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Biomedical subjects

F Hefti

Publications and source records attributed to F Hefti.

At least 253 records · Page 14Linked to original sources
PubMed1980

Precursor control of neurotransmitter synthesis.

Studies performed during the past decade have shown that the rates at which certain neurons produce and release their neurotransmitters can be affected by precursor availability, and thus by the changes in plasma composition that occur after ingestion of the precursors in purified form or as constituents of foods. Thus, tryptophan administration or a plasma ratio of tryptophan to other large neutral amino acids, thereby raising brain tryptophan levels, increasing the substrate saturation of tryptophan hydroxylase, and accelerating the synthesis and release of serotonin. Tyrosine administration or a high-protein meal similarly elevates brain tyrosine and can accelerate catecholamine synthesis in the CNS and sympathoadrenal cells, while the consumption of lecithin or choline increases brain choline levels and neuronal acetylcholine synthesis. The physiologic and biochemical mechanisms that must exist in order for nutrient consumption to affect neurotransmitte synthesis have been characterized and include: 1) the lack of significant feedback control of plasma levels of the precursor; 2) the lack of a real "bloodbrain barrier" for the precursor, i.e. the ability of the plasma level of the precursor to control its influx into, or efflux from, the CNS; 3) the existence of a low-affinity (and thus unsaturated) transport system mediating the flux of the precursor between blood and brain; 4) low-affinity kinetics for the enzyme that initiates the conversion of the precursor to the transmitter; and, 5) the lack of end-product inhibition of the enzyme, in vivo, by its ultimate product, the neurotransmitter. The extent to which neurotransmitter synthesis in any particular aminergic neuron happens to be affected by changes in the availability of its precursor probably varies directly with the neuron's firing frequency. This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose. It also allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state. (for example, tyrosine administration raises blood pressure in hypotensive rats, lowers it in hypertensive animals, and has little effect on blood pressure in normotensive animals; the elevation in blood pressure probably reflects enhanced catecholamine release from sympathoadrenal cells, while the reduction in hypertensive animals probably results from increased catecholamine release within the brain-stem.) Such predictions are now being tested clinically in many institution. Available evidence suggests that lecithin or cholie administration can diminish the frequency of abnormal movements in patients with tardive dyskinesia...

Behavior↗
PubMed1979

Spike activity and histofluorescence correlated in the giant dopamine neurone of Planorbis corneus.

The relationship between catecholamine fluorescence and electrical activity of the nerve cell has been investigated in the giant dopamine neuron (GDN) of the left pedal ganglion of the European water snail, Planorbis corneus. Electrical recordings were performed in vitro with intracellular microelectrodes on 35 GDN. The ganglion was frozen to -195 degrees C with the electrode in situ and processed for histochemical microfluorimetry. The intensity of catecholamine fluorescence was measured over different places (42/cell) throughout the cytoplasm of the GDN. In order to investigate the temporal relation between histochemical and electrophysiological parameters, the activity of 21 GDN was changed by administration of nicotine to the bathing solution (10(-5)--10(-7) M). This treatment was followed by depolarization in most of the GDN, with increased firing in two thirds and decreased activity in one third of the spontaneously active cells, whereas hyperpolarization was seen in 4 GDN, accompanied by a decrease in firing. Acetylcholine (10(-5) M) tested on one GDN caused depolarization and increased firing. A signigicant positive correlation was found between the fluorescence intensity of individual GDN and the firing rate of these cells as observed during the last 60 sec or the last 10 sec before freezing. The correlation coefficient dropped markedly when the first rates of the 2nd, 3rd, or 4th and 5th min before freezing were correlated with cellular fluorescence intensity. Intensity was not correlated with the resting membrane potential recorded at the time of freezing. The intensity response to activation was not uniform throughout the cytoplasm of GDN. Neurons with increased mean fluorescence intensity regularly showed small clusters and cristae of intensely fluorescent material surrounded by less fluorescent parts of the cytoplasm. This morphological observation of increased intensity differences between cytoplasmic structures was confirmed by the statistics of the intensity values determined in individual cells. The present observations demonstrate the existence of a relation between cell firing and neuronal dopamine fluorescence at the level of the individual nerve cell. The activity immediately preceding the time of freezing of the cell appears to be most important. Certain components of the cytoplasm appear to react preferentially; their subcellular nature remains to be elucidated. The link between electrical activity and cellular dopamine fluorescene was found to be basically the same in the giatn invertebrate neuron and in the dopamine nerve cells of rat substantia nigra.

Animals↗
PubMed1979

Lateralized hunger: ipsilateral attenuation of cortical spreading depression-induced feeding after unilateral 6-OHDA injection into the substantia nigra.

Unilateral injections of 6-hydroxydopamine into the substantia nigra in the rat significantly attenuated cortical spreading depression (CSD)-induced eating from the hemisphere ipsilateral but not contralateral to the lesion. The lateralized decrease in elicited feeding was correlated with postlesion body weight loss, striatal catecholamine depletion (dopamine, 94%; norepinephrine, 52%) and amphetamine-induced ipsilateral turning, and can be characterized as an inability of the lesioned nigrostriatal system to maintain the CSD-elicited response rather than a failure to induce it. The interhemispheric control procedure allows us to exclude various general sensory and motor deficits to account for the decrement of feeding, and to attribute the feeding deficit to a reduced nigrostriatal transmission. It is suggested that CSD-induced feeding is due to an activation of integrative sensorimotor systems (especially the nigrostriatal dopamine system), rather than to homeostatic imbalances.

Amphetamine↗
PubMed1976

A quantitative correlation between single unit activity and fluorescence intensity of dopamine neurones in zona compacta of substantia nigra, as demonstrated under the influence of nicotine and physostigmine.

In order to investigate the possible relationship between neuronal activity and cellular fluorescence intensity, extracellular recordings of single unit activity and determinations of fluorescence intensity of dopamine (DA) neurones by histochemical microfluorimetry were performed in the same (rostral) part of zona compacta of substantia nigra in male rats. In urethane anaesthesia, zona compacta neurones characteristically showed a slow and fairly regular type of firing. Nicotine (1 mg/kg s.c.) induced a transient decrease in unit activity for 1 min followed by a sustained increase in firing rate. During that stage, 4-5 neurones/rat were recorded at different anteroposterior levels, each during 200 sec. Microfluorimetric examination of the fluorescence intensity developed at the end of the 30-min observation period by the DA neurones of the same area revealed a marked rise in cellular fluorescence intensity. Similar results were obtained with a lower dose of nicotine and/or a shorter observation period. Additional microiontophoretic experiments supported the view that extracellular recordings of the correlative electrophysiological-microfluorimetric investigation belonged to DA neurones. Release of DA from terminals was indicated by an increase in HVA concentration of caudate-putamen in rats subjected to the same nicotine treatment. When tested on one cell during a prolonged period of time, physostigmine (0.25 mg/kg i.p.) caused an initial increase in firing rate of zona compacta neurones (5-10 min) followed by a decrease of unit activity (15-23 min). In agreement with previous observations in mice, fluorescence intensity of nigral DA neurones likewise showed a biphasic change with an initial rise and subsequent decrease (examined at 9.5 and 22-23.5 min, respectively). When mean unit activity and mean fluorescence intensity of individual rats out of various experimental groups were related to each other, a highly significant positive correlation between neuronal fluorescence intensity and firing rate was found. The results obtained with physostigmine demonstrate that mean intensity closely paralleled mean unit activity in time, so that this correlation was maintained. These findings indicate that cellular fluorescence intensity of DA neurone groups can be used as an index of the level of neuronal activity, except for cases where a drug treatment interferes directly with catecholamine synthesis or storage mechanisms.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Comparison of nerve growth factor's effects on development of septum, striatum, and nucleus basalis cholinergic neurons in vitro.

In the central nervous system, nerve growth factor (NGF) affects basal forebrain cholinergic neurons during early development and in the adult mammalian brain. These neurons are located in medial septum, diagonal band of Broca, and nucleus basalis of Meynert. While the effects of NGF on the development of septal cholinergic neurons are well documented, only little is known about the influence of NGF on development of cholinergic neurons in the nucleus basalis. In addition to the basal forebrain cholinergic neurons, there are cholinergic interneurons in the corpus striatum, which form an anatomically and functionally distinct population of cholinergic neurons. These striatal interneurons have been reported to respond to NGF during early development; however, it is not known whether the effects of NGF on their development are similar to those on septal cholinergic neurons. We prepared cultures of dissociated cells from fetal rat septum, striatum, and nucleus basalis and investigated the development of cholinergic neurons localized in these three different areas in the presence or absence of NGF. We now report that, first, cholinergic neurons of striatum and nucleus basalis develop a more extensive fiber network and contain more acetylcholinesterase (AChE) per neuron than do cholinergic neurons of septum. The amount of choline acetyltransferase (ChAT) per cholinergic neuron is approximately the same in all three culture types when grown in the absence of NGF. Second, NGF treatment increases and anti-NGF treatment decreases the number of AChE-positive neurons in cultures of low plating density, suggesting that NGF is able to promote survival of cholinergic neurons of all three areas studied. Third, NGF increases the total length of fibers and the number of branching points of cholinergic neurons in septal cultures but not in cultures of striatum and nucleus basalis. Fourth, NGF treatment increases AChE activity in septal but not in nucleus basalis or striatal cultures, suggesting that AChE activity reflects the extent of the fiber network of cholinergic neurons of all areas. Fifth, NGF treatment produces severalfold elevations in ChAT activity in septal cultures and more modest increases in cultures of nucleus basalis and striatum, suggesting that NGF is able to stimulate ChAT activity also in the absence of a stimulatory effect on survival and fiber growth. Our results demonstrate that, during early development, NGF is able to affect survival and differentiation of all three populations of forebrain cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMedDate not supplied

Development of cholinergic pedunculopontine neurons in vitro: comparison with cholinergic septal cells and response to nerve growth factor, ciliary neuronotrophic factor, and retinoic acid.

The well-documented role of nerve growth factor (NGF) in the function of cholinergic neurons in the mammalian basal forebrain can be regarded as a paradigm for the action of trophic substances on CNS neurons. Although several growth factors have been identified in recent years, the specificities and importance of such factors for the development of the nervous system are still unknown. In the present study it has been tested whether NGF affects the group of pedunculopontine cholinergic neurons. This population, which has been described in detail only recently, is located more caudally than but resembles, in some aspects, the basal forebrain cholinergic neurons. The cell bodies are located in the metencephalic pedunculopontine and dorsolateral tegmental nuclei. Similar to the forebrain cholinergic neurons, they are medium to large in size and ascend centrally with long axons. Projection areas are widespread throughout the mesencephalon and diencephalon. Dissociated pontine and septal cells of fetal rat brain (embryo ages E14 to E17) were grown in culture for 7 to 14 days in the presence or absence of NGF. Furthermore, a possible action of retinoic acid and ciliary neuronotrophic factor (CNTF) on cholinergic neurons of both the basal forebrain and the pontine area were tested. Differentiation of cultured cholinergic neurons was assessed by biochemical determination of choline acetyltransferase (ChAT) activity and by immunocytochemical staining for ChAT. NGF in concentrations of 1 to 1,000 ng/ml medium increased the number of immunostained cells and the staining intensity in ChAT immunocytochemistry and enhanced ChAT activity by at least 100% above control levels in septal cultures, thus confirming earlier results. In marked contrast, the same concentrations of NGF failed to influence ChAT activity or immunocytochemical staining in cultures of the pontine area. Retinoic acid (10(-8) M to 10(-5) M) and CNTF (0.2 and 2.0 ng/ml, corresponding to 1 and 10 trophic units, as defined in the ciliary ganglion cell assay) failed to enhance ChAT activity in either culture system and did not potentiate the NGF-mediated increase of ChAT activity in septal cultures. Our results, which indicate that pedunculopontine cholinergic neurons do not respond to NGF during development, are in line with those of NGF-receptor visualization studies that failed to demonstrate such receptors on cholinergic pontine cells in postnatal and adult rats. The findings further underline the specificity of NGF action in the central nervous system and, in particular, do not support the idea of transmitter-specific neurotrophic factors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗