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Biomedical subjects

L Pieri

Publications and source records attributed to L Pieri.

At least 55 records · Page 3Linked to original sources
PubMed1981

Selective antagonists of benzodiazepines.

Benzodiazepines produce most, if not all, of their numerous effects on the central nervous system (CNS) primarily by increasing the function of those chemical synapses that use gamma-amino butyric acid (GABA) as transmitter. This specific enhancing effect on GABAergic synaptic inhibition is initiated by the interaction of benzodiazepines with membrane proteins of certain central neurones, to which drugs of this chemical class bind with high affinity and specificity. The molecular processes triggered by the interaction of these drugs with central benzodiazepine receptors, and which result in facilitation of GABAergic transmission, are still incompletely understood. Theoretically, benzodiazepines could mimic the effect of hypothetical endogenous ligands for the benzodiazepine receptors, although there is no convincing evidence for their existence; in vitro studies indicate that benzodiazepines might compete with a modulatory peptide which is present in the supramolecular assembly formed by GABA receptor, chloride ionophore and benzodiazepine receptor and which reduces the affinity of the GABA receptor for its physiological ligand. The mechanisms of action of benzodiazepines at the molecular level are likely to be better understood following our recent discovery of benzodiazepine derivatives, whose unique pharmacological activity is to prevent or abolish in a highly selective manner at the receptor level all the characteristic centrally mediated effects of active benzodiazepines. Here, we describe the main properties of a representative of this novel class of specific benzodiazepine antagonists.

Animals↗
PubMed1981

Pharmacology of midazolam.

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Anesthetics↗
PubMed1976

The effect of diphenylhydantoin, diazepam and clonazepam on the activity of Purkinje cells in the rat cerebellum.

Spike discharges of single cerebellar Purkinje cells were recorded continuously with extracellular microelectrodes in unanesthetized curarized rats. The intravenous injection of diphenylhydantoin in doses between 10 and 100 mg kg-1 did not substantially alter the activity of Purkinje cells within 2--3 h. The two benzodiazepines, diazepam and clonazepam, already in low i.v. doses (0.03--0.1 mg kg-1) consistently and reversibly depressed the firing rate. Our results do not support the previously advanced hypothesis that these drugs reduce epileptiform activities by increasing the output from the cerebellar cortex. They rather point to the possibility that a reduced firing rate of cerebellar Purkinje cells mediates at least in part ataxia and muscular hypotonia observed after the drugs.

Action Potentials↗
PubMed1976

Changes of rat cerebellar guanosine 3',5'-cyclic phosphate by dopaminergic mechanisms in vivo.

Apomorphine produced a dose-dependent increase of the cGMP level in the cerebellum. Haloperidol and scopolamine completely prevented this increase, and reserpine reduced the increase to 50%. LSD elevated cerebellar cGMP, and this effect was also abolished by haloperidol. It is suggested that the primary site of action of these drugs is the caudate nucleus, from which two neuronal pathways could trigger the increase of cGMP in the cerebellum.

Animals↗
PubMed1975

Disappearance of supra-ependymal 5-HT axons in the rat forebrain after electrolytic and 5,6-DHT-induced lesions of the medial forebrain bundle.

The present study was intended to demonstrate the origin of supra-ependymal 5-hydroxytryptamine axons in the rat forebrain. Electrolytic lesions and injections of 5,6-dihydroxytryptamine (10 mug in 4 mul) were carried out unilaterally in and close to the medial forebrain bundle in the posterior hypothalamus of rats. Ten to 14 days later, terminal axons and formaldehyde-induced indolealkylamine fluorescence had virtually disappeared supra-ependymally in the lateral ventricles and interventricular foramina ipsilateral to the lesion if the indolealkylamine axons passing through the medial part of the medial forebrain bundle had been destroyed. No changes were observed, electron microscopically or fluorescence histochemically, in ventricles contralateral to the lesion. It is concluded that the supra-ependymal serotonergic nerve terminals in the lateral ventricles and interventricular foramina originate, uncrossed, from non-terminal axons passing through the medial forebrain bundle in the posterior hypothalamus.

5,6-Dihydroxytryptamine↗
PubMed1975

Improved rapid method to check electrode localizations in the brain.

A modification of known rapid methods to check electrode localization in the brain is described: the essential point consists in immersing the brain, after fixation in 4 percent Formalin, in pure heptane at -30 degrees C for 5 hr. Unstained sections, cut with the freezing microtome, are placed uncovered on glass slides and photographed (in an enlarger, as if they were negatives) either wet, to obtain a contrast resembling Weil staining, or dry, to obtain a picture corresponding to Nissl staining.

Animals↗
PubMed1975

A comparison of drug-induced rotation in rats lesioned in the medial forebrain bundle with 5,6-dihydroxytryptamine or 6-hydroxydopamine.

Drug-induced rotational behaviour was studied in two groups of rats with differing chemical lesion of the right medial forebrain bundle (MFB). 6-hydroxydopamine (6-OH-DA), 3.5 mug, injected in one group, induced a marked lowering of dopamine (DA) and noradrenaline (NA) in the right hemiforebrain. 5,6-Dihydroxytryptamine (5,6-HT), 10 mug, injected in a second group, produced a profound and long-lasting depletion of 5-hydroxytryptamine (5-HT) and DA, but not of NA. Rotational behaviour induced in both groups by DA receptor agonists (apomorphine, piribedil, L-DOPA, ergometrine, ergocornine, 2-bromo-alpha-ergocryptine, ergocristine, methylergometrine) and agents releasing DA (d-methamphetamine, methylphenidate) were qualitatively identical and quantitatively very similar, suggesting a minor role of 5-HT striatal terminals in these experimental conditions. LSD induced contralateral rotation by direct stimulation of the DA receptor, while L-5-hydroxy-tryptophan (L-5HTP) was inactive.

5,6-Dihydroxytryptamine↗
PubMed1975

Possible involvement of GABA in the central actions of benzodiazepines.

The effects of several benzodiazepines on a variety of nervous activities known or presumed to depend on GABA are presented and compared with those of agents that deplete or increase the level of endogenous GABA: antagonism of various convulsant agents in mice, enhancement of presynaptic inhibition in the spinal cord and the cuneate nucleus of cats, decrease of the spontaneous firing rate of cerebellar Purkinje cells in cats and rats, antagonism of bicuculine-induced depression of the strio-nigral-evoked potential in the cat, potentiation of haloperidol-induced catalepsy in rats, GABA-mimetic actions on drug-induced PGO-waves in cats and on eserine-induced circling in guinea pigs. Diazepam slightly increased the GABA level in the cat spinal cord and in the total brain of mice and rats; this increase does not seem to be due to an increase of GABA synthesis. It is concluded that benzodiazepines probably enhance presynaptic inhibition at all levels of the neuraxis and that this effect requires not only the presence of GABA but is also dependent on an activity of GABA-ergic neurons. Benzodiazepines also appear to enhance postsynaptic inhibition where this is mediated by GABA. Many actions of benzodiazepines can be tentatively explained by a stimulus-bound enhancement of GABA effects.

Aminobutyrates↗