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G Pepeu

Publications and source records attributed to G Pepeu.

At least 127 records · Page 7Linked to original sources
PubMed1988

Muscarinic modulation of purine release from electrically stimulated rat cortical slices.

The release of 3H-labeled purines at rest and during electrical stimulation was investigated in slices of rat cortex prelabeled with [3H]adenine and perfused with Krebs solution. A linear relationship was found between radioactivity efflux and stimulation frequency from 2.5 to 20 Hz. At frequencies of less than 2.5 Hz, no increase in radioactivity efflux was detected. The amount of tritium released per pulse increased with stimulation frequency up to 10 Hz and declined at 20 Hz. The tritium efflux from the slices at rest and at a stimulation frequency of 10 Hz, analyzed by HPLC with ultraviolet absorbance detection at 254 nm, consisted mostly of adenosine, inosine, and hypoxanthine. The 3H-labeled purine release evoked by 10-Hz stimulation increased with current intensity from 15 to 100 mA/cm2. At 20 mA/cm2, addition of 0.5 microM tetrodotoxin to the superfusing Krebs solution brought about a 98% decrease of 3H-labeled purine release. At higher current strength, the percentage of tetrodotoxin-sensitive-evoked tritium efflux was smaller. At 30 mA/cm2, 86% of the evoked release was tetrodotoxin sensitive. Under these stimulation conditions, tritium efflux showed a 69% decrease when the slices were superfused with calcium-free Krebs solution containing 0.5 mM EGTA. The muscarinic agonist oxotremorine (30 microM) significantly enhanced the 10-Hz-stimulated 3H-labeled purine release. The effect of oxotremorine was partially prevented by tetrodotoxin, was antagonized by atropine (1.5 microM), and was mimicked by addition of physostigmine (3.8 microM) to the superfusion fluid. Atropine alone did not affect the evoked release, and none of the drugs modified the basal tritium efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1987

GABA-receptor stimulation enhances norepinephrine-induced polyphosphoinositide metabolism in rat hippocampal slices.

The effect of gamma-aminobutyric acid (GABA)receptor stimulation on norepinephrine (NE)-induced metabolism of polyphosphoinositides (PIPs) was studied in rat hippocampal slices. Inositol phosphates (IPs), PIPs, and phosphatidic acid were measured. NE induced formation of IPs and phosphatidic acid in a dose-dependent manner with an EC50 of 4.5 microM. GABA, 3-aminopropanesulphonic acid (3APS) and muscimol did not affect PIPs breakdown, but they strongly increased (greater than 100%) PIPs metabolism induced by 1 microM NE. Their action was antagonized by bicuculline (10 microM). We discuss the implications of these findings in hippocampal neurotransmission.

Animals↗
PubMed1987

Recovery of cortical acetylcholine output after ganglioside treatment in rats with lesion of the nucleus basalis.

The changes in acetylcholine release from the cerebral cortex induced by a unilateral electrolytic lesion of the nucleus basalis and by a treatment with GM1 monosialoganglioside (30 mg/kg i.p. for 20 days) were investigated. Acetylcholine release was measured using the cortical cup technique in rats transected at midpontine level. In the lesioned rats treated with saline an ipsilateral 38% decrease in acetylcholine release was observed. GM1 treatment prevented the decrease and brought about a 30% contralateral increase. These results indicate that GM1 induces a functional recovery of the cholinergic neurons ascending to the cortex.

Acetylcholine↗
PubMed1987

Phospholipase C activation induced by noradrenaline in rat hippocampal slices is potentiated by GABA-receptor stimulation.

We have studied the effect of gamma-aminobutyric acid (GABA) and other GABA-receptor agonists (3-aminopropanesulphonic acid and muscimol) on the noradrenaline-induced stimulation of polyphosphoinositide metabolism in rat hippocampal slices. Formation of water-soluble inositol phosphates, and polyphosphoinositide metabolism were studied in hippocampal slices prelabelled with [3H]myoinositol. Noradrenaline induced formation of inositol mono-, bis- and trisphosphate during 10 min incubation in the presence of lithium; activation of phospholipase C by noradrenaline was also reflected by the hydrolysis of polyphosphoinositides and by the increased metabolism of phosphatidylinositol. GABA-receptor agonists were unable to activate per se phospholipase C; however, when added together with a low concentration of noradrenaline, they greatly potentiated the noradrenaline-stimulated polyphosphoinositide metabolism. We conclude that GABA-receptor agonists potentiate the effect of noradrenaline on polyphosphoinositide turnover and we discuss the role of this neurotransmitter interaction in the physiology of the hippocampus.

Animals↗
PubMed1987

An analysis of cholecystokinin-induced increase in acetylcholine output from cerebral cortex of the rat.

The effect of colecystokinin (CCK-8) on the release of ACh from the cerebral cortex was studied in urethane-anaesthetized rats with the cortical cup technique. The increase in output of ACh brought about by the administration of CCK-8 1.5 micrograms/kg (i.p.) was prevented by pretreatment with haloperidol (1 mg/kg i.p.) and by lesions of the nucleus basalis magnocellularis and substantia nigra but it was reduced only slightly by bilateral vagotomy. Conversely, none of the treatments abolished the decrease in output of ACh brought about by CCK-8 at a dose of 10 micrograms/kg (i.p.). Local injection of CCK-8 into the nucleus basalis had no effect. Therefore, CCK-8 appears to increase cortical cholinergic activity by indirectly stimulating the cholinergic neurones of the nucleus basalis through dopaminergic neurones.

Acetylcholine↗
PubMed1987

Effect of pyroglutamic acid stereoisomers on ECS and scopolamine-induced memory disruption and brain acetylcholine levels in the rat.

The acquisition of a passive avoidance conditioned response was disrupted in the rat by electroconvulsive shock (ECS) and scopolamine administration. D,L-pyroglutamic acid (D,L-PCA) 500 and 1000 mg/kg, administered as arginine salt 120 min before the retest, prevented both the ECS and scopolamine-induced amnesia. Arginine alone was ineffective. Scopolamine brought about a 52 and 39% decrease, respectively, in cortical and hippocampal acetylcholine (ACh) levels, measured by means of a gas-chromatographic method. D,L-PCA 500 and 1000 mg/kg also prevented the decrease in brain ACh level. When the two isomers were studied separately, D-PCA was more effective than L-PCA and antagonized scopolamine-induced amnesia at the doses of 250 and 500 mg/kg. In conclusion, D,L-PCA is active on cortical and hippocampal cholinergic mechanisms and, like other 2-oxopyrrolidone derivatives, shows cognition-enhancing properties.

Acetylcholine↗
PubMed1987

Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine.

The effect of cognition-enhancing agents oxiracetam and aniracetam on scopolamine-induced amnesia and brain acetylcholine decrease was investigated in the rat. Acetylcholine levels were measured by means of a gas-chromatographic method. Scopolamine (0.63 mg/kg IP 60 min before training) prevented the acquisition of a passive avoidance conditioned response ("step through": retest 30 min after training) and brought about a 64, 56 and 42% decrease in acetylcholine level in the cortex, hippocampus and striatum respectively. Oxiracetam (50 and 100 mg/kg IP) administered 30 min before scopolamine reduced the scopolamine-induced amnesic effect and decrease in acetylcholine level in the cortex and hippocampus, but not in the striatum. Lower and higher doses of oxiracetam were ineffective. Aniracetam (100 mg/kg PO) also prevented scopolamine-induced amnesia but attenuated acetylcholine decrease in the hippocampus only. Aniracetam (300 mg PO) reduced acetylcholine decrease in the hippocampus but did not prevent scopolamine-amnesia. In conclusion, oxiracetam and aniracetam exert a stimulatory effect on specific central cholinergic pathways. However, a direct relationship between cognition-enhancing properties and cholinergic activation needs further confirmation.

Acetylcholine↗
PubMed1986

Oxiracetam prevents electroshock-induced decrease in brain acetylcholine and amnesia.

In the rat, 1 min following electroshock (ECS) a 46 and 39% decrease in acetylcholine levels was found in the hippocampus and cerebral cortex, respectively. The decrease in the hippocampus was still statistically significant 30 min after ECS. The ECS applied 1 min after training also disrupted the performance of a passive avoidance conditioned response ('step down') tested 30 min later. Oxiracetam (100 and 300 mg/kg i.p.) administered 90 min before training prevented, in a dose-dependent manner, the decrease of acetylcholine in the cerebral cortex and hippocampus. Oxiracetam prevented the ECS disruption of the acquisition of a passive avoidance response. At the dose of 300 mg/kg the acetylcholine level 1 min after ECS was significantly higher than in the sham-treated rats. Piracetam at the same doses was inactive. These results support the hypothesis that oxiracetam may prevent the disruption of the conditioned response by acting on cortical and hippocampal cholinergic mechanisms.

Acetylcholine↗
PubMed1986

Effect of BM-5, a presynaptic antagonist-postsynaptic agonist, on cortical acetylcholine release.

The effect of N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl) acetamide (BM-5) on acetylcholine release from the cerebral cortex was investigated in unanaesthetized and urethane-anaesthetized rats. BM-5 at doses ranging from 0.3 to 5 mg/kg i.p. enhanced acetylcholine output in both groups of rats. The maximum increase occurred with 0.5 mg/kg in the unanaesthetized and 2 mg/kg in the anaesthetized rats. The effect lasted approximately 60 min. At the largest doses peripheral muscarinic effects including salivation, chromodachryorrhea and rhinorrhea were also seen. These results demonstrate that BM-5 exerts presynaptic antagonistic and postsynaptic agonistic effects on muscarine receptors in vivo also.

Acetylcholine↗
PubMed1986

Are the neurochemical and behavioral changes induced by lesions of the nucleus basalis in the rat a model of Alzheimer's disease?

A review of the work on the neurochemical, electroencephalographic and behavioral changes induced in the rat by lesions of the nucleus basalis is presented. The similarities and differences between the effects of the lesions and the neurochemical and clinical alterations characterizing senile dementia of Alzheimer type are pointed out. The decrease in choline acetyltransferase (ChAT) activity in the cortex following unilateral or bilateral electrolytic or neurotoxic lesions of the nucleus basalis are described and compared with the decrease in ChAT activity found in the cortex and hippocampus of patients affected by senile dementia. At variance with the latter condition, in rats with lesions of the nucleus basalis a spontaneous recovery in cortical ChAT activity has been observed 3-6 months after the lesion. The lesions of the nucleus basalis decrease high affinity choline uptake activity which, however, undergoes a rapid recovery. Lesions also decrease spontaneous and drug-stimulated ACh release from the cerebral cortex. Transitory changes in the number of muscarinic binding sites have been reported in the cerebral cortex of the lesioned rats while a decrease in the number of muscarinic binding sites has generally been found in the cerebral cortex of patients with senile dementia. [3H] glutamate uptake in the striatum of the lesioned rats was not affected. In both lesioned rats and patients affected by senile dementia, a decrease of low voltage high frequency electrocortical activity has been reported. Unilateral and bilateral lesions of the nucleus basalis bring about an impairment of the acquisition of active and passive avoidance responses and of the rewarded alternation discriminatory tasks involving working memory and spatial memory. On the other hand, memory impairment is a typical symptom of senile dementia. In conclusion, the lesions of the nucleus basalis only partly mimic the complex clinical picture of senile dementia of Alzheimer type. They offer, nevertheless, a useful tool for understanding the critical role of the central cholinergic pathways in some of the cognitive processes and identifying potentially useful pharmacological treatments.

Alzheimer Disease↗
PubMed1986

Changes in cortical acetylcholine output induced by modulation of the nucleus basalis.

The modulatory inputs of the cholinergic neurons of the nucleus basalis have been investigated in midpontine transected and freely moving rats by measuring acetylcholine release from the cerebral cortex using the cortical cup technique. Acetylcholine release was found to be the same in both groups of rats indicating similar levels of activity of the cholinergic neurons ascending to the cortex. The electrical stimulation of the nucleus basalis was always followed by an increase in acetylcholine release. Conversely, in some experiments only the stimulation of the midbrain reticular formation enhanced acetylcholine output. The stimulation of the nucleus accumbens prevented the increase in acetylcholine release elicited by amphetamine. The dose-dependent increase in acetylcholine output following IP administration of amphetamine was also prevented by the 6-hydroxydopamine induced degeneration of the dopaminergic fibres. However injection of apomorphine in the nucleus basalis did not modify acetylcholine output. Direct injection of the GABAergic agonist muscimol resulted in a decrease in acetylcholine output which was prevented by picrotoxin. In conclusion, the cholinergic neurons ascending to the cortex can be inhibited by GABA receptors located in the nucleus basalis and stimulated indirectly by dopaminergic fibres.

Acetylcholine↗
PubMed1986

Effect of adenosine, adenosine derivatives, and caffeine on acetylcholine release from brain synaptosomes: interaction with muscarinic autoregulatory mechanisms.

Synaptosomes, prepared from rat cerebral cortex and hippocampus, were preincubated with [methyl-3H]choline. The effect of adenosine, cyclohexyladenosine, N-ethylcarboxamide adenosine, 2'-deoxyadenosine, and oxotremorine on K+-evoked 3H efflux was investigated. High-voltage electrophoretic separation showed that in the presence of physostigmine, the K+-evoked 3H efflux from hippocampal synaptosomes was 90% [3H]acetylcholine and 10% [3H]choline. Adenosine (30 microM) and oxotremorine (100 microM) both decreased [3H]acetylcholine release from hippocampal synaptosomes. The effect was inversely proportional to the KCl concentration and disappeared at a KCl concentration of 50 mM. Cyclohexyladenosine was approximately 3,000 times more active than adenosine, whereas N-ethylcarboxamide adenosine and 2'-deoxyadenosine were inactive. This indicates that A1 adenosine receptors were involved in the inhibitory effect. Caffeine antagonized the adenosine effect, and at a concentration of 100 microM, it stimulated [3H]acetylcholine efflux. The inhibitory effect of oxotremorine was as great in cortical as in hippocampal synaptosomes. In contrast, adenosine was much less active in cortical than in hippocampal synaptosomes. When inhibitory concentrations of adenosine and oxotremorine were added together into the incubation medium, the effect of adenosine on [3H]acetylcholine release was consistently reduced. An interaction between muscarinic and A1 adenosine presynaptic receptors at a common site modulating acetylcholine release can be assumed.

Acetylcholine↗
PubMed1986

Chronic caffeine treatment reduces caffeine but not adenosine effects on cortical acetylcholine release.

The effects of both adenosine and caffeine on the release of acetylcholine (ACh) were investigated in slices of cerebral cortex taken from rats pretreated for 30 days with caffeine (100 mg kg-1 daily, dissolved in their drinking water) at rest and during electrical stimulation at frequencies of 0.2, 1 and 5 Hz. The effect of this treatment on adenosine binding sites was also investigated in cortical membranes using N-cyclohexyl-[3H]-adenosine ([3H]-CHA) as a ligand. The chronic caffeine treatment did not change animal growth patterns. Spontaneous exploratory activity appeared to be increased at the 3rd day but was unchanged at the 30th day when compared with controls. Caffeine-treatment increased the number of high affinity binding sites for [3H]-CHA by 64% over the control values. Low affinity binding site density and affinity constants were unaffected. Adenosine 30 microM added to the superfusion fluid decreased electrically stimulated ACh release both in rats drinking tap water and rats drinking caffeine. In rats drinking tap water, caffeine added to the superfusion fluid at a concentration of 50 microM enhanced ACh release, while at 0.5 mM it decreased ACh output from the slices. Both effects were abolished by pretreatment with caffeine in vivo. The results indicate that prolonged consumption of high doses of caffeine causes changes in the responsiveness of cholinergic neurones to caffeine. The change is not shared by adenosine, through whose recognition sites caffeine is believed to act. It is therefore possible that the adaptive changes following repeated caffeine administration involve either only the coupler-transducer mechanism activated by the antagonist, or effects unrelated to receptors.

Acetylcholine↗
PubMed1986

Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition.

Oxiracetam at 100 and 300 mg/kg i.p. dose levels increased acetylcholine (ACh) utilization in the rat cerebral cortex and hippocampus. ACh utilization was assessed by measuring, with a gas chromatographic method, the decrease in ACh level after inhibiting its synthesis by 15 micrograms intracerebroventricularly (i.c.v.) injection of hemicholinium (HC-3). ACh steady state levels were not affected. Piracetam (300 mg/kg i.p.) also increased ACh utilization in the hippocampus. Repeated daily administration of oxiracetam 100 mg/kg i.p. caused a 31% increase in high-affinity choline uptake (HACU) in the hippocampus. A single administration of 300 mg/kg i.p. of oxiracetam and piracetam also increased HACU rate in the hippocampus. However, the effect of piracetam was over within 3 h, while 3 h after its administration oxiracetam still caused a 40% increase in HACU rate. Oxiracetam (100 mg/kg i.p.) significantly antagonized the impairment in the acquisition of an active-avoidance conditioned response (pole climbing) associated with the inhibition of ACh synthesis by HC-3. These results indicate that oxiracetam enhances the activity of the septohippocampal cholinergic pathways, and to a lesser extent, of the cortical cholinergic network.

Acetylcholine↗
PubMed1985

Muscarinic mobilization of choline in rat cerebral cortex does not involve alterations of blood-brain barrier.

Efflux of choline from the rat cerebral cortex in vivo was investigated using the cup technique. After removal of the dura mater, the cup was placed on the cortex. Transmission and scanning electron microscopy revealed that the cortex was separated from the cup solution (100-300 microliter) by basal lamina, pia mater, arachnoid (with discrete defects) and remainders of the subdural neurothelium. Two kinds of experiments were carried out to determine: efflux of unlabelled choline into the cup solution; and translocation of radioactivity from the plasma into the cup solution (via blood-brain barrier and leptomeningeal layers) during i.v. infusion of [3H]choline or [14C]inulin. The former process was highly temperature-sensitive in contrast to the latter. Penicillin-G-sodium, which is known to damage the blood-brain barrier, was added to the cup solution, enhanced efflux of unlabelled choline, and caused a 5-fold increase in the rates of translocation of radioactivity during infusion of either labelled choline or inulin. In contrast, physostigmine (3 X 10(-4) M, added to cup solution) failed to enhance 3H-translocation, but markedly facilitated the efflux of unlabelled choline; this effect was highly temperature-sensitive and was blocked by atropine. It is concluded that activation of muscarinic receptors enhanced the choline efflux from cortical tissue. This effect was caused by cellular mobilization of choline presumably through an action on the metabolism of phosphatidylcholine. The effect was not due to alterations in the translocation of choline from the plasma to the cup solution, i.e. through permeability changes in the blood-brain barrier and in the leptomeningeal 'barrier'.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗