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Biomedical subjects

H Simon

Publications and source records attributed to H Simon.

At least 163 records · Page 9Linked to original sources
PubMed1989

Limbic system, basal ganglia, and dopaminergic neurons. Executive and regulatory neurons and their role in the organization of behavior.

Mesencephalic dopaminergic neurons appear to be involved in the organization of the behavioral response. They seem to facilitate the functioning of the integrative structures they innervate and to have a coordinated functioning, thus regulating the information transfer between these structures. In the present paper these two aspects have been investigated by behavioral and neurochemical approaches. Experimental studies were focused on the dopaminergic innervation of the nucleus accumbens.

Amygdala↗
PubMed1988

Memory disturbances following ibotenic acid injections in the nucleus basalis magnocellularis of the rat.

The behavioral effects of lesions of the nucleus basalis magnocellularis (NBM) on two spatial discrimination tasks (place navigation and cross maze) were examined in the rat. These tasks were designed to test reference memory. Lesions by bilateral injection of ibotenic acid into the NBM led to a severe and permanent impairment in the learning of the cross maze task. In the learning of the place navigation task, the rats with lesions showed only a transient deficit. Immediately after the removal of the platform, the rats with lesions explored the quadrant (NE) previously containing the platform as long as controls and above chance levels. The rats with lesions did not extinguish exploration like the controls, seen as a reduction both in time spent in the NE quadrant and in swimming activity. Taken together, the results showed that (1) NBM lesions impair reference memory, but (2) spare other aspects of memory. On the basis of the results in the place navigation task, procedural memory was assumed to remain intact after lesion of the NBM. Biochemical assays of choline acetyltransferase (ChAT) in various brain regions in the lesioned animals demonstrated a reduced ChAT activity in the neocortical projections of the NBM but not in the hippocampus. However, it cannot be decided from this work whether behavioral deficits result from the lesion of cholinergic or of non-cholinergic cells in the NBM.

Animals↗
PubMed1988

Locomotor hyperactivity in the rat after infusion of muscimol and [D-Ala2]Met-enkephalin into the nucleus basalis magnocellularis. Possible interaction with cortical cholinergic projections.

Locomotor activity in the rat was studied after infusion of GABAergic and enkephalinergic agonists into the nucleus basalis magnocellularis (NBM) of the forebrain. The experiments were designed to find out whether pharmacological blockade of cholinergic neurons in the NBM had similar behavioral effects to those observed after lesion of the same structure. Three experiments were carried out. In the first experiment, infusion of the GABAergic agonist muscimol (50 ng) into the NBM led to a marked locomotor hyperactivity. In the second experiment, it was shown that muscimol-induced locomotor response was reduced by pretreatment with the GABAergic antagonist picrotoxin (3 mg/kg). Further, locomotor hyperactivity was also observed after injection of the indirect GABA agonist, ethanolamine-o-sulfate (50 micrograms) into the NBM. The third experiment was designed to investigate the relationship between the blockade of NBM cholinergic neurons and the development of locomotor hyperactivity. The locomotor hyperactivity produced by the cholinergic antagonist scopolamine (0.4 mg/kg) was increased two-fold after infusion of 10 ng muscimol into the NBM. This dose of muscimol on its own had no effect on locomotor behavior. Similar enhancement of the locomotor response to that found with GABAergic agonists was observed after infusion of [D-Ala2]Met-enkephalinamide (2.5 micrograms) into the NBM. This enkephalin mediated locomotor response was blocked by the opiate antagonist naloxone (2 mg/kg). Pharmacological manipulations of the afferent inputs to the NBM could therefore be of value in studies on the behavioral role of cholinergic neurons in the NBM.

Animals↗
PubMed1988

Lesion of dopaminergic terminals in the amygdala produces enhanced locomotor response to D-amphetamine and opposite changes in dopaminergic activity in prefrontal cortex and nucleus accumbens.

In a previous study using differential pulse voltammetry we demonstrated an interaction between dopaminergic activity in the amygdala and the nucleus accumbens. In the present study, by post-mortem biochemical measurements, we showed that bilateral 6-OHDA lesions of DA innervation of the amygdala leads to an increase in DA activity in the nucleus accumbens (DOPAC/DA ratio +24%) and a reduction (DOPAC/DA ratio -40%) in the prefrontal cortex. In addition, after these lesions in the amygdala, there was an increased behavioral sensitivity to D-amphetamine, demonstrated by enhanced locomotor activity. Increased understanding of the interregulations between dopaminergic activity in forebrain structures may help explain forebrain functions and/or dysfunctions.

Amygdala↗
PubMed1988

Behavioural deficits induced by an electrolytic lesion of the rat ventral mesencephalic tegmentum are corrected by a superimposed lesion of the dorsal noradrenergic system.

The bilateral electrolytic lesion of the ventral mesencephalic tegmentum (VMT) induces, in the rat, behavioural deficits such as locomotor hyperactivity and disappearance of spontaneous alternation ('VMT syndrome'). When a specific 6-hydroxy dopamine (6-OHDA) destruction of the dorsal noradrenergic (NA) ascending pathway was superimposed to an electrolytic lesion of the VMT, animals recovered a normal locomotor activity and the possibility to alternate. Since many studies indicate that the development of the 'VMT syndrome' is linked to the disruption of the dopaminergic (DA) meso-cortico-limbic transmission, it is proposed that the recovery observed is due to an interaction between NA and DA ascending systems in cortical and/or subcortical structures; noradrenergic innervation would have a permissive role on the expression of the 'VMT syndrome', possibly via a mechanism of heteroregulation of DA receptors by NA fibers.

Animals↗
PubMed1988

Increased sensitivity to amphetamine and facilitation of amphetamine self-administration after 6-hydroxydopamine lesions of the amygdala.

The effects of 6-OHDA lesions of dopamine terminals within the amygdala were investigated on i) (+) amphetamine-induced locomotor hyperactivity and ii) the acquisition of intravenous self-administration of (+) amphetamine. The lesioned rats exhibited increased locomotor activity in response to (+) amphetamine (0.75 and 1.5 mg/kg), but not at the higher dose (3 mg/kg). Self-administration of (+) amphetamine was also significantly greater than in controls. Biochemical analysis of the 6-OHDA-induced lesions of the amygdala indicated increased turnover of dopamine (DOPAC/DA) in the nucleus accumbens. We hypothesize that the behavioural effects were mediated by amygdala-accumbens interactions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Analysis of the nourseothricin-resistance gene (nat) of Streptomyces noursei.

A gene (nat) conferring resistance to the streptothricin antibiotic nourseothricin (Nc) was cloned from the producer Streptomyces noursei into Streptomyces lividans on the vector pIJ702 to form pNAT1. The nat gene was localized on a 1-kb SalI-MboI fragment, which also carries the nat promoter. Divergent promoter activity from the nat promoter region was identified on the cloned fragment using promoter probe plasmids pIJ486 and pIJ487. The nat gene is not expressed from its own promoter in Escherichia coli as shown by its failure to promote cat expression in promoter-less plasmid pBB100 and by the expression of NcR in only one orientation, when cloned in pUC19. In S. lividans 7A, harbouring plasmid pNAT1, an Nc-acetylating activity (NAT) was associated with the cloned resistance gene. The substrate specificity of NAT correlated well with the substrate range of the acetyltransferase in S. noursei and Tn1825-determined streptothricin resistance in Gram-negative bacteria. Moreover, an extract of S. lividans carrying pNAT1 showed specific serological cross-reactivity with an extract of E. coli carrying Tn1825.

Acetyltransferases↗
PubMed1988

Expert system for pathologists to generate an image analysis program for tumor grading.

The pathologist is usually not an expert in engineering or image analysis. We have, therefore, developed an expert system, entitled PARTICLE, to help pathologists producing image analysis programs by which to tackle problems in histological pathology, including tumor grading. The PARTICLE expert system is based on karyometric data, using the AMBA/R dialogue and programming system.

Diagnosis, Computer-Assisted↗
PubMed1988

Reductions of 2-enals, dehydrogenation of saturated aldehydes and their racemisation.

Enoate reductase or clostridia containing this enzyme (Clostridium tyrobutyricum or C. kluyveri) catalyse the reduction of alpha,beta-unsaturated aldehydes (enals). The enantiomeric purity of the saturated aldehydes obtained from alpha-substituted enals is usually rather low and depends heavily on the reaction conditions. The reduction of the corresponding allyl alcohols to the saturated alcohols leads to much higher enantiomeric purities, though the reduction of the enal corresponding to the allyl alcohol to the saturated aldehyde is an intermediary step in the reaction sequence allyl alcohol----saturated alcohol. The explanation seems to be the racemisation of saturated aldehydes caused by enoate reductase. This is illustrated by the reduction of (E)-2-methylcinnamyl aldehyde to (R)-2-methyl-3-phenylpropanal or (R)-2-methyl-3-phenylpropanol under different conditions and measuring the racemisation of the aldehyde as well as the hydrogen-deuterium exchange of 3-phenylpropanal. In contrast to saturated carboxylates saturated aldehydes can be dehydrogenated to alpha,beta-unsaturated aldehydes (enals) by enoate reductase in the presence of electron acceptors such as oxygen or dichlorophenol indophenol. Under these conditions enoate reductase shows in the presence of oxygen a surprisingly high half life (greater than 20 h) as compared to that which is observed when the enzyme was used as a reductase with NADH in the presence of oxygen. In this case the enzyme is inactivated within a few minutes.

Aldehydes↗
PubMed1988

Automated histometry in fibrocystic breast disease.

Ductal epithelial proliferations of the mammary gland in biopsy material from 101 patients, including 52 with proliferative fibrocystic disease (mastopathy), were quantitatively analyzed by means of the Robotron A 6471 system together with AMBA/R software. Based on reproducible data obtained for distinct karyometric and histometric features, significant differences were found to exist between epithelial proliferations without atypical hyperplasia (mastopathy II) and those with atypia (mastopathy III). The multiparameter analysis also produced some hints that cases of proliferative mastopathy III can be divided into two groups having different risks of developing carcinoma.

Cell Division↗
PubMed1987

Dopamine-GABA interactions in the nucleus accumbens and lateral septum of the rat.

The relationships between dopaminergic afferents and GABAergic neurones were studied at the electron microscopic level in the rat lateral septum and nucleus accumbens by coupling 6-hydroxydopamine degeneration and gamma-aminobutyric acid (GABA) immunocytochemistry. Degenerating fibres were observed in the two regions making synaptic contact with GABA-immunoreactive and non-labelled cell bodies and dendrites. It is concluded that dopaminergic afferents to the septum and the nucleus accumbens contact, among others, a population of GABAergic cells. A similar route of regulation of the basalo-cortical and septo-hippocampal cholinergic pathways by dopaminergic afferents is proposed.

Animals↗
PubMed1987

Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry.

Buspirone is a non-benzodiazepine drug with anxiolytic properties. It has been reported to induce a marked increase in the metabolism of dopamine in the striatum and the nucleus accumbens which is similar to that induced by neuroleptics. It has been suggested that the effect observed in the striatum reflects an action of buspirone on dopaminergic autoreceptors in both terminals and cell bodies. In the present study, presynaptic effects of buspirone on dopaminergic metabolism in the nucleus accumbens were investigated, and they were compared to the effects of the classical neuroleptic, haloperidol. Dopaminergic terminals were isolated by infusion of tetrodotoxin into the median forebrain bundle in order to evaluate the effects of buspirone and haloperidol on presynaptic receptors. Changes in dopamine metabolism were determined by in vivo voltammetry. Buspirone administered after interruption of the impulse flow did not affect dopamine metabolism. In contrast haloperidol treatment led to an increase in metabolism of dopamine. It is concluded that buspirone did not act at the presynaptic level and furthermore on dopaminergic autoreceptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Spontaneous and graft-induced behavioral recovery after 6-hydroxydopamine lesion of the nucleus accumbens in the rat.

In the present study the long-term evolution of behavioral deficits following a local lesion of the dopaminergic innervation of the nucleus accumbens with 6-hydroxydopamine (6-OHDA) was compared in two groups of rats: lesioned animals and animals bearing a dopaminergic implant in the nucleus accumbens. Lesioned animals gradually recovered on various behavioral tests (amphetamine-induced locomotion, exploration, hoarding) and were indistinguishable from the control group on most parameters by 10 months postlesion. The deficits were, however, reinstated by a second intra-accumbens 6-OHDA lesion, a finding which suggests a role for dopaminergic reinnervation in the observed recovery. Conversely, grafted animals still displayed marked deficits even 10 months after grafting, although the lesioned areas were well reinnervated by the graft. These results indicate that the graft, while being unable on its own to compensate for part of the deficits, can nevertheless impair and compete with endogenous processes leading to behavioral recovery following a local lesion.

Animals↗
PubMed1987

Catecholamines and conditioned blocking: effects of ventral tegmental, septal and frontal 6-hydroxydopamine lesions in rats.

The performance of rats on the conditioned blocking test of learned inattention was measured in a two-way shuttle avoidance task after sham and dopamine (DA)-depleting lesions of the frontal cortex, septum and ventral tegmental area (VTA). Animals were trained on two sessions with tone and/or light as conditioned stimuli. One group was trained with both stimuli on both sessions. A second group was trained on the first session with one stimulus and on the second with both stimuli. The blocking of conditioning to the added stimulus (b) was tested by presenting the stimuli (a and b) separately and measuring the blocking ratio (avoidance to b/a + b) and response latencies. No deficits were recorded on tests of sensory and motor ability. The VTA group alone showed a hyperlocomotor response to apomorphine treatment and did not acquire the avoidance response. The appearance of blocking in the septal group was delayed until the end of the test session. Blocking was mildly attenuated in the frontal group. DA levels were depleted by about 80% and noradrenaline (NA) levels by, respectively, 20 and 50% in frontal and septal areas. This suggests that the level of DA activity or the balance between the activity of DA and NA in frontal and limbic regions can contribute to efficient associative conditioning and/or the normal ability of rats not to attend to a redundant stimulus.

Animals↗
PubMed1987

Bovine serum albumin--haloperidol as a tool for the study of dopaminergic transmission: behavioural and neurochemical effects following a single injection in the nucleus accumbens.

Bovine serum albumin haloperidol (BSA-Hal) is a macromolecular complex with 14 molecules of haloperidol immobilized on the BSA protein backbone. This compound produces a selective, long lasting and reversible blockade of dopamine receptor activity. Its action was demonstrated by the ability to trigger a high rate of ipsilateral amphetamine-induced rotation up to 6 days after a single unilateral injection of the conjugate into the striatum. In the present study, the effect of the blockade of dopamine transmission in the nucleus accumbens (n.Acc) on spontaneous and learned behaviors was tested. The results indicate that the specific and long lasting blockade of dopamine receptors by bilateral injection of BSA-Hal in the n.Acc (1.6 micrograms/2 microliters) induced deficits in spontaneous alternation in a Y-maze on the 2nd and 5th days after the injection but not on the 11th day of the experiment, impaired acquisition but not retention in a radial 8-arm maze, increased latency to escape during learning in the place navigation task. These findings confirm the involvement of the n.Acc system in processes that have been generally attributed to the limbic system.

Animals↗
PubMed1987

Mitochondria catalyze the reduction of NAD by reduced methylviologen.

Mitochondria from beef heart and yeast catalyze the reduction of NAD to NADH at the expense of reduced methylviologen (MV+). Based on protein the specific activity of mitochondria for this reaction is about 10 20-times higher than the consumption of oxygen in the presence of succinate or NADH. In 2H2O buffer (4S)-[4-2H]NADH is formed in high enantiomeric excess if the reduced methylviologen is electrochemically regenerated.

Animals↗