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Biomedical subjects

B Scatton

Publications and source records attributed to B Scatton.

At least 217 records · Page 12Linked to original sources
PubMed1982

Brain 3,4-dihydroxyphenylethyleneglycol levels are dependent on central noradrenergic neuron activity.

The effect of manipulations aimed to alter brain noradrenergic neuron activity on the levels of free and conjugated DOPEG in discrete brain areas was studied in the rat. Electrical stimulation of the medial forebrain bundle for 10-20 min produced a frequency dependent elevation of free and conjugated DOPEG concentrations in the anterior cerebral cortex and in the hippocampus. In contrast, acute interruption of noradrenergic nerve impulse flow by application of tetrodotoxin (50-100 ng) into the medial forebrain bundle markedly diminished cortical and hippocampal DOPEG levels at 0.5-2 h post-injection. Cortical conjugated and free DOPEG levels were also reduced (by 80-96%) 2-3 weeks after bilateral electrolytic lesion of the locus coeruleus, 6-hydroxydopamine-induced lesion of the ascending noradrenergic pathways or noradrenergic denervation by the neurotoxic agent DSP4. Finally, the alpha-adrenoceptor blocking agents yohimbine (1-10 mg/kg, ip) and RX 781094 (3-10 mg/kg, ip) increased whereas the alpha-adrenergic agonist clonidine (0.01-1 mg/kg, sc) decreased DOPEG levels in the cerebral cortex, hypothalamus and septal areas. These data indicate that free and conjugated DOPEG formation is dependent on, and may serve as an index of, central noradrenergic neuron activity.

Animals↗
PubMed1982

Differential effects of inescapable footshocks and of stimuli previously paired with inescapable footshocks on dopamine turnover in cortical and limbic areas of the rat.

The effect of electric footshocks and of exposure to environmental stimuli paired with electrical shocks upon the dopaminergic activity in various cortical and limbic areas of the rat were evaluated by measuring dihydroxyphenylacetic acid (DOPAC) levels in these areas. In animals exposed to a 20 min electric footshock session DOPAC concentrations were significantly increased in the antero-medial and sulcal frontal cortices, olfactory tubercle, nucleus accumbens and amygdaloid complex (by 66, 37, 28, 55 and 90% respectively). Re-exposure of rats to an environment where they had been shocked 24 h earlier induced an elevation of DOPAC content only in the anteromedial frontal cortex (by 47%). Plasma corticosterone levels were elevated in both situations. No change in serotonin or 5-hydroxyindolacetic acid content of these areas could be detected in either situation. The results show that electric footshocks and environmental stimuli associated to previous shocks both activate central dopaminergic systems, although the patterns of activation are different.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Cortical modulation of striatal function.

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

High doses of haloperidol in schizophrenia. A clinical, biochemical, and pharmacokinetic study.

The effects of high doses of haloperidol on clinical status and plasma neuroleptic and prolactin concentrations and CSF levels of homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were investigated in three paranoid schizophrenic patients over six weeks. The patients had been receiving haloperidol. Oral dosages were increased at weekly intervals from 10 to 200 mg/day and then reduced to 10 mg/day. The increase did not affect paranoid symptoms. Neurological side effects were slightly increased in two patients and moderately reduced in one. Plasma prolactin levels, initially high, increased when the dosage was increased to 100 mg/day but did not increase further. The CSF levels of HVA and GABA increased to day 7 but returned to initial values on day 28 in two patients; they were decreased to day 28 in one patient.

Adult↗
PubMed1982

A radioenzymatic technique for the measurement of free and conjugated 3,4-dihydroxyphenylethylene-glycol in brain tissue and biological fluids.

A simple, sensitive and specific radioenzymatic assay for the measurement of 3,4-dihydroxyphenylethyleneglycol (DOPEG) was developed. The assay is based on the conversion of the compound to its O-methylated derivative in the presence of catechol-O-methyltransferase and [3H]S-adenosyl-methionine. The tritiated 3-methoxy-4-hydroxyphenylethyleneglycol formed is selectively extracted in organic solvents and isolated by thin layer chromatography. After oxidation to vanillin the O-methylated compound is extracted and measured by liquid scintillation spectrophotometry. This assay has been applied to the measurement of free and conjugated DOPEG in a variety of biological tissues and fluids. Both free and conjugated DOPEG were readily detected in discrete rat brain areas. Substantial amounts of free and conjugated DOPEG were also measured in ventricular perfusates from freely moving rats. Finally, the presence of DOPEG was also demonstrated in human cerebrospinal fluid, plasma and urine. Only the free form of DOPEG was found in cerebrospinal fluid, whereas both unconjugated and conjugated forms were present in plasma and urine.

Animals↗
PubMed1982

Dopamine deficiency in the cerebral cortex in Parkinson disease.

We measured the concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in several cortical areas from controls and parkinsonian patients. Substantial amounts of dopamine and its metabolites were detected in hippocampus and entorhinal, cingulate, and frontal cortex of controls. In parkinsonian patients the levels of dopamine and its metabolites were reduced in these neocortical areas and hippocampus. Diminution of cortical dopaminergic transmission may play a role in the mental impairment of some Parkinson patients.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. II. Specificity of progabide (SL 76002) and SL 75102 for the GABA receptor.

Progabide and its immediate metabolite SL 75102 displace [3H]gamma-aminobutyric acid (GABA), [3H]muscimol and [3H]isoguvacine from their binding sites to membranes prepared from rat brain or human cerebellum and increase (SL 75102) [3H]flunitrazepam binding to rat cerebral cortex membranes. In contrast, these compounds have very weak or no effects on alpha or beta noradrenergic, histamine, muscarinic cholinergic or glycine receptors or on the [3H]imipramine or [3H]kainate binding sites. Neither progabide nor SL 75102 inhibit GABA synthesis, metabolism or uptake. Also, the uptake of norepinephrine, serotonin and dopamine into synaptosomes of cerebral regions is not affected by progabide. [3H]GABA release from substantia nigra slices is decreased by SL 75102 and progabide, in agreement with the hypothesis of a GABAergic autoreceptor controlling GABA release from its nerve terminals. These data suggest a specific agonist action of progabide and SL 75102 on GABA receptors.

Animals↗
PubMed1982

Functional and biochemical evidence for the lack of cardiac presynaptic alpha-2 adrenoceptor stimulant properties of cirazoline (LD 3098), a potent alpha-1 adrenoceptor agonist in dogs and rats.

In pithed rats, i.v. injection of cirazoline produced pressure effects which were antagonized in a competitive manner by the relatively selective alpha-1 adrenoceptor blocker, prazosin (0.01--0.1 mg/kg i.v.) but not by the relatively selective alpha-2 adrenoceptor blocker, yohimbine (0.3 mg/kg i.v.). The latter agent, however, inhibited the increases in arterial pressure produced by UK-14,304, a preferential alpha-2 adrenoceptor agonist. In contrast, both yohimbine and prazosin reduced the pressor effects of clonidine. In intact anesthetized, vagotomized rats or in pithed rats with a submaximal tachycardia evoked by electrical stimulation of the spinal cord, clonidine and oxymetazoline, in contrast to cirazoline (5.0 micrograms/kg i.v.), decreased heart rate through excitation of alpha-2 adrenoceptors. This lack of effect of cirazoline was not due to a concomitant pre- or postjunctional action of cirazoline leading to an enhanced chronotropic response to released norepinephrine because in phentolamine-pretreated rats cirazoline did not modify the neural sympathetic tachycardia. Although cirazoline potentiated the heart rate elevated by an i.v. infusion of either norepinephrine, isoproterenol, or aminophylline, this effect was probably of hemodynamic origin. In pithed rats with a submaximal neural tachycardia, cirazoline, like phentolamine (10.0--30.0 micrograms/kg i.v.), inhibited the decrease in heart rate produced by clonidine, suggesting that it possesses alpha-2 adrenoceptor blocking properties. In spinal dogs, cirazoline (10.0 micrograms/kg i.v.) modified neither base-line heart rate nor the tachycardia evoked by an intracoronary artery infusion of norepinephrine. In the same preparation, continuous electrical stimulation of cardioaccelerator sympathetic nerve fibers produced a sustained positive chronotropic effect accompanied by an increase in the coronary sinus venous plasma norepinephrine content. Neither parameter was significantly changed by cirazoline; however, clonidine at the same dose as used for cirazoline produced approximately 50% inhibition of the experimental neural tachycardia. Finally, cirazoline, like phentolamine at 10.0 micrograms/kg i.v., failed to block, cardiac presynaptic alpha-2 adrenoceptors in the spinal dog. These results indicate that cirazoline is a potent alpha-1 adrenoceptor agonist that lacks cardiac presynaptic alpha-2 adrenoceptor stimulant properties in either dogs or rats. In the latter species, cirazoline was found also to block cardiac presynaptic alpha-2 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1982

Urethane inhibits cardiovascular responses mediated by the stimulation of alpha-2 adrenoceptors in the rat.

Clonidine and oxymetazoline (4.0 microgram/kg i.v. or i.a.) evoked a marked bradycardia in either methylatropine-pretreated conscious or pentobarbital-anesthetized (55 mg/kg i.p.), vagotomized rats. Urethane (1.2 g/kg i.p.) inhibited by more than 50% this effect which is mediated through the stimulation of peripheral and/or central neuronal alpha-2 adrenoceptors. However, in adrenalectomized rats only the inhibition of oxymetazoline by urethane was significantly less pronounced. In pithed rats in which the adrenal glands were either left untouched or surgically removed, urethane significantly attenuated the clonidine or oxymetazoline-induced decreases in experimental neural sympathetic tachycardia although it neither changed the base-line nor the experimentally elevated heart rate. Urethane, in contrast to pentobarbital, increased plasma epinephrine concentrations in intact but not in adrenalectomized or in pithed rats. Elevation of plasma epinephrine did not result from the low arterial pressure level associated with urethane anesthesia since the increase of this parameter with vasopressin did not abolish the effect of urethane. Furthermore, guanethidine-pretreated rats, when anesthetized with urethane, exhibited a higher heart rate and plasma adrenaline value than those anesthetized with pentobarbital. The elevated heart rate was decreased by either propranolol or adrenalectomy. The bradycardia produced by injecting clonidine into the lateral cerebral ventricles of either intact or adrenalectomized rats was markedly less in urethane- than in pentobarbital-anesthetized animals. Whereas in pentobarbital-anesthetized rats the peak heart rate effects of i.v. or i.c.v. clonidine were similar, in urethane-anesthetized animals the effects of clonidine were more inhibited when it was given centrally than when it was given peripherally. In pithed rats, the cumulative dose-pressor response curves elicited by the relatively selective alpha-2 adrenoceptor agonists, B-HT 930 and M-7, were depressed by urethane significantly more than those produced by the relatively selective alpha-1 adrenoceptor agonists, phenylephrine and cirazoline, or by angiotensin II. Urethane also decreased the pressor responses evoked by clonidine, oxymetazoline and norepinephrine which stimulate both alpha-1 and alpha-2 adrenoceptors. However, the extent of this inhibition was less than that of B-HT 920 and M-7 but greater than that of cirazoline and phenylephrine. These results show that urethane inhibits cardiovascular responses that are mediated by peripheral and central alpha-2 adrenoceptors. Furthermore, urethane increases the central drive to the adrenal medulla and this leads to the secretion of epinephrine. This may be partly responsible for the inhibitory activity of urethane on oxymetazoline-induced bradycardia. Although the basic mechanism by which urethane impairs responses mediated by alpha-2 adrenoceptors remains to be determined, it is advised that urethane anesthesia should be avoided, particularly for cardiovascular studies.

Adrenalectomy↗
PubMed1982

[Use of haloperidol in high doses in schizophrenia. Clinical, biochemical and pharmacokinetic study].

The effect of high doses of haloperidol on the clinical status, plasma neuroleptic and prolactin concentrations as well as on CSF HVA and GABA levels was investigated in 3 paranoid schizophrenic patients over a 6 weeks period. When the study was initiated patients had been on haloperidol (10 mg a day) for 4-10 weeks. Oral doses were increased at weekly intervals from 10 (day 0) to 100 (day 7) and 200 (days 14 to 28) mg a day and then reduced to 100 (day 35) and 10 (day 42) mg/day. A linear relationship was observed between plasmatic levels and daily doses of haloperidol. In neither patient, the increase in haloperidol dosage affected paranoid symptoms. Neurological side effects were slightly increased in 2 cases and moderately reduced in one case. Prolactin plasma levels, already high at the onset of the study rose when increasing the dose to 100 mg a day but did not increase further despite increment in the haloperidol dosage. CSF levels of HVA and GABA rose from day 0 to day 7 but were back to the initial values on day 28 in 2 patients and were decreased from day 0 to day 28 in one patient. For the 3 patients a close correlation was observed between changes in CSF HVA and GABA levels. It is concluded that high doses of haloperidol, although causing biochemical changes compatible with the occurrence of dopamine target cell supersensitivity, do not lead to any clinical improvement in the 3 studied schizophrenic patients.

Adult↗
PubMed1981

Determination of 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid in rat and human brain and biological fluids by reversed-phase high-performance liquid chromatography with electrochemical detection.

A rapid and sensitive method for the concurrent determination of 5-hydroxytryptophan, serotonin and 5-hydroxyindole acetic acid by reversed-phase high-performance liquid chromatography with electrochemical detection has been developed. The separation of the indolic compounds was achieved using a phosphate-citric acid eluent containing 5% methanol. Detection limits in the low picogram range were found. The method has been applied to the determination of the indolic compounds in rat and human brain tissues, as well as in human plasma and cerebrospinal fluid. Tissue and plasma preparation required only deproteinization before chromatography, while cerebrospinal fluid was directly applied to the column.

5-Hydroxytryptophan↗
PubMed1981

Differential changes in DOPAC levels in the hippocampal formation, septum and striatum of the rat induced by acute and repeated neuroleptic treatment.

Acute administration of haloperidol, sulpiride and chlorpromazine produces an elevation of hippocampal, septal and striatal DOPAC levels. The ED50 of haloperidol is similar in all areas but the maximal effect is much lower in the hippocampal formation than in septum and striatum. Repeated administration (11 days) of haloperidol causes a less pronounced increase (tolerance) in DOPAC levels in all regions investigated than acute treatment, the hippocampal formation being the most susceptible to this tolerance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

[Biochemical mechanism of action of neuroleptics (author's transl)].

This review is devoted to the analysis of the mechanism of action of neuroleptics. The effects of these compounds on cerebral dopaminergic transmission and on the metabolism of various neurotransmitters are reviewed. Ample evidence derived from behavioral, clinical and biochemical studies indicates that a diminution of cerebral dopaminergic transmission (due to a blockade of dopaminergic receptors) probably accounts for the therapeutic activity (as well as some side effects) of neuroleptics. The tubero-infundibular dopaminergic system appears to play a major role in the neuroendocrine side effects of neuroleptics. Blockade of striatal dopaminergic transmission may probably be accounted for the extrapyramidal side effects induced by these drugs. As suggested by various biochemical data obtained in both animals and humans, the meso-cortico-limbic dopaminergic system appears to be the anatomical substrate of the antipsychotic action of neuroleptics. Recent results also suggest a modulatory influence of the frontal cortex on neuroleptic-induced extrapyramidal side effects. Finally, other cerebral neurotransmitters (noradrenaline, neuropeptides) might be involved in the mechanism of action of neuroleptic agents.

Animals↗