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H Simon

Publications and source records attributed to H Simon.

At least 73 records · Page 4Linked to original sources
PubMed1996

Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission.

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg/kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.

Adrenalectomy↗
PubMed1996

Early and later adoptions have different long-term effects on male rat offspring.

Both prenatal and postnatal environmental factors exert complex influences on the development of an organism. Previous studies have demonstrated that intervening events during the prenatal period can have different and even opposite effects than similar intervening events occurring in the postnatal period. We have reported previously that early postnatal adoption prevents prenatal stress-induced long-term impairments in glucocorticoid feedback. To characterize further the effects of adoptions during the postnatal period, adoptions have been performed at different times, and the effect on the postnatal ontogeny of the hypothalamo-pituitary-adrenal axis has been investigated. Adoptions were performed during the first hour after birth (A1) and on the fifth (A5) and twelfth (A12) days after birth. At each of these times, other litters (S1, S5, S12) underwent a "separation" controlling for the 1 min maternal separation necessary for the adoptions. Locomotor behavior, cognition, and stress-induced corticosterone secretion in the adult male offspring have been examined, along with maternal behavior. Early adoption (A1) was found to prevent the prolonged stress-induced secretion of corticosterone evident in early separated (S1) offspring. Similarly, A1 rats demonstrated lower novelty-induced locomotion and improved recognition performance in a Y-maze compared to S1 offspring. However, later adoption (A5, A12) prolonged stress-induced corticosterone secretion, increased the locomotor response to novelty, and disrupted cognitive performance in the offspring. Only the early adoption increased maternal licking behavior, a factor that may have a protective effect on the pups. Taken together, these results suggest that the same postnatal manipulation realized at different times can induce different, or even opposite, effects on the behavioral and neuroendocrine characteristics of the adult offspring.

Aging↗
PubMed1996

Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission.

An increase in the activity of mesencephalic dopaminergic neurons has been implicated in the appearance of pathological behaviors such as psychosis and drug abuse. Several observations suggest that glucocorticoids might contribute to such an increase in dopaminergic activity. The present experiments therefore analyzed the effects of corticosterone, the major glucocorticoid in the rat, both on dopamine release in the nucleus accumbens of freely moving animals by means of microdialysis, and on locomotor activity, a behavior dependent on accumbens dopamine. Given that glucocorticoids have certain state-dependent neuronal effects, their action on dopamine was studied in situations differing in dopaminergic tonus, including during the light and dark phases of the circadian cycle, during eating, and in groups of animals differing in their locomotor reactivity to novelty. Dopaminergic activity is increased in the dark period, further increased during food-intake, and is higher in rats defined as high responders to novelty than in low responders. Corticosterone, peripherally administered in a dose that approximates stress-induced plasma concentrations, increased extracellular concentrations of dopamine, and this increase was augmented in the dark phase, during eating, and in high responder rats. Corticosterone had little or no effects in the light phase and in low responder rats. Corticosterone also stimulated locomotor activity, an effect that paralleled the release of dopamine and was abolished by neurochemical (6-hydroxydopamine) depletion of accumbens dopamine. In conclusion, glucocorticoids have state-dependent stimulant effects on mesencephalic dopaminergic transmission, and an interaction between these two factors might be involved in the appearance of behavioral disturbances.

Animals↗
PubMed1996

EPR and Mössbauer spectroscopic studies on enoate reductase.

Enoate reductase (EC 1.3.1.31) is a protein isolated from Clostridium tyrobutyricum that contains iron, labile sulfide, FAD, and FMN. The enzyme reduces the alpha,beta carbon-carbon double bond of nonactivated 2-enoates and in a reversible way that of 2-enals at the expense of NADH or reduced methyl viologen. UV-visible and EPR potentiometric titrations detect a semiquinone species in redox intermediate states characterized by an isotropic EPR signal at g = 2.0 without contribution at 580 nm. EPR redox titration shows two widely spread mid-point redox potentials (-190 and -350 mV at pH 7. 0), and a nearly stoichiometric amount of this species is detected. The data suggest the semiquinone radical has an anionic nature. In the reduced form, the [Fe-S] moiety is characterized by a single rhombic EPR spectrum, observed in a wide range of temperatures (4. 2-60 K) with g values at 2.013, 1.943, and 1.860 (-180 mV at pH 7.0). The gmax value is low when compared with what has been reported for other iron-sulfur clusters. Mössbauer studies reveal the presence of a [4Fe-4S]+2/+1 center. One of the subcomponents of the spectrum shows an unusually large value of quadrupole splitting (ferrous character) in both the oxidized and reduced states. Substrate binding to the reduced enzyme induces subtle changes in the spectroscopic Mössbauer parameters. The Mössbauer data together with known kinetic information suggest the involvement of this iron-sulfur center in the enzyme mechanism.

Binding Sites↗
PubMed1996

Purification and partial characterisation of a reversible artificial mediator accepting NADH oxidoreductase from Clostridium thermoaceticum.

An NAD(H)-dependent artificial mediator accepting pyridine nucleotide oxidoreductase present in Clostridium thermoaceticum has been purified 50-fold by three chromatographic steps to apparent electrophoretical homogeneity with a yield of 25%. By PAGE and gel filtration the molecular mass of the native enzyme was estimated to be 200 kDa and 210 kDa, respectively. By SDS/gel electrophoresis, a single band was found at 17000 Da, suggesting a homododecamer. Reducing carbamoylmethylviologen or hexacyanoferrate(III) with NADH, the enzyme was most active at pH 10 and the specific activities were 100 mumol min-1 mg-1 protein and 800 mumol min-1 mg-1 protein, respectively. The K(m) values for hexacyanoferrate(III), carbamoylmethylviologen and NADH at pH 8.5 were determined to be 0.40, 0.55 and 1.1 mM, respectively. Other electron acceptors for the dehydrogenation of NADH were 2,6-dichlorophenolindophenol, anthraquinone-2,6-disulphonate, ubiquinone 0 and FAD. In the reduction of NAD+ with reduced methyl viologen (MV+), the specific activity was about 225 mumol min-1 mg-1 protein at the pH maximum of 5.0. The K(m) values for reduced methylviologen, NADH and NAD+ were 1.0, 1.1 and 0.25 mM, respectively. The enzyme had 10.6 atoms iron and 12.7 atoms sulphur per dodecamer. A significant content of flavin or molybdopterin cofactor could not be detected. The first 45 amino acids of the oxidoreductase show a surprisingly high degree of identity or similarity with the ribosomal L12 protein of various eubacteria, the acyl carrier proteins of microorganisms, but also with bovine heart mitochondria and a 3-phosphoglycerate dehydrogenase as well as a gyceraldehyde-3-phosphate dehydrogenase from bacteria and pea chloroplasts, respectively.

2,6-Dichloroindophenol↗
PubMed1996

Long-term effects of prenatal stress and handling on metabolic parameters: relationship to corticosterone secretion response.

The prenatal and postnatal environment exerts a long-term influence on the stress-response of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the long-term effects of prenatal and postnatal manipulations and their related changes on glucocorticoid secretion were examined on metabolic parameters in adult rats. Plasma glucose levels, body weight and basal feeding behavior were measured. We show that modifications of the prenatal and postnatal environment have opposite long-term effects on these parameters, except for blood glucose, which was increased in prenatally stressed animals. Although the mechanisms underlying these phenomena remain to be elucidated, the observations show that perinatal manipulations have long-term effects on metabolic functions related to HPA activity.

Animals↗
PubMed1996

Administration of amphetamine does not increase the functional efficacy of dopaminergic grafts made in infancy.

Previous reports have evoked the possibility that a priming stimulation of grafted dopaminergic (DA) neurones by amphetamine enhances their efficacy in behavioural tests performed several days later. The present study was designed to test this hypothesis. Five days after the unilateral destruction of the DA mesotelencephalic system of 3-day-old rat pups, DA grafts were implanted into the denervated neostriatum of half of the lesioned pups. At adulthood, lesion and graft groups were subdivided into 4 subgroups which received one of the following treatments: saline or amphetamine injection in an environment where the behavioural test was subsequently conducted (paired environment) or in an unrelated environment (unpaired environment). Five days later, rotational response to a tail-pinch stress was tested in the paired environment. In these conditions, we found no evidence for a priming effect of amphetamine. Animals that received amphetamine or saline in the unpaired environment displayed the same rotational response to the tail-pinch stress. On the other hand, a conditioning influence of the environment was detected. Thus, the effect previously described might have been caused by a conditioning effect and/or might be due to differences in the experimental conditions. This suggests that 'priming' the graft with amphetamine does not provide a general strategy to enhance the functional efficacy of DA grafts.

Amphetamine↗
PubMed1996

Preoperative concomitant radiochemotherapy in squamous cell carcinoma of the esophagus: results of a study of 56 patients.

PURPOSE: Today the prognosis for patients with esophageal carcinoma still remains quite poor. In the last few years interesting results have been obtained by associating radio- and chemotherapy with or without surgery with this type of cancer. In this work we report the results of concomitant radio- and chemotherapy in a split-course schedule preceeding surgery for the treatment of squamous cell carcinomas of the esophagus. METHODS AND MATERIALS: Fifty-six patients with squamous cell carcinomas of the esophagus were treated between April 1989 and September 1993 in the Centre Hospitalier Universitaire in Brest, France with two courses of preoperative concomitant radiochemotherapy, separated by a 2-week interval, and followed by surgery (each course 18.5 Gy in five fractions, days 1-5 with continuous infusion 5-fluorouracil (5-FU) 800 mg/m2 days 1-5 and cisplatinum 70 mg/m2 day 2). Patients who had responded well to preoperative treatment (response > 50%) received four more courses of chemotherapy alone. The two patients who were not operated and those with palliative surgery received a third course of radiochemotherapy (radiotherapy 12 Gy in five fractions, days 1-5). RESULTS: Fifty-four patients were operated on. Twenty-one showed histological complete response at surgery (37.5% of the whole group). Actuarial survival for the 56 patients was 55% at 3 years and 30% at 4 years, with a median survival of 37.4 months (40.4 months for complete responders to preoperative treatment). Toxicity of preoperative concomitant radio-chemotherapy was low (5-FU had to be stopped in one patient because of cardiac rythm disturbances and in another patient because of aplasia Grade 4 associated with infection after the first course). Postoperative mortality was 11% (six patients). CONCLUSION: This combination of preoperative radiochemotherapy followed by surgery seems to improve both response rates and survival in patients with esophageal cancer when compared with previous patients treated with surgery alone in our hospital or with results found in literature and it warrants further studies.

Aged↗
PubMed1996

Dose-dependent aversive and rewarding effects of amphetamine as revealed by a new place conditioning apparatus.

Amphetamine-induced place conditioning was evaluated in mice using a newly designed apparatus. It was demonstrated that this apparatus provides a neutral set of cues devoid of rewarding or aversive properties and can reveal place preference or aversion after pairings with drugs (amphetamine and morphine for preference and naloxone for aversion) known to produce such effects. Moreover, repeated pairings of environmental cues with either 2 or 3 mg/kg d-amphetamine resulted in significant conditioned place preference on a drug free test, whilst repeated pairings with a lower dose of the drug (1 mg/kg) resulted in significant conditioned place aversion. Finally, a small number of mice showed opposite responses in comparison with group means at low as well as at high doses of amphetamine. These results suggest that amphetamine may promote conditioned place preference or avoidance depending on dosage and individual susceptibility.

Amphetamine↗
PubMed1996

Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly--a life-span study in rats.

Inter- and intra-individual differences in hypothalamo-pituitary adrenal (HPA) axis activity and behavioral reactivity to novelty between young and old rats were evidenced in this longitudinal life-span study. Higher responders to novelty (HR) had a higher corticosterone secretion which showed a quicker increase with age than did the others (LR); the differences in response to novelty observed in youth were no longer apparent in the old rats. Response to novelty in youth is a predictive factor of accelerated aging of the HPA axis. These early changes, which precede the appearance of the memory deficits, may be a causal factor. Disappearance of behavioral and endocrinological inter-individual differences at 21 months highlights the importance of not restricting aging studies to old subjects.

Aging↗
PubMed1996

Novelty-seeking in rats--biobehavioral characteristics and possible relationship with the sensation-seeking trait in man.

A behavioral trait in rats which resembles some of the features of high-sensation seekers in man has been characterized. Given that the response to novelty is the basis of the definition of sensation-seeking, individual differences in reactivity to novelty have been studied on behavioral and biological levels. Certain individuals labeled as high responders (HR) as opposed to low responders (LR) have been shown to be highly reactive when exposed to a novel environment. These groups were investigated for free-choice responses to novel environments differing in complexity and aversiveness, and to other kinds of reinforcement, i.e. food and a drug. The HR rats appeared to seek novelty, variety and emotional stimulation. Only HR individuals have been found to be predisposed to drug-taking: they develop amphetamine self-administration whereas LR individuals do not. They also exhibit a higher sensitivity to the reinforcing properties of food. On a biological level, compared to LR rats, HR animals have an enhanced level of dopaminergic activity in the nucleus accumbens both under basal conditions or following a tail-pinch stress. HR and LR rats differ in reactivity of the corticotropic axis: HR rats exposed to a novel environment have a prolonged secretion of corticosterone compared to LR rats. The association of novelty, drug and food seeking in the same individual suggests that these characteristics share common processes. Differences in dopaminergic activity between HR and LR rats are consistent with results implicating these dopaminergic neurons in response to novelty and in drug-taking behavior. Given that rats self-administer corticosterone and that HR rats are more sensitive to the reinforcing properties of corticosteroids, it could be speculated that HR rats seek novelty for the reinforcing action of corticosterone. These characteristics may be analogous to some for the features found in human high-sensation seekers and this animal model may be useful in determinating the biological basis of this human trait.

Animals↗
PubMed1996

The antitumor agent cisplatin inhibits DNA gyrase and preferentially induces gyrB gene expression in Escherichia coli.

Cisplatin is a widely used anticancer agent that exerts its biological activity principally by damaging DNA. Although detailed knowledge exists concerning mechanisms that lead to cisplatin adducts in DNA, there are few insights into the processes that result in its antitumor action. To explore some of the cellular responses elicited by cisplatin treatment, we studied its influence on DNA supercoiling and DNA gyrase gene expression in E. coli. We found that cisplatin inhibits DNA gyrase in a concentration-dependent manner leading to a transient alteration of DNA supercoiling and to an induction of gyrase gene expression. The induction effect was asymmetrical, affecting gyrB stronger than gyrA. Furthermore, we studied the influence of cisplatin on the supercoiling activity of purified DNA gyrase in vitro and found that cisplatin was an efficient inhibitor of DNA gyrase in the standard assay. However, cisplatin was an excellent inhibitor when added to DNA gyrase before it could interact with its substrate. In this assay GyrB was also more affected by cisplatin than GyrA. This strongly suggests that cisplatin inhibits DNA gyrase primarily by direct interaction with the enzyme. The data from this work present evidence that further cellular responses following cisplatin treatment include DNA gyrase inhibition, altered DNA supercolling and enhanced DNA gyrase gene expression. This suggests an important role of DNA topology in the induction of defense mechanisms against the action of cisplatin in addition to the processes related to DNA damage and repair.

Antibodies↗
PubMed1996

Intravascular ultrasound for evaluation of coronary arteries.

Intravascular ultrasound (IVUS) has emerged form a research tool to an intrinsic part of modern invasive cardiology. The main reason is the capability to obtain "in vivo" histology. For the first time it is possible to base decisions not only on lumenograms but also on vessel wall assessment. The capabilities of IVUS can be divided in its (a) diagnostic and (b) intervention associated potentials. Diagnostic strength of IVUS is the ability to monitor compensatory coronary artery enlargement as a response to arteriosclerosis, to assess intermediate lesions, to reveal occult left main stem disease, and angiographycally "silent" arteriosclerosis. The intervention associated potentials of IVUS are the ability to allow optimal device selection, i.e. rotablators in calcified lesions or atherectomy devices in large plaque burden. The effects of PTCA on vessel wall morphology can be studied in great detail and the effect on luminal gain can be assessed almost on-line. Several groups showed, that the residual plaque area even after angiographycally successful PTCA lies still in the range of 60%. A significant reduction of this number may influence longterm outcome after PTCA. Minimal luminal areas and residual plaque area after PTCA seem to be an indicator of restenosis, while the presence or absence of dissections seem to be less predictive. Intravascular monitoring of stent expansion led to high-pressure stent deployment with significant increase in post-procedural luminal diameters and finally the ability to withhold anticoagulation in patients with optimal stent deployment. In the future, integrated devices, like balloons on intravascular ultrasound catheters, steerable catheters, integrated flow and pressure transducers, tissue characterization, and 0.018 "intravascular ultrasound guide-wires will further enhance the usefulness of IVUS.

Angioplasty, Balloon, Coronary↗
PubMed1995

Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor.

Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia. Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS.

Animals↗
PubMed1995

Requirement for neuregulin receptor erbB2 in neural and cardiac development.

The receptor erbB2/neu is a member of the epidermal growth factor receptor (EGFR or erbB) family that also includes erbB3 and erbB4. Amplification of the erbB2/neu gene is found in many cancer types and its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. Investigation of the biology of erbB2 led to the identification of a family of ligands termed neuregulins which included the neu-differentiation factors, the heregulins, a ligand with acetylcholine-receptor-inducing activity and glial growth factor. Several lines of evidence suggest that heterodimerization of erbB2 with other erbB receptors is required for neuregulin signalling. Here we investigate the developmental role of erbB2 in mammalian development in mice carrying an erbB2 null allele. We find that mutant embryos die before E11, probably as a result of dysfunctions associated with a lack of cardiac trabeculae. Development of cranial neural-crest-derived sensory ganglia was markedly affected. DiI retrograde tracing revealed that the development of motor nerves was also compromised. Our results demonstrate the importance of erbB2 in neural and cardiac development.

Animals↗
PubMed1995

Social stress increases the acquisition of cocaine self-administration in male and female rats.

The effect of social stress on the vulnerability to commence cocaine self-administration was examined in Sprague-Dawley rats repeatedly exposed to aggressive attack by a same-sex opponent. Both sexes were studied, since the factors influencing the acquisition of drug self-administration in females have not been defined. Male and female rats encountered an aggressive male or lactating female opponent on four separate occasions over the course of one week. Control male and female rats were not exposed to attack. All animals were implanted with jugular catheters, and six days later placed into the self-administration box, where a nose-poke in the designated 'active hole' resulted in a 20 microliters injection of cocaine (0.32 mg/kg). Nose-pokes in an 'inactive' hole had no effect. Male and female rats that had experienced social stress self-administered more cocaine than non-defeated controls. The difference between the stressed and non-stressed animals in the number of cocaine injections was not present during the first few days of exposure to cocaine, but became more pronounced over time. Social stress increased the number of responses for cocaine, but did not alter the number of non-specific responses. Sex differences in self-administration were not significant. Therefore, social status appears to be a potent influence in the onset of drug taking behavior in both male and female rats.

Aggression↗