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Biomedical subjects

P Simon

Publications and source records attributed to P Simon.

At least 379 records · Page 21Linked to original sources
PubMed1986

Antidepressant-like effects of diphenylhydantoin in mice: involvement of alpha-adrenoceptors.

Several studies have indicated that alpha-adrenergic systems are implicated in the anticonvulsant activity of diphenylhydantoin. We now report that in mice prazosin (0.125 mg/kg), a blocker of alpha 1-adrenoceptors, reverses the effects exerted by diphenylhydantoin (256 mg/kg) in tests which are predictive of antidepressant activity: reserpine-induced ptosis and immobility which are caused by inescapable, aversive situations. These date indicate that alpha-adrenoceptors are not only involved in the anticonvulsant action of diphenylhydantoin, but also in its antidepressant-like effects.

Animals↗
PubMed1986

Synthesis and genotoxicity of acetoxyoxirane, the epoxide of vinyl acetate.

Acetoxyoxirane, the epoxide of vinyl acetate and a potential reactive intermediate, was synthesized and characterized by 13C-nuclear magnetic resonance (13C-NMR) and mass spectroscopy. The compound induced lesions (endonuclease-sensitive and alkali-labile sites) in supercoiled PM2 DNA in vitro and was directly mutagenic toward Salmonella typhimurium TA100. The mutagenicity of the epoxide in phosphate buffer (pH 7.4, 37 degrees C) decreased, with an initial half-life of 2.8 minutes, and mutagenicity was completely abolished by addition of S-9 mix. Acetoxyoxirane did not induce unscheduled DNA synthesis on incubation with Syrian hamster embryo fibroblasts (SHE cells). These findings may possibly be explained by an effective inactivation of acetoxyoxirane by esterases when these are present in the biological system. This view is consistent with the lack of acetoxyoxirane detected in rat liver microsomal incubations of vinyl acetate.

Animals↗
PubMed1986

Noradrenergic and opioid mediation of tricyclic-induced reversal of escape deficits caused by inescapable shock pretreatment in rats.

The present study was undertaken to investigate the possible involvement of a noradrenergic and opioid mediation of the reversal by tricyclic antidepressants of escape deficits produced by inescapable shock pretreatment. Rats were first exposed to 60 inescapable shocks (15 s duration, 0.8 mA, every min +/- 15 s) and 48 h later subjected, to daily shuttle-box sessions (30 trials/day, ITI: 30 s) during 3 consecutive days. Twice-daily IP injection of desipramine or clomipramine (total daily dose: 32 mg/kg) prevented escape deficits. Penbutolol (0.125; 0.25; 0.5 mg/kg), prazosin (1; 2 mg/kg) and naloxone (0.5; 1 mg/kg) given once a day dose-dependently attenuated the beneficial effect of tricyclic antidepressants in reducing the number of escape failures in rats exposed to shock pretreatment. In agreement with data obtained in the forced-swimming model, these findings support the notion that activation of noradrenergic and opioid receptors is an important factor in the mediation of the effects of tricyclic antidepressants in animal models of depression.

Animals↗
PubMed1986

Acute versus repeated administration of desipramine in rats and mice: relationships between brain concentrations and reduction of immobility in the swimming test.

Immobility scores in the swimming test and brain concentrations of desipramine were determined in rats and mice following repeated injection of the antidepressant versus acute administration of either a behaviorally effective or ineffective dose of the drug. Five injections (IP) of desipramine (each injection being performed at the measured T1/2 of the drug in the brain) reduced immobility scores by 30%, whereas this regimen resulted in brain drug concentrations not different from those obtained after a single, behaviorally ineffective dose of desipramine. It is suggested that the enhanced "antidepressant" response such as that frequently observed in animals after repeated injection of imipramine-like drugs does not involve accumulation of the drug in the brain.

Animals↗
PubMed1986

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice.

Clenbuterol, isoproterenol and salbutamol increased the latency in the licking response of mice on the hot plate at 56.5 degrees C. This effect was dose-related and obtained after IP administration. Clenbuterol was active at lower doses than isoproterenol and salbutamol, a result which is consistent with its better penetration in the central nervous system. Moreover, the effect of clenbuterol was stereospecific, the (-)-isomer being the active form. Our results suggest the implication of central beta-adrenoceptors in the modulation of the response to a painful stimulation.

Albuterol↗
PubMed1986

Integrity of the thyroglobulin locus in tricho-rhino-phalangeal syndrome II.

The thyroglobulin gene has been mapped to chromosome band 8q24 by several investigators. This is the band implicated in the causation of Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome II). We have examined a restriction fragment length polymorphism at the thyroglobulin locus in a patient with Langer-Giedion syndrome and 8q deletion in order to: (1) localize the Langer-Giedion deletion more precisely, (2) define the relative map positions of the thyroglobulin gene and the Langer-Giedion locus. The results indicate that the locus of the thyroglobulin gene is intact in the patient with an interstitial deletion of proximal band 8q24.1 which confirms its more distal localization reported earlier by Bergé-Lefranc et al. (1985). It also assigns the critical region for the causation of Langer-Giedion syndrome to the proximal part of band 8q24, viz. 8q24.11----q24.13.

Child↗
PubMed1986

Absence of human chorionic somatomammotropin during pregnancy associated with two types of gene deletion.

Complete absence of human somatomammotropin (hCS) was demonstrated in two patients experiencing an otherwise uneventful pregnancy. After delivery, DNA was prepared from the neonate blood or from the placenta and the integrity of the hCS-hGH gene cluster was investigated by Southern blotting and hybridization with an hCS cDNA probe. Patient 1 was found to be homozygous for a deletion involving hCS-A, hGH-V, and hCS-B. Patient 2 was a double heterozygote, with one chromosome bearing the same deletion as that of patient 1, while in the other, only the hCS-A gene was missing. Considerations relative to the frequency of the defect are derived from the present results.

Chromosome Deletion↗
PubMed1986

Chronic beta-adrenergic stimulation increases in mice the sensitivity to methysergide and the number of cerebral high affinity serotonin binding sites (5-HT-1).

Reserpine administration in mice causes, among other effects an akinesia which can be reversed by the serotonin agonist-antagonist methysergide. The effect of methysergide is potentiated by clenbuterol, a beta-adrenergic agonist, which itself causes hypomotility. Potentiation is weak after a single injection of clenbuterol, but becomes much stronger after repeated administration for 12 days. This treatment also causes a 50% increase in the number of high affinity 5-HT-1 binding sites in the brain. This increase would explain the increased potency of methysergide against reserpine-induced akinesia. These results show that: a beta-adrenergic drug, clenbuterol modulates the serotoninergic system; this modulation takes its importance after chronic treatment only; this interrelation may be important in depressive illness since it is observed on a test used in the screening of antidepressant drugs.

Animals↗
PubMed1986

Performance deficit induced by low doses of dopamine agonists in rats. Toward a model for approaching the neurobiology of negative schizophrenic symptomatology?

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.

Amisulpride↗
PubMed1986

Interleukin 1 and protein kinase C activator are dissimilar in their effects on Il-2 receptor expression and Il-2 secretion by T lymphocytes.

T lymphocytes respond to mitogenic stimulation by expressing the receptor for interleukin 2 (Il-2) and secreting Il-2; once the receptor is expressed, Il-2 induces these cells to proliferation. In the present report using mouse T lymphocytes, thymocytes, and the lymphoma cell line EL4, we studied receptor expression and Il-2 secretion as early parameters for T-lymphocyte activation in response to ionomycin, concanavalin A (Con A), 12-O-tetradecanoyl-phorbol 13-acetate (TPA), and interleukin 1 (Il-1). Il-1 is required for mitogenic response of lymphocyte preparations that are rigorously depleted of macrophages. On its own, Il-1 had very little effect on Il-2 secretion and Il-2 receptor expression by T lymphocytes. TPA strongly synergized with ionomycin both for Il-2 secretion and for Il-2 receptor expression whereas Il-1 did not. Il-1 required the simultaneous presence of ionomycin and TPA to have any demonstrable effect on T lymphocytes from spleen and on thymocytes. However, on EL4 cells which were also partially responsive to TPA alone, Il-1 showed strong synergy with TPA to induce Il-2 secretion and Il-2 receptor expression. The effect of Il-1 on EL4 cells was dose dependent where increasingly higher concentrations of Il-1 in the presence of a fixed concentration of TPA caused higher percentage of EL4 cells to become Il-2 receptor positive. The present results suggest that Il-1 does not cause its effect on T lymphocytes via the same mechanism of protein kinase C activation that has been proposed for TPA.

Animals↗
PubMed1986

Behavioral deficits induced by low doses of apomorphine in rats: evidence for a motivational and cognitive dysfunction which discriminates among neuroleptic drugs.

In order to further assess the alterations (motor, motivational or cognitive) that might underlie animal behavioral deficits associated with a reduced dopamine transmission, the effects of apomorphine at doses thought to stimulate dopaminergic autoreceptors were studied on rat operant behavior. Apomorphine (30 micrograms/kg SC) decreased the number of food rewards obtained, when rats trained on a continuous reinforced schedule were shifted to schedules of fixed ratio higher than 2:FR3, FR4, and FR8. In rats shifted to a FR4 schedule, apomorphine (7.5, 15, 30, 60 micrograms/kg SC) dose-relatedly reduced the number of rewards obtained. In rats subjected to previous extinction sessions, apomorphine (30 micrograms/kg) did not affect lever pressing reinstated on presentation of primary reinforcers but inhibited responding renewed on presentation of secondary reinforcers. Under a FR(3 + 1) schedule where the last (rewarded) response was distinct from the initial (non-rewarded) responses, the detrimental effect of apomorphine on response rates was considerably weaker than under a conventional FR4 schedule. The reward deficits caused by apomorphine under the FR4 schedule were dose-dependently and completely reversed by amisulpride (0.125, 0.25, 0.5, 1 and 2 mg/kg), pimozide (0.125 mg/kg), sulpiride (8, 16, 32 and 64 mg/kg), but not by conventional neuroleptics (namely chlorpromazine, fluphenazine, haloperidol, metoclopramide and thioridazine). It is suggested that behavioral deficits associated with a reduced dopamine transmission such as that caused by low doses of apomorphine involve motivational and cognitive dysfunctions rather than motor impairments. In account of its differential sensitivity to neuroleptic drugs, apomorphine-induced deficit might have some relevance for a further delineation of the mechanisms of action of these compounds.

Animals↗
PubMed1986

The lesion of serotonergic neurons does not prevent antidepressant-induced reversal of escape failures produced by inescapable shocks in rats.

The present study was aimed at testing the hypothesis (based mainly on biochemical evidence) of the implication of brain serotonergic neurons in the induction of learned helplessness (escape deficit) and its reversal by antidepressants in rats. After desipramine (25 mg/kg IP)-pretreatment rats were either sham-operated or infused with 5,7-dihydroxytryptamine (5,7-DHT, 3 micrograms of free base in 0.4 microliter saline containing 0.02% ascorbic acid) into the midbrain raphe area. Three weeks later, experimental animals were exposed to 60 randomized inescapable shocks (0.8 mA; 15 sec duration), control rats being not shocked, and 48 hr later, they were subjected to daily shuttle-box sessions (30 trials/day; ITI = 30 sec) on 3 consecutive days in order to assess escape deficits. After inescapable shock pretreatment separate groups of rats were given twice daily injections of clomipramine (total daily dose: 32 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg), nialamide (32 mg/kg) or saline. After behavioral testing, animals were sacrificed, and tryptophan hydroxylase activity was assayed in the cerebral cortex, the hippocampus and the striatum. We found that damage to serotonergic neurons associated with a 70% loss of tryptophan hydroxylase activity altered neither escape deficits produced by prior exposure to inescapable shock, nor the ability of either antidepressant studied to reverse escape failures in the shuttle-box paradigm. These findings cast some doubts on the hypothesized crucial role of serotonergic neurons in helpless behavior and its reversal by antidepressants.

Animals↗
PubMed1986

Shuttle-box deficits induced by inescapable shocks in rats: reversal by the beta-adrenoreceptor stimulants clenbuterol and salbutamol.

Beta-adrenoreceptor stimulants such as salbutamol and clenbuterol have been reported to be effective in depressive states and to share many actions with classical antidepressants in animals. To further explore the antidepressant activity of these drugs, we investigated their effects in rats subjected to helplessness training. Rats were first exposed to inescapable shock pre-treatment (60 shocks, 15 sec duration, 1 mA every minute +/- 15 sec) and 48 hr later, shuttle-box training (30 trials/day, ITI: 30 sec) was initiated in order to evaluate escape and avoidance deficits. Rats pretreated with inescapable shocks exhibited escape and avoidance deficits when tested for subsequent responding in a shuttle-box. The deficits are particularly marked at the third training session. Daily IP injections of clenbuterol (total daily dose: 0.5 and 0.75 mg/kg) and salbutamol (16 and 24 mg/kg) prevented escape deficits as did daily injections of classical antidepressants such as desipramine (16 and 24 mg/kg/day) and clomipramine (16 and 24 mg/kg/day). These data extend previous results bearing on the similarity of action of beta receptor stimulants and tricyclic antidepressants and further support the notion of a close relationship between noradrenergic function, more especially beta-adrenoreceptors, and "helpless" behavior.

Adrenergic beta-Agonists↗
PubMed1986

Psychopharmacological profile of salsolinol.

SAL is a tetraisoquinolein (T.I.Q.), resulting from the condensation of acetaldehyde and dopamine. SAL, injected intraperitoneally, is active in tests commonly used to screen potential antidepressants. This effect is especially studied by using antagonism of apomorphine, reserpine, oxotremorine-induced hypothermia. The noradrenergic system seems to be involved in the mechanism of action.

Animals↗
PubMed1986

The calcium entry blockers: anti-manic drugs?

The reported property of calcium antagonists as antimanic drugs has been investigated in three models of hyperactivity in mice. The hyperactivity was induced by amphetamine, oxolinic acid or reserpine after inhibition of monoamine oxydase (MAO). Nicardipine (a dihydropyridine derivative) reduces the three hyperactivities, verapamil (a diphenylalkylamine derivative) reduces only oxolinic acid hyperactivity, and diltiazem (a benzothiazepine derivative) was active except in the MAOI-reserpine test. Levomepromazine used as a reference drug reduced the three hyperactivities. The three calcium entry-blockers reduce the different hyperactivities at doses which already decrease motor activity. And so, it seems that their action was not specific. On the contrary, levomepromazine antagonizes MAOI-reserpine induced hypermotility at a dose which is not sedative. These results do not strengthen the property of calcium antagonists as antimanic drugs.

Amphetamines↗
PubMed1986

The influence of simultaneous exposure to carbon disulfide and hydrogen sulfide on the peripheral nerve toxicity and metabolism of carbon disulfide in rats.

Three groups of 10 male Sprague-Dawley rats were exposed daily, 5 days a week for 25 weeks, either to 500 ppm carbon disulfide (CS2), 50 ppm hydrogen sulfide (H2S), or to both of them as a mixture and were periodically examined for sensory and motor tail nerve conduction velocity (SNCV, MNCV). A concomitant control group of 10 rats was used. In addition, rats exposed to 500 ppm CS2, and those simultaneously exposed to 500 ppm CS2 and 50 ppm H2S, were twice examined for 24-h urine excretion of 2-thio-thiazolidine-4-carboxylic acid (TTCA) in the course of the experimental period. Simultaneous exposure to CS2 and H2S had no significant interactive effect on nerve conduction velocities. A significant time-dependent slowing down of MNCV and SNCV occurred as the result of chronic exposure to CS2, including exposure to 500 ppm CS2 and to the mixture of 500 ppm CS2 and 50 ppm H2S, but did not occur after chronic exposure to 50 ppm H2S. With combined exposure to 500 ppm CS2 and 50 ppm H2S, the quantity of TTCA excreted in 24-h urine was not significantly different from that occurring in response to CS2 exposure alone. On the basis of these results it is suggested that chronic exposure to H2S would neither influence CS2-induced peripheral nerve toxicity nor obscure the interpretation of the measurement of urinary TTCA as a biological indicator of CS2 exposure.

Animals↗