Biomedical subjects

M Le Moal

Publications and source records attributed to M Le Moal.

At least 55 records · Page 3Linked to original sources

PubMed1999

Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender.

Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals.

Adrenocorticotropic Hormone↗

PubMed1999

The promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats.

The effect of systemic administration of the neurosteroid pregnenolone sulfate (PREG-S) on sleep-wakefulness cycle and on spatial memory performances was investigated in male Sprague-Dawley rats. In the first experiment, the effect of PREG-S administration (saline, 4.75, 47.5 mg/kg, i.p.) on 24 h EEG recording was evaluated. In the second experiment, spatial memory performance in a two-trial memory task was evaluated after post-acquisition administration of similar doses of PREG-S as in the first experiment. Results show that PREG-S increases paradoxical sleep and improves the performance on the memory task yielding similar dose response curves. Starting 4 h after administration of 47.5 mg/kg PREG-S, paradoxical sleep is increased for 10 h. The PREG-S effect on spatial memory lasts for at least 24 h after injection. These results suggest that an enhancement of paradoxical sleep may be involved in the promnesic effects of this neurosteroid.

Animals↗

PubMed1999

Effects of amphetamine and cocaine treatment on c-Fos, Jun-B, and Krox-24 expression in rats with intrastriatal dopaminergic grafts.

Activation of dopaminergic (DA) transmission by psychostimulants increases c-fos expression. d-Amphetamine-induced c-fos activation is reduced in the neostriatum deprived of DA afferents. Dopaminergic grafts implanted into the denervated neostriatum induce a c-fos hyperexpression when challenged with d-amphetamine, which is correlated with the exaggerated compensation of d-amphetamine-induced rotation. The aim of the present study was to test the generality of this phenomenon and the effects of DA grafts on the expression of three immediate early gene-coded proteins (c-Fos, Jun-B, Krox-24) following a challenge with either d-amphetamine or cocaine. c-fos basal expression was low in the neostriatum and was increased by the administration of psychostimulants. These effects were blocked by the DA lesion and restored by the DA grafts. A c-fos hyperexpression was observed within the grafted neostriatum, which was correlated with the compensation of d-amphetamine- or cocaine-induced rotation. Basal levels of Jun-B- and Krox-24-LI nuclei were high within the neostriatum. Administration of d-amphetamine or cocaine did not influence the expression of these IEG-coded proteins. Jun-B expression was not affected by the surgical procedure. In contrast, lesion of DA afferents of neostriatum decreased Krox-24 basal expression, an effect reversed by the grafts. Thus, the expression of c-fos but not Jun-B or Krox-24 appeared to be a good marker for the rotational behavior exhibited by DA-grafted rats challenged with drugs that increased DA transmission. This generalized c-fos overshoot indicates an abnormal activation of postsynaptic neurons by dopamine and points to its value as an indicator of the deleterious effects of DA grafts.

Animals↗

PubMed1999

Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity.

From a classical viewpoint, tolerance to analgesic effects of opiates refers to the decreased effectiveness of a given opiate following its repeated use. Despite much research, it has not been conclusively demonstrated in vivo that functional changes observed at the opioid receptor level in the responsiveness to opiates account for development of tolerance. An alternative hypothesis is that opioid receptors remain operative following repeated opiate administration but that opioid receptor activation rapidly induces a prolonged increase in pain sensitivity which opposes the predominant opiate analgesic effect following repeated opiate administration. We recently showed that a single heroin administration induces an enhanced pain sensitivity for several days, a phenomenon which is prevented by the non-competitive N-methyl-D aspartate receptor antagonist MK-801. Herein we report that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold which progressively masked a sustained heroin analgesic functional effect. MK-801 prevented such opiate-induced allodynia and thereby prevented development of an apparent decrease in the effectiveness of heroin. These results indicate that intermittent heroin administration induced a persistent increase in the basal pain sensitivity which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance.

Analgesics, Opioid↗

PubMed1999

Infusion of neurosteroids into the rat nucleus basalis affects paradoxical sleep in accordance with their memory modulating properties.

The neurosteroids pregnenolone sulfate and allopregnanolone affect memory processes in an opposite manner, pregnenolone sulfate acts as a potent memory-enhancer whereas allopregnanolone impairs memory performance. The mechanisms underlying these memory modulating properties have yet to be elucidated. We have previously reported that infusions of either neurosteroid into the nucleus basalis magnocellularis, one of the main forebrain cholinergic nuclei, differentially affect spatial memory in rats. The relationships between memory performance and paradoxical sleep are well documented, therefore we investigated whether neurosteroids infused into the nucleus basalis magnocellularis affected the sleep-wakefulness cycle in rats, measured by electroencephalographic recordings. Results show that pregnenolone sulfate (5 ng) increased by 12%, whereas allopregnanolone (2 ng) decreased by 24%, the duration of paradoxical sleep in the 24 h interval following injection compared to control recordings. Pregnenolone sulfate inhibits GABA(A) receptors whereas allopregnanolone stimulates them. Since cholinergic neurons of the nucleus basalis magnocellularis are GABA-modulated, it may be postulated that these neurosteroids modify paradoxical sleep by acting on the cholinergic transmission. This may account, at least in part, for the memory modulating properties of these compounds.

Animals↗

PubMed1999

Functional heterogeneity in dopamine release and in the expression of Fos-like proteins within the rat striatal complex.

The dorsolateral striatum, and the core and shell of the nucleus accumbens are three major anatomical regions of the striatal complex. The shell is considered as a part of the extended amygdala, and is involved in the control of motivation and reward. The core and the striatum are considered central to sensory motor integration. In this study we compared the responses of these three regions to mild stress and drugs of abuse by measuring extracellular dopamine (DA) concentrations and Fos-like immunoreactivity (Fos-LI). The results are summarrized as follows. (i) In unchallenged conditions, extracellular DA concentrations were highest in the dorsolateral striatum and lowest in the core, whereas Fos-LI was highest in the shell and lowest in the dorsolateral striatum. (ii) After challenges that increase DA by depolarizing DAergic neurons (injection stress or 2 mg/kg morphine), the shell presented the largest increase in DA levels and Fos-LI. (iii) After the administration of a DA-uptake blocker (15 mg/kg cocaine), the percentage increase in DA was still largest in the shell. However, the absolute increase in DA and Fos-LI in the shell and the dorsolateral striatum were similar. (iv) After a full D1 agonist (SKF82958), Fos-LI was highest in the shell and lowest in the dorsolateral striatum. In conclusion, the nucleus accumbens shell seems to be the area of the striatal complex most functionally reactive to stress and drugs of abuse. However, the dorsolateral striatum and the core appear functionally distinct, as for most of the parameters studied these two regions differed.

Animals↗

PubMed1999

Adrenalectomy increases neurogenesis but not PSA-NCAM expression in aged dentate gyrus.

Ageing is accompanied by a decline in neurogenesis and in polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and by elevated basal levels of circulating corticosterone. In a companion study, we demonstrated that suppression of corticosterone by adrenalectomy increased neurogenesis and PSA-NCAM expression in the dentate gyrus of adult rats. Here we show that adrenalectomy increased neurogenesis in this structure in old rats, as measured by the incorporation of 5-bromo-2'-deoxyuridine in neuronal progenitors. This effect was prevented by corticosterone replacement. In contrast, PSA-NCAM expression remained unchanged in comparison with controls. Thus, in the aged brain, stem cells are still present and able to enter the cell cycle. This may point to ways of protecting or treating age-related cognitive impairments.

Adrenal Glands↗

PubMed1999

Release of endogenous dopamine in cultured mesencephalic neurons: influence of dopaminergic agonists and glucocorticoid antagonists.

Several electrochemical techniques allow the measurement of dopamine release in freely moving animals and brain slices. In this report, we applied one of these techniques, coulometry, coupled to high-performance liquid chromatography (HPLC), to the study of dopamine release in primary cultures of embryonic mesencephalic dopaminergic neurons. Between day 9 and 33 of culture, concentrations of dopamine, above the detection threshold, were found in the incubation buffer (Krebs ringer buffer, KRB). Concentrations of dopamine in the incubation buffer reflected neuronal release as they were: (i) positively correlated with the number of tyrosine hydroxylase-positive dopamine neurons in the culture; (ii) tetrodotoxin (TTX) sensitive and Ca2+ dependent; (iii) increased by a depolarizing stimulus, e.g. K+ (20 mM), or by the indirect dopamine agonists amphetamine and cocaine; (iv) decreased by a hyperpolarizing stimulus, e.g. the dopamine D2-like receptor agonist quinpirole. Dopamine release in this model was also sensitive to the manipulation of glucocorticoids, potent modulators of dopamine release in vivo. Long-term treatment of the cell cultures with RU 39305, a selective antagonist of glucocorticoid receptors (GR), but not with spironolactone, a selective antagonist of mineralocorticoid receptors (MR), dose-dependently decreased K+-stimulated dopamine release. In conclusion, these results demonstrate an in vitro model that allows the studying of the release of endogenous dopamine in cell cultures and the effects of glucocorticoid hormones on the release dynamics.

Animals↗

PubMed1999

Cocaine self-administration increases the incentive motivational properties of the drug in rats.

A progressive increase in the frequency and intensity of drug use is one of the major behavioural phenomena characterizing the development of addiction. The nature of the drug-induced adaptations involved in this escalating drug intake remains unknown. Some theories propose that this escalation is due to a progressive decrease (tolerance) in the reinforcing or incentive effects of the drug. Alternative views posit that with chronic use the reinforcing or incentive effects of drugs increase, by a sensitization or a learning mechanism. In this report, we address the question of whether escalating cocaine intake is paralleled by an increase or a decrease in the reinforcing and incentive effects of the drug. Using the experimental model of intravenous drug self-administration with a within-session dose-response paradigm, we first studied the course of cocaine intake over 14 sessions in rats. After acquisition of cocaine self-administration, cocaine intake progressively increased at each dose tested. Then rats, previously allowed to self-administer cocaine during either six or 29 sessions, were compared in three different tests of the incentive and reinforcing effects of cocaine: cocaine-induced reinstatement of self-administration, cocaine-induced runway and cocaine-induced place conditioning. As compared with rats briefly exposed to cocaine self-administration (six sessions), rats with the longer experience (29 sessions) exhibited a higher intake of cocaine paralleled by a higher responsiveness in the cocaine-induced reinstatement and runway tests. Both groups of rats were similarly sensitive to the rewarding effects of the drug as evaluated by the threshold dose of cocaine inducing place conditioning. Our results demonstrate that escalating cocaine intake is paralleled by an increase in the motivational properties of the drug in the absence of apparent signs of tolerance to the reinforcing or incentive effects of cocaine.

Animals↗

PubMed1999

Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat.

There is growing evidence that stress during prenatal and postnatal periods of life can modify adaptive capacities in adulthood. The hypothalamo-pituitary-adrenal axis may mediate an animal's responses to perinatal stressful events and thus serve as a neurobiological substrate of the behavioural consequences of these early events. However, little is known about the long-term effects of prenatal stressors throughout the entire life of the animals. The focus of the present study was to examine the long-term influences of a prenatal and postnatal stress on glucocorticoid secretion and cognitive performance. Prenatal stress of rat dams during the last week of pregnancy and postnatal daily handling of rat pups during the first 3 weeks of life were used as stressors. The long-term effects of these manipulations were analysed using a longitudinal approach throughout the entire life of the animals, and were repeatedly tested in adulthood (4-7 months), middle age (13-16 months) and in later life (20-24 months). The study demonstrated that prenatal stress and postnatal handling induced opposite effects on both glucocorticoid secretion and cognitive performance. Prenatal stress accelerated the age-related hypothalamo-pituitary-adrenal axis dysfunctions; indeed, circulating glucocorticoids levels of prenatally stressed middle-aged animals are similar to old control ones, and also induced cognitive impairments. In contrast, postnatal handling protected from the age-related neuroendocrine and behavioural alterations. These results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age-related memory deficits.

Aging↗

PubMed1999

The neurosteroid pregnenolone sulphate increases dopamine release and the dopaminergic response to morphine in the rat nucleus accumbens.

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Clinical studies in humans have associated some of these hormones with a generic sensation of 'well-being' and with pathologies such as depression. In rodents, the neurosteroid pregnenolone sulphate (Preg-S) has been shown to present antidepressant-like effects. These observations suggest that neurosteroids could interact with reward-related processes, mood and motivation. However, the possible neural substrates of such an effect remain unclear. In this report, we studied the action of Preg-S on the activity of the mesencephalic dopaminergic projection to the nucleus accumbens which is considered one of the biological substrates of motivation and reward. Both the direct effect of Preg-S and the influence of this hormone on the dopaminergic response to the pharmacological reward provided by the opiate morphine, were studied by means of microdialysis. Pregnenolone sulphate dose-dependently increased dopamine release in the nucleus accumbens. Furthermore, this hormone doubled the dopaminergic response to morphine. These effects were observed for Preg-S doses of 100, 200, and 400 pmol injected intracerebroventricularly. The stimulant effect of Preg-S on dopamine could mediate some of the behavioural effects of neurosteroids and in particular the interaction of these hormones with mood and motivation.

Affect↗

PubMed1999

Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis.

The hippocampal formation is one of the brain areas where neurogenesis persists during adulthood, with new neurons being continuously added to the population of dentate granule cells. However, the functional implications of this neurogenesis are unknown. On the other hand, the hippocampal formation is particularly concerned with the detection of novelty, and there are indications that dentate granule cells play a significant role in this function. Recently, the existence of inter-individual differences in behavioural reactivity to novelty has been evidenced, related to differences in the reactivity of the hypothalamic-pituitary-adrenal axis (HPA). Rats that are highly reactive to novelty (HR) exhibit a prolonged corticosterone secretion in response to novelty and to stress when compared with low reactive rats (LR). Taking advantage of the existence of these inter-individual differences, we investigated whether neurogenesis in the dentate gyrus is correlated with the behavioural trait of reactivity to novelty. Rats were first selected according to their locomotor reactivity to a novel environment. Two weeks later, cell proliferation, evaluated by the incorporation of 5-bromo-2'-deoxyuridine (BrdU) in progenitors, was studied by immunohistochemistry. We found that cell proliferation in the dentate gyrus was negatively correlated with locomotor reactivity to novelty. Indeed, cell proliferation in LR rats was twice that observed in HR rats. In contrast, survival of nascent neurons was not influenced by the behavioural trait of reactivity to novelty. Using an unbiased stereology, we show that LR rats had more cells within the granule cell layer of the dentate gyrus than did HR rats. These results demonstrate the existence of inter-individual differences in neurogenesis and total granule cell number within the dentate gyrus. These differences in hippocampal plasticity can be predicted by the behavioural trait of reactivity to novelty.

Animals↗

PubMed1999

[Corticosteroid hormones and the brain].

The anatomical and functional links between the hormone stress axis and the cortico-limbic brain regions which integrate emotion and motivation are well documented. It is important, considering the consequences of stress on the brain, to take into account the regulatory buffer capacities of the personality-cognitive processes. Another point of interest is evaluation of the long term effects of repeated life events on chronic environmental pressures which induce brain negative feedback defects and, subsequently, insidious cellular changes in regions such as the hippocampus that lead to memory or adaptive impairments. An example is provided by perinatal stress that induces, later in life, both hormonal and cognitive deleterious changes.

Adrenal Cortex Hormones↗

PubMed1998

Reaction of sleep-wakefulness cycle to stress is related to differences in hypothalamo-pituitary-adrenal axis reactivity in rat.

Acute stress is known to modify sleep-wakefulness cycle, although with considerable interindividual differences. The origin of these individual differences remains unknown. One possibility is an involvement of the hypothalamo-pituitary-adrenal axis (HPA), as its reactivity is correlated with an individual's behavioral reactivity to stress, and it is known to influence the sleep-wakefulness cycle. The present study was designed to analyze relationships between natural differences in behavioral reactivity to stress associated with differential HPA reactivity and stress-induced changes in sleep-wakefulness. Adult rats were classified into two sub-groups according to their locomotor reactivity to a mild stress (novel environment): the 'low responders (LR)' and the 'high responders (HR)' animals exhibited different glucocorticoid secretion in response to stress. We show that immobilization stress induced an increase in wakefulness in LR animals and a decrease in wakefulness in HR animals. On the other hand, paradoxical sleep was increased in both LR and HR animals. Moreover, we observed that LR animals slept more than the HR animals, whereas the two groups had similar levels of paradoxical sleep. These results indicate that the response of the sleep-wakefulness cycle to stress is related to the behavioral reactivity to stress, in turn governed by the individual's reactivity of the HPA axis. The involvement of dopaminergic mechanisms is discussed.

Animals↗

PubMed1998

Dopamine-dependent responses to morphine depend on glucocorticoid receptors.

Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 microg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction.

Animals↗

PubMed1998

Prenatal stress enhances stress- and corticotropin-releasing factor-induced stimulation of hippocampal acetylcholine release in adult rats.

There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral responses to stress in the adult offspring. For instance, prenatal stress enhances emotional reactivity, anxiety, and depressive-like behaviors associated with a prolonged stress-induced corticosterone secretion and a reduction in hippocampal corticosteroid receptors. Among the neurotransmitters involved in these hormonal and behavioral responses, acetylcholine may play a critical role. However, it is unknown whether prenatal stressful events also may influence the development of cholinergic systems. In the present study, hippocampal acetylcholine was measured, by in vivo microdialysis, in both male and female adult prenatally stressed rats, under basal conditions, after a mild stress (saline injection) or after intracerebroventricular administration of corticotropin-releasing factor (CRF; 0.1 nM). No difference in basal release of acetylcholine was observed between control and prenatally stressed rats of both genders. Mild stress was found to increase hippocampal acetylcholine release to a greater extent in prenatally stressed rats than in controls. In males, the CRF-induced increase in hippocampal acetylcholine release was larger in prenatally stressed rats, as compared with controls, during the first hour after the injection and in females during the third hour after the injection. These data indicate that prenatal stress has long-term effects on the development of forebrain cholinergic systems. The augmented increase in hippocampal acetylcholine release after the mild stress and CRF injection in prenatally stressed rats may be involved in some of the hormonal and behavioral abnormalities found in prenatally stressed rats.

Acetylcholine↗

PubMed1998

Sensitization to the motor effects of contingent infusions of heroin but not of kappa agonist RU 51599.

It has been postulated that behavioral sensitization could reflect drug-induced changes that are central to the development of drug abuse; however, it is still unknown whether behavioral sensitization can arise during a "voluntary" and "self-controlled" consumption of drugs and consequently play a role in drug abuse. For this reason, we studied the possible sensitization of motor activity during ten consecutive intravenous self-administration (SA) sessions of one of the most largely abused opiates the mu agonist heroin [30 microg/infusion (inf)]. We also studied in similar conditions the new kappa agonist RU 51599 (6.5, 20 and 100 microg/inf). Heroin and RU 51599 were compared because both drugs are self-administered by rodents, but the reinforcing properties of RU 51599 are very weak compared to those of heroin. At low ratio requirement rats developed SA of both heroin and RU 51599; however, a progressive increase in drug-induced locomotor activity over subsequent sessions was observed only for heroin but not for RU 51599. Sensitization of the motor effects of heroin developed over a period of time during which the intake of the drug was constant. In conclusion, sensitization can develop during the voluntary consumption of an addictive drug such as heroin. These results are in line with the hypothesis that sensitization could play a role in the etiology of drug abuse.

Animals↗

PubMed1998

The role of stress in drug self-administration.

Environmental experiences have an important effect on the sensitivity of an individual to drugs of abuse. Studies of drug self-administration in laboratory animals have shown that both physical and psychological stressors facilitate the acquisition of drug self-administration, probably by increasing the reinforcing efficacy of drugs of abuse. Stressors also facilitate the reinstatement of drug taking even after prolonged periods of withdrawal. The adrenal hormones, glucocorticoids, which increase the sensitivity of mesencephalic dopaminergic neurones to drugs, seem to be one of the biological substrates of the effects of stress on the propensity to develop drug intake. In this review, Pier Vincenzo Piazza and Michel Le Moal discuss theories of drug abuse, the influence of different stressful experiences on drug self-administration and their possible mechanisms of action.

Adrenal Cortex Hormones↗