aspartate but reduced that of GABA. 3. These effects were mediated through mecamylamine-sensitive receptors but the ganglionic blocking agent was devoid of any primary activity. 4. The inhibition of GABA efflux induced by nicotine 3.6 mg kg-1, s.c., was abolished by methysergide 2 mg kg-1, i.p. and was reduced by naloxone 3 mg kg-1, i.p. pretreatment, suggesting the involvement of tryptaminergic and opioid systems. In contrast, muscarinic and catecholamine antagonists were ineffective. 5. Chronic treatment with nicotine (3.6 mg kg-1, twice daily for 16 days) reduced the facilitatory effect of [3H]-D-aspartate and abolished the inhibition of endogenous GABA efflux. 6. A slight increase in the number of nicotinic binding sites (by use of [3H]-nicotine as ligand) was found in the neocortex of chronically treated guinea-pigs. 7. The higher degree of tolerance to chronic nicotine treatment shown by GABA as compared with [3H]-D-aspartate efflux suggests that adaptative changes of the inhibitory neuronal pools prevail. This may contribute to the reinforcing and addictive properties of nicotine.

Acetylcholine↗
PubMed1991

Alpha-2 adrenoreceptor-mediated decrease in gamma-aminobutyric acid outflow in cortical slices and synaptosomes during morphine tolerance.

Morphine tolerance has proven to be accompanied by alterations in the efficiency of many neuronal signals, as well as by an inversion of the noradrenergic signal response of cortical acetylcholine terminals and gamma-aminobutyric acid (GABA) neurons in vivo (decreased acetylcholine and increased GABA release in normal animals, vice versa in tolerant). The latter observation may be relevant in interpreting morphine withdrawal, because the noradrenergic neuron firing rate increases dramatically during its course. This study was designed as an attempt to anatomically localize the inversion of the GABA response to norepinephrine. Because this phenomenon is observed in cortical slices and synaptosomes, it can be postulated that it occurs in the neocortex at the level of the intracortical GABA nerve terminals. Pharmacological analysis demonstrates that although the stimulation observed in controls is alpha-1 adrenoreceptor-mediated, the inhibition in tolerant animals is exerted via alpha-2 adrenoreceptors. Therefore, an increase in number or an improved coupling to the transduction system of alpha-2 adrenoreceptors is hypothesized. This observation gives a clue to a molecular interpretation of the inversion of GABA response to norepinephrine in tolerant animals, which may be of heuristic value in terms of biological interpretation of morphine tolerance.

Animals↗
PubMedDate not supplied

Effect of alpha-adrenoreceptors in the control of spontaneous motility and morphine withdrawal syndrome.

The effects of different alpha-2 agonists on the spontaneous motility in naive and morphine tolerant mice were studied. Clonidine caused a reduction at the lower (1-3 micrograms Kg-1 i.p.) and higher (100 micrograms Kg-1 i.p.) doses and no effect at 10-30 micrograms Kg-1 i.p. in naive mice, while an increase was found at the intermediate doses (10-30 micrograms Kg-1 i.p.) in morphine tolerant mice. The clonidine-induced inhibition on spontaneous motility at the lower and higher doses was prevented both in naive and tolerant mice by idazoxan pretreatment. In morphine-treated animals the increase induced by clonidine was antagonized by prazosin. The action of guanabenz and guanfacine on locomotion differed from clonidine, by producing inhibition only at higher doses (100-300 micrograms Kg-1 i.p.). Clonidine, but not guanfacine or guanabenz, prevented the withdrawal syndrome precipitated by naloxone. Thus the only alpha-2 agonistic properties do not appear sufficient to explain the prevention of morphine abstinence by clonidine in mice, which can represent a single model to screen anti-withdrawal drugs.

Adrenergic alpha-Agonists↗