[Neuroleptics or antipsychotic agents].
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Amino Acid Sequence↗
Biomedical subjects
A Dresse
Publications and source records attributed to A Dresse.
Hydrogen peroxide hyperpolarizes rat CA1 pyramidal neurons by inducing an increase in potassium conductance.
It has been suggested that hydrogen peroxide is involved in cascades of pathological events affecting neural cells. The aim of this study was therefore to examine whether this molecule is able by itself to modify membrane properties of pyramidal neurons in the CA1 region of the rat hippocampus. Intracellular recordings in the slice preparation showed that 3.3 mM hydrogen peroxide hyperpolarized all neurons tested (n = 41) by 11 +/- 3 mV. This effect persisted in the presence of tetrodotoxin. It developed slowly, was reversible and reproducible. In the presence of tetrodotoxin, the extrapolated reversal potential of this effect was -95 +/- 5 mV in 2.5 mM external potassium. This value was not significantly different from the one obtained with the GABAB agonist baclofen (10 microM) (-98 +/- 5 mV). It shifted when the concentration of external potassium was increased to 10.5 mM (from -96 +/- 5 to -62 +/- 4 mV), in close agreement with the Nernst equation potassium ions. The hyperpolarization was significantly reduced (by 65 +/- 22%) by the potassium channel blocker barium (100 microM). We suggest that hydrogen peroxide is able to induce an increase in potassium conductance in rat CA1 pyramidal neurons. The exact mechanism by which it produces this effect (direct action on channels or indirect effect) remains to be determined.
Animals↗
Towards a pharmacological approach of Alzheimer's disease based on the molecular biology of the amyloid precursor protein (APP).
After heart disease, cancer and stroke, Alzheimer's disease (AD) is the fourth major cause of death in the developed countries. Due to demographic changes, this situation will further worsen in the future. With the use of molecular biology techniques, important progress has recently been made in the understanding of the molecular changes leading to some forms of this disabling illness. The first step was the partial sequencing of the amyloid protein accumulating in the senile plaques and vascular deposits characteristic of AD. This allowed the cloning of a cDNA coding for a long amyloid precursor protein (APP). During the last few years, independent reports have described the presence of several reproducible point mutations in specific codons of APP in early onset familial Alzheimer patients. These mutations are responsible for an abnormal processing of APP, leading to the formation of pathological beta/A4 amyloid deposits. beta/A4 has been shown to possess neurotrophic properties in embryonic neurones and to be a potent neurotoxic agent in differentiated hippocampal neurones. More recently, modifications of intracellular calcium, activation of kinases, free radical generation and anomalies in potassium channels have been described as possible mechanisms of beta/A4 toxicity. Some forms of Apo-E lipoprotein may be an additional risk factor. Hence, it now seems possible to elaborate a coherent theory to explain the cascade of events leading to the development of AD. Genetically induced point mutations or environmental factors may produce a modification of the APP metabolism and processing. As a consequence, abnormal deposits of beta/A4 are formed. They may exert direct or indirect neurotoxic actions. A degeneration of cholinergic, catecholaminergic and other neurones follows, leading to the well known cognitive and behavioural changes of AD.
Alzheimer Disease↗
A subtractive hybridization method to isolate tissue-specific transcripts: application to the selection of new brain-specific products.
A method based on subtractive hybridization of brain complementary DNAs with peripheral messenger RNAs has enabled us to construct an enriched brain-specific cDNA library. Single-stranded cDNAs (ssc DNAs) were synthesized from brain polyadenylated mRNAs and subsequently hybridized with peripheral mRNAs immobilized on nitrocellulose membrane. Unhybridized sscDNAs were converted into double-stranded cDNAs and cloned into plasmid pUC13. The screening of the resulting library showed that a high percentage of the cloned cDNAs corresponded to mRNAs specifically transcribed in the brain.
Animals↗
Differential effects of picrotoxin and RO 15-1788 on high and low ethanol concentrations on rat locus coeruleus in vitro.
In an in vitro electrophysiological single-cell recording model, ethanol had an inhibitory effect on locus coeruleus (LC) neurons at both low (0.1 mmol/l) and high (500 mmol/l) concentrations. In order to test if the benzodiazepine-GABA (gamma-aminobutyric acid) receptor complex could be implicated in this effect, we tested the interaction of these ethanol concentrations with picrotoxin (100 mmol/l) and RO 15-1788 (10 nmol/l). RO 15-1788 reversed the inhibitory effect induced by ethanol 500 mmol/l, but not by ethanol 0.1 mmol/l; picrotoxin reversed the effects of both concentrations. This indicates that the mechanisms of action of ethanol on LC neurons are not the same for high and low concentrations. Furthermore, the effect of concentrations related to a behavioral effect (greater than 10 mmol/l) was reversed by a low-calcium medium that abolishes transmitter release. Therefore, the inhibition induced by ethanol 500 mmol/l seems to be due to the release of an endogenous benzodiazepine-like compound.
Animals↗
[Contribution of electrophysiology to the study of tianeptine and other antidepressive agents].
Intravenous perfusion of tianeptine reduces the frequency of coeruleus locus neural discharge. It does not affect the rate of neural discharge in the dorsal raphe, increase the rate of neural discharge in the ventral tegument air and the rate of discharge in the pyramidal cells of the hippocampus (CA1). In comparison, intravenous perfusion of clomipramine decreases the rate of neural discharge in the coeruleus locus, the dorsal raphe, the ventral tegument air (temporarily) and the pyramidal cells of the hippocampus. Iontophoretic application of tianeptine does not affect the response of pyramidal cells in the hippocampus to application of serotonin or gamma amino-butyric acid (GABA), but lowers recovery time after iontophoretic administration of serotonin or GABA. Iontophoretic application of clomipramine increases pyramidal cell response to serotonin but not to GABA and lengthens the recovery time after serotonin and GABA. The results are in agreement with the fact that tianeptine, unlike clomipramine, increases serotonin capture. Tianeptine leads to an original electrophysiologic pattern distinct from classic antidepressants and clomipramine.
Animals↗
Acute amphetamine-induced subsensitivity of A10 dopamine autoreceptors in vitro.
Extracellular recordings were obtained from spontaneously active, presumed dopamine (DA) neurons of the ventral tegmental area (VTA) of the rat in a slice preparation. Bath-applied (+)-amphetamine (AMPH) (1-30 microM) induced a concentration-dependent decrease in the firing rate of these neurons, which tended to saturate with the highest concentrations used (n = 11). This inhibitory effect was dependent on the activation of D2 receptors since it was reversed by the D2 antagonist sulpiride (n = 8). However, the most striking effect of AMPH was the induction of a prominent subsensitivity of DA autoreceptors: whereas in 18 out of 20 control neurons, the D2 agonist BHT 920 (100 nM) produced a rapid and complete inhibition of the firing, this was observed in none out of 11 neurons 10 min after the end of the application of AMPH (1-30 microM) (P less than 0.001). In these cells, the mean percent inhibition produced by BHT 920 was only 47 +/- 8%. This subsensitivity remained unchanged after 20 min and declined after one hour. This effect was specific, since the sensitivity of GABAB receptors to baclofen (500 nM-1 microM) was not modified by the application of AMPH (n = 12). These results suggest that AMPH-induced DA autoreceptor subsensitivity can be produced acutely and may be the first step in a cascade of events leading to behavioral sensitization to this compound.
Amphetamine↗
Yohimbine can induce ethanol tolerance in an in vitro preparation of rat locus coeruleus.
Noradrenergic neurons have been implicated in the development of ethanol dependence and tolerance. Moreover, the development of an hyposensitivity of alpha 2 adrenoceptors has been postulated during long-term exposition to ethanol. In order to test the putative role of alpha 2 receptors in ethanol intoxication, we have studied the interaction between ethanol and yohimbine, an alpha 2 antagonist, on the spontaneous firing rate of rat locus coeruleus (LC) in an in vitro slice model. The spikes from single neurons were recorded by glass microelectrodes. Ethanol at 100 mM, a concentration that parallels the behavioral effects in the human and in the animals, inhibits the firing activity of some LC cells. This inhibition was quickly reversed after stopping the ethanol perfusion and was observed for each further administration. However, if yohimbine (20 microM) was simultaneously perfused, the ethanol-induced inhibition was rapidly antagonized. This effect is reversible after long time washout of yohimbine. This suggests that alpha 2 adrenoceptors could be implicated in the inhibitory effect of ethanol on LC noradrenergic neurons and perhaps in the development of tolerance. However, other hypotheses are discussed, because yohimbine can also antagonize other types of receptors.
Animals↗
Evidence for the presence of N-methyl-D-aspartate receptors in the ventral tegmental area of the rat: an electrophysiological in vitro study.
Extracellular recordings were obtained from spontaneously active, presumed dopaminergic neurons of the ventral tegmental area (VTA) of the rat in a slice preparation. Bath-applied N-methyl-D-aspartate (NMDA) (1-20 microM) activated all neurons tested (n = 36). This effect was clearly concentration-dependent (n = 14), quickly reversible and reproducible. No bursting type of discharge was observed during NMDA infusion. The NMDA receptor blocker DL-2-amino-5-phosphonovaleric acid (50 microM) reversibly antagonized the increase in cell firing produced with 10 microM NMDA by 83.5 +/- 3% (mean +/- S.E.M.) (n = 8, P less than 0.05). Lowering the Mg2+ concentration of the perfusion fluid to one-third of its normal value significantly enhanced the excitatory effect of 5 microM NMDA (n = 7, P less than 0.05), but not of 500 nM carbachol (n = 6). Finally, NMDA did not modify the sensitivity of dopaminergic autoreceptors of VTA neurons (n = 8), when compared to controls (n = 10). These observations strongly support the presence of specific NMDA receptors in the VTA.
2-Amino-5-phosphonovalerate↗
Influence of fenfluramine and norfenfluramine stereoisomers on the firing rate of central monoaminergic neurons in the rat.
The influence of acute administration of stereoisomers of fenfluramine and norfenfluramine on the firing rate of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. The firing rate of dorsal raphe (DR) and locus coeruleus (LC) neurons was inhibited. The parent drugs were more active on DR neurons than on LC neurons, and the converse was true for the demethylated metabolites. In both cases the d isomers were more active than the l isomers. No effect was observed on the electrical activity of A10 dopaminergic neurons. These differences in potency and selectivity could have therapeutic implications.
Animals↗
Effect of BHT 920 on monoaminergic neurons of the rat brain: an electrophysiological in vivo and in vitro study.
BHT 920 was originally described as a dopamine autoreceptor agonist. In this study, the effect of this compound on the firing rate of noradrenergic locus coeruleus, serotonergic dorsal raphe and dopaminergic ventral tegmental area neurons was examined both in the anaesthetized rat and in rat brain slices. Extracellular recordings were performed in cells whose identity was determined by electrophysiological, pharmacological and histological criteria. In vivo, BHT 920 inhibited the firing of locus coeruleus neurons (ID50: 14.5 +/- 4.7 micrograms/kg, mean +/- SEM) and ventral tegmental area neurons (ID50: 7 +/- 3 micrograms/kg) at very low doses. As a comparison, the ID50 of clonidine on locus coeruleus cells was 5.5 +/- 0.6 microgram/kg and the ID50 of apomorphine on ventral tegmental area neurons was 13 +/- 3 micrograms/kg. BHT 920 also decreased the firing of dorsal raphe cells, but this effect was obtained at higher doses (ID50: 57 +/- 11 micrograms/kg). The in vitro study confirmed the results obtained in vivo. BHT 920 potently inhibited the firing of locus coeruleus cells (IC50: 71 +/- 28 nM) and was less potent than clonidine (IC50: 5.3 +/- 0.98 nM). The compound also inhibited the firing of ventral tegmental area neurons at very low concentrations (IC50: 21 +/- 3.3 nM), being more potent than apomorphine (IC50: 56 +/- 29 nM). BHT 920 only slightly decreased the firing rate of dorsal raphe neurons at 50 microM, showing that the drug has little direct effect on these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Comparison of the effect of morphine on locus coeruleus noradrenergic and ventral tegmental area dopaminergic neurons in vitro.
Extracellular single-cell recordings were performed on rat brain slices to compare the effects of morphine on noradrenergic neurons of the locus coeruleus (LC) and on dopaminergic neurons of the ventral tegmental area (VTA). Morphine inhibited the firing of LC neurons at very low concentrations. The mean IC50 was 13.4 +/- 1nM (mean +/- SEM) (n = 7). Moreover, the inhibitory effect of morphine was identical in slices obtained from rats anesthetized with chloral hydrate or from non-anesthetized rats. On the contrary, morphine did not have any influence on the firing of most VTA neurons (N = 20) up to 100 microM, and did not modify the sensitivity of their autoreceptors (N = 8). It is concluded that morphine potently inhibits the firing of LC neurons in vitro both in slices of anesthetized and not anesthetized animals and has no direct excitatory effect on VTA dopaminergic neurons of the rat.
Adrenergic Fibers↗
Electrophysiological effects of ethanol on monoaminergic neurons: an in vivo and in vitro study.
Monoaminergic neurons have been shown to play a role in both the intoxicating and chronic effects of ethanol. We present here the results of a study about the acute effects of ethanol on serotonergic raphe nucleus, noradrenergic locus coeruleus, and dopaminergic ventral tegmental area. These nuclei were investigated electrophysiologically by recording the spontaneous firing rate of single neurons using glass microelectrodes, both in vivo in chloral hydrate anesthetized rats and in vitro in brain slices. Ethanol was perfused intravenously at a rate ranging from 0.2 mg/kg/min to 0.2 g/kg/min in vivo, and at concentrations between 10(-8) M and 1 M in vitro. We observed that each monoaminergic nucleus had its own pattern of responses to acute ethanol perfusion, and that high and low concentrations have different actions, suggesting a biphasic effect. For example, in slices, ethanol concentrations higher than 10 mM induce an excitation in most raphe and ventral tegmental area neurons, and an inhibition of firing in locus coeruleus neurons. The results were comparable in the in vivo model, but much more heterogenous. We conclude that the effect of ethanol on the monoaminergic neurons is specific of the type of neuron, and that a biphasic effect is commonly found.
Animals↗
Dopamine and acetylcholine release in thalamus of non-parkinsonian and parkinsonian subjects.
A study of neurotransmitter release has been performed on human brain biopsies obtained during the course of a therapeutic neurosurgical procedure. The electrically evoked-release of 3H-dopamine and 3H-acetylcholine was studied on slices from the thalamus of two parkinsonian and two non-parkinsonian subjects. Electrical stimulation of the non-parkinsonian thalamus increased the dopamine release but had no effect on acetylcholine release. This characteristic response had been previously observed in the normal rat thalamus. In contrast, the parkinsonian thalamus responded with a sharp increase in acetylcholine release without concomitant increase in dopamine release indicating the possible existence of an inhibitory control effect action of dopamine on acetylcholine release as seen in rat striatum.
Acetylcholine↗
Galanin decreases the activity of locus coeruleus neurons in vitro.
A brain slice preparation was used to examine the effects of galanin on the spontaneous firing rate of locus coeruleus noradrenergic neurons. Galanin (10(-9)-10(-7) M), added to the bath, inhibited the firing of 14 out of 19 neurons in a concentration-dependent manner. The observed effect was quite variable, ranging from 20 to 100% at 10(-7) M. Experiments performed in low-Ca2+, high-Mg2+ medium also showed a significant inhibition by galanin (10(-7) M) in three out of five neurons, which suggests that the peptide acts directly.
Animals↗
Electrophysiological effects of neurotensin on dopaminergic neurones of the ventral tegmental area of the rat in vitro.
The effects of neurotensin on the spontaneous firing rate of presumed dopaminergic neurones of the ventral tegmental area of the rat, were studied in a slice preparation of brain by extracellular single-cell recordings. Bath-applied neurotensin excited all cells which were studied (N = 25). This effect was concentration-dependent; the threshold was 10(-10) M and maximal activation (about 30 spikes/10 sec) was obtained with 10(-6) M. The EC50 (half-maximal effective concentration) was roughly estimated at 35 nM. The action of neurotensin was mimicked by neurotensin 8-13 (N = 6), but not neurotensin 1-8 (N = 6). It persisted in low-calcium, high-magnesium solutions (N = 5) and therefore probably resulted from a direct activation of neurotensin receptors. The responses to neurotensin were long-lasting (30-60 min after a 10 min 10(-7) M infusion) and exhibited little tachyphylaxis. Dose-response curves to the dopaminergic agonist BHT920 showed that, during the infusion of 10(-7) M neurotensin, dopaminergic autoreceptors of some neurones were less sensitive than in control conditions. This was not a non-specific effect produced by the excitation, since it was not observed during the infusion of another excitant, N-methyl-D-aspartate (NMDA). These results show that neurotensin potently activates presumed dopaminergic neurones in the ventral tegmental area in vitro; it may also decrease the effectiveness of the autoreceptors of some neurones.
Adrenergic alpha-Agonists↗
[Study of new brain peptides using genetic engineering methods].
Using the methods of molecular biology, we have been able to clone 5 rat brain specific cDNAs coding for brain specific proteins. The partial sequencing of the first of those clones gave no homology with the genes contained in Genebank and EMBL data bank. In the future, we intend to look for a possible effect of those brain specific proteins on the neuronal activity of rat brain neurons.
DNA, Circular↗
[Pediculosis of the hairy skin].
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Animals↗