Biomedical subjects

M Le Moal

Publications and source records attributed to M Le Moal.

At least 127 records · Page 7Linked to original sources

PubMed1995

Opposite effects on hippocampal corticosteroid receptors induced by stimulation of beta and alpha 1 noradrenergic receptors.

Central corticosteroid receptors play an important role in the regulation of the secretion of corticosterone. Although these receptors are thought to be regulated by circulating levels of corticosterone, there is evidence for direct neural control. For example, it has been shown that noradrenergic lesions can both increase and decrease corticosteroid receptors depending on the brain structure involved. In the present study, we investigated the role of different noradrenergic receptors in the rat, by examining the effect of the acute administration of agonists and antagonists of beta and alpha 1 noradrenergic receptors on hippocampal type I and type II corticosteroid receptor levels. The effects of these drugs were studied in adrenalectomized animals whose plasma levels of corticosterone were maintained in the physiological range by implantation of coritcosterone pellets. Our results show that the beta receptor agonist salbutamol (5 mg/kg) increased the number of type I and type II hippocampal corticosteroid receptors. This effect was blocked by the beta receptor antagonist propranolol (5 mg/kg), which had no effect on its own. In contrast, the alpha 1 receptor agonist phenylephrine (100 micrograms) reduced the number of type I and type II corticosteroid receptors, whereas the alpha 1 receptor antagonist prazosin (0.5 mg/kg) increased type I receptors. The effect of prazosin was attributed to an increase in the relative beta tonus resulting from blockade of alpha 1 receptors. Its effect was reversed by the simultaneous injection of the beta receptor antagonist propranolol. In conclusion, our results show that noradrenergic transmission can have both a facilitatory and an inhibitory action on central corticosteroid receptors by acting respectively on beta and alpha 1 noradrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗

PubMed1995

Amphetamine-induced conditioned activity in rats: comparison with novelty-induced activity and role of the basolateral amygdala.

A within-subject design was used to investigate the behavioral and neural basis of the conditioned activity induced by amphetamine in male Wistar rats. In this design, conditioned activity was inferred when the activity of a given rat following a vehicle injection was greater in its amphetamine-paired environment (CS+) than in its vehicle-paired environment (CS-). Conditioned activity (a) did not change in magnitude with the number of conditioning sessions, (b) did not differ from the level of activity recorded during the first exposure to the CS- (novelty), (c) had an extinction rate that was similar to the rate of habituation to the CS-, and (d) was not impaired by a bilateral excitotoxic lesion of the basolateral amygdala. Results are discussed in light of the incentive conditioning and habituation theories of conditioned activity.

Animals↗

PubMed1995

d-fenfluramine increases striatal extracellular dopamine in vivo independently of serotonergic terminals or dopamine uptake sites.

The effect of various doses of the serotonin (5-HT) release-inducing agent d-fenfluramine (d-fenf) on extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in vivo in the striatum of halothane-anesthetized rats, following systemic and local administration. At 5 and 10 but not 2.5 mg/kg, d-fenf administered intraperitoneally significantly increased DA extracellular concentration and reduced DOPAC outflow. A concentration-dependent enhancement of DA dialysate content was also found following intrastriatal application (5, 10, 25, and 50 microM). The bilateral administration of 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, did not modify the effect on extracellular DA concentration of 25 microM d-fenf locally applied into the striatum. The enhancement of extracellular DA level induced by 25 microM d-fenf was slightly but significantly reduced by the local application of 25 microM citalopram. The blockade of DA uptake sites by nomifensine (0.1, 0.3, and 1 microM) did not modify significantly the effect of d-fenf. The rise of DA outflow induced by 25 microM d-fenf was strongly reduced in the presence of 1 microM tetrodotoxin (TTX) or by the removal of Ca2+ from the perfusion medium. The results obtained show that d-fenf increases the striatal extracellular DA concentration by a Ca(2+)-dependent and TTX-sensitive mechanism that is independent of striatal 5-HT itself or DA uptake sites.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Stress-induced sensitization and glucocorticoids. I. Sensitization of dopamine-dependent locomotor effects of amphetamine and morphine depends on stress-induced corticosterone secretion.

Repeated exposures to stress sensitize motor and addictive effects of drugs of abuse. Recently, it has been shown that stress-induced behavioral sensitization depends on the secretion of glucocorticoids. We investigated if sensitization of dopamine-dependent effects of psychostimulants and opioids was influenced by glucocorticoid. Sensitization of the dopaminergic response to drugs is considered the neural substrate of behavioral sensitization and has been implicated in vulnerability to drug abuse. Dopamine-dependent effects of psychostimulants and opioids were evaluated by injecting either amphetamine into the nucleus accumbens (10 micrograms/side) or morphine into the ventral tegmental area (VTA) (1 microgram/side). The locomotor response to psychostimulants and opioids injected in these brain areas depends on the mesencephalic dopaminergic transmission. Drug-induced locomotion was compared in male rats in which corticosterone secretion was either in +tct or experimentally suppressed by an adrenalectomy associated with a substitutive treatment reproducing basal levels of the hormone. Eight days of food restriction (80% of the initial body weight) were used as a stressor. Suppression of stress-induced corticosterone secretion abolished food restriction-induced sensitization of the locomotor effects of intra-accumbens amphetamine and intra-VTA morphine. This effect was corticosterone dependent since the restoration of corticosterone levels in the range of those induced by stress totally reinstates sensitization. Our results suggest that glucocorticoids control stress-induced sensitization by changing the sensitivity of the mesencephalic dopaminergic transmission to drugs of abuse. Since dopaminergic effects of drugs are related to their addictive properties, secretion of glucocorticoids may be one of the factors determining the enhanced vulnerability to drugs observed in stressed subjects.

Amphetamine↗

PubMed1995

Stress-induced sensitization and glucocorticoids. II. Sensitization of the increase in extracellular dopamine induced by cocaine depends on stress-induced corticosterone secretion.

Secretion of glucocorticoids seems to control stress-induced sensitization of the behavioral effects of drugs of abuse by acting on the mesencephalic dopaminergic transmission, the principal neural substrate of sensitization. In order to investigate the mechanisms of this interaction between glucocorticoids and dopamine, we studied the sensitization of the increase in extracellular concentration of dopamine induced by cocaine in male rats in which corticosterone secretion was either intact or blocked. Extracellular concentrations of dopamine were evaluated in the nucleus accumbens of freely moving animals by means of microdialysis. Metyrapone, an inhibitor of corticosterone synthesis, was used to block stress-induced corticosterone secretion. Food-restriction (90% of the initial body weight) was the stressor used to induce sensitization. It was found that metyrapone (100 mg/kg s.c. twice a day for 8 d) suppressed stress-induced sensitization of the increase in accumbens dopamine induced by cocaine (10 mg/kg, i.p.) and sensitization of cocaine-induced locomotion Metyrapone suppressed both the development and the expression of sensitization. Thus, sensitization was equally blocked when the metyrapone treatment started either 1 d before the start of food-restriction or 8 d later, that is, when food-restriction-induced sensitization to cocaine was already established. In conclusion, our results suggest that glucocorticoids modify sensitization of the behavioral effects of cocaine by acting on extracellular concentrations of dopamine. Since addictive properties of psychostimulants seem mediated by the increase in extracellular concentrations of dopamine they induce, these findings may have implications for the development of new therapeutic strategies of addiction.

Animals↗

PubMed1995

Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress.

The development of the organism is subjected to critical and complex influences during the perinatal period. Prenatal and postnatal stresses can have different long-term behavioral effects, and appropriate postnatal manipulations can counteract the behavioral effects of prenatal stress. In the present study, we investigated the involvement of changes in the activity of the hypothalamo-pituitary-adrenal (HPA) axis in the long-term effects of prenatal and postnatal events and of interactions between them. We investigated stress-induced corticosterone secretion and hippocampal corticosteroid receptors in male adult rats submitted to prenatal and/or postnatal manipulations. Repeated restraint during the last week of pregnancy was used as prenatal stressor, and adoption at birth was used to change the postnatal environment. We found that (1) prenatal stress prolongs stress-induced corticosterone secretion in adult rats, which was attributed to the observed decrease in central corticosteroid receptors; (2) adoption, irrespective of the stress experience of the foster mother, reverses the effects of prenatal stress; and (3) adoption per se increases maternal behavior and decreases the stress-induced corticosterone secretion peak in the adult offspring. In conclusion, certain prenatal and postnatal manipulations appear to have opposite long-term effects on the activity of the HPA axis, and adoption, probably by modifying maternal behavior, can protect against the effects of prenatal stress. Thus, changes in the activity of the HPA axis may be one of the biological substrates of the long-term effects of certain perinatal events.

Animals↗

PubMed1994

Inhibition of corticosterone synthesis by Metyrapone decreases cocaine-induced locomotion and relapse of cocaine self-administration.

Several studies have recently shown that basal and stress-induced secretion of corticosterone may enhance vulnerability to drugs of abuse. In this report, we studied the effects of metyrapone, an inhibitor of the synthesis of corticosterone, on cocaine-induced locomotion and on the relapse of cocaine self-administration. Locomotor response to cocaine was studied because psychomotor effects of drugs have been shown to be related to their reinforcing properties. Self-administration was studied in the relapse phase since blockade of relapse is central to the therapy of addiction. Before these behavioral tests, rats in different experimental groups were injected subcutaneously with either metyrapone (100 mg/kg) or vehicle, twice a day for 8 days. Metyrapone treatment reduced cocaine-induced locomotor activity and relapse of cocaine self-administration, without inducing a nonspecific disruption of motor or food-directed behaviors. Under these experimental conditions, the metyrapone treatment totally blocked stress-induced corticosterone secretion but did not modify basal corticosterone levels. These results confirm the involvement of glucocorticoids in the pathophysiological mechanisms underlying vulnerability to drug abuse, and may have implications for the development of new therapeutic strategies of drug addiction.

Analysis of Variance↗

PubMed1994

Animals predisposed to develop amphetamine self-administration show higher susceptibility to develop contextual conditioning of both amphetamine-induced hyperlocomotion and sensitization.

It has been shown that rats, like humans, display individual differences in the propensity to develop psychostimulant self-administration. Animals showing the highest locomotor reactivity to novelty (HRs: High Responders) are more prone to develop amphetamine self-administration than rats having a low locomotor response to novelty (LRs: Low Responders). The present study was designed to ascertain whether individual differences are also present in the conditioning of drug effects, a process involved in the maintenance of addiction. After pairing the drug effect with a particular set of environmental cues, only HRs showed conditioned hyperlocomotion and environment-specific sensitization to the effect of amphetamine. Unconditioned sensitization was, however, observed in LRs but not in HRs. The environment-specific sensitization disappeared on extinction of the conditioned hyperlocomotion in HRs, indicating that conditioning facilitates the expression of sensitization. In contrast, an inhibitory influence of conditioning on sensitization emerged from the analysis of the same results over all the experimental groups, without taking individual differences into account. In conclusion, our results show that: (i) locomotor reactivity to novelty predicts both vulnerability to develop self-administration and contextual conditioning of drug effects, which suggests that the two phenomena are two related features and that conditioning plays an important role not only in the maintenance of drug intake but also in its development; (ii) conditioned and unconditioned sensitization can be developed separately in different individuals which suggests that they are independent phenomena; (iii) analysis of individual differences is relevant to pharmacological studies, especially with respect to drugs of abuse.

Amphetamine↗

PubMed1994

The increase in striatal neuropeptide Y immunoreactivity induced by neonatal dopamine-depleting lesions in rats is reversed by intrastriatal dopamine-rich transplants.

The aim of the present experiment was to test whether: (i) the destruction of the dopaminergic meso-telencephalic pathway in neonatal rats induces an increase in the density of Neuropeptide Y immunoreactive (NPY-IR) neuronal perikarya within the denervated neostriatum; (ii) embryonic dopaminergic neurons grafted into the neonatal neostriatum could block such an effect of the lesion. As a control, density of NPY-IR neurones was also examined in rats lesioned and/or grafted at adulthood. The ascending dopaminergic system of 3-day-old rat pups or adult rats was unilaterally lesioned by intrahypothalamic injection of 6-hydroxydopamine. Grafting was performed six days later. The neonatal lesion increased the number of NPY-IR neurones on the lesioned side by 24% as compared to the contralateral neonstriatum. This increase was abolished in the neostriatum bearing dopaminergic grafts as evaluated six weeks after grafting. These effects are similar to that observed in animals lesioned and/or grafted as adults and further extend the range of post-lesion modifications which can be reversed by the implantation of embryonic DA neurones to neonates.

Amphetamine↗

PubMed1994

Reactivity to novelty during youth as a predictive factor of cognitive impairment in the elderly: a longitudinal study in rats.

A life-span study of certain behavioral traits was conducted in rats. Animals were repeatedly tested in a circular corridor for reactivity to novelty and in a recognition memory task for cognitive abilities. These measures revealed important inter-individual differences in young as well as in old subjects. Some of these differences appear with aging (memory deficits) and others disappear (high reactivity to novelty). Moreover, a relationship between high reactivity to novelty in youth and deficits in memory recognition in elderly was found. Rats that are high-responders to novelty had age-related memory impairments whereas the low-responder rats did not. While the biological mechanism linking these two behavioral traits remains to be demonstrated, this study shows that age-related impairments can be predicted by factors detectable early in life.

Aging↗

PubMed1994

Cocaine sensitivity in Roman High and Low Avoidance rats is modulated by sex and gonadal hormone status.

Repeated exposure to stressful stimuli or psychostimulants increases sensitivity to the motoric effects of these drugs, i.e. behavioral sensitization. The objective of the present experiment was to determine the interaction between factors that modulate psychostimulant sensitivity, i.e. sex and circulating gonadal hormone levels, in rats with a genetically distinct locomotor response to novelty: Roman Low Avoidance rats (RLA) freeze while Roman High Avoidance rats (RHA) remain motorically active. Ninety-six male and female RHA and RLA rats were gonadectomized (GDX) just after weaning or as adults, or left gonadally intact. Each rat received a total of 9 injections of cocaine hydrochloride (10 mg/kg, IP), at 3-4 day intervals for 5 weeks. Locomotor activity was measured after each injection, and stereotypes were rated 1 x/week. Open field behavior (10 min) and plasma corticosterone were measured 2 weeks after the final injection. Overall, the RHA line was more sensitive to (1) cocaine's stereotypic effects, and (2) the influence of ovarian hormones on the cocaine's acute and sensitizing effects on locomotor activity. Therefore, genetic background not only determines cocaine sensitivity, but also the influence of gonadal hormones on locomotor activity. These interactions are relevant when considering the genetic contribution to abuse liability.

Animals↗

PubMed1994

Social isolation-induced enhancement of the psychomotor effects of morphine depends on corticosterone secretion.

Short-term social isolation has been shown to increase individual reactivity to addictive drugs, although the biological factors involved in this effect are largely unknown. In this study, we investigated the influence of corticosterone secretion on the effects of social isolation on the response to opioids. The effects of social isolation on morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy. The animals in the latter group were implanted with subcutaneous corticosterone pellets (50 mg), which slowly release corticosterone, producing stable plasma levels within the physiological range. Social isolation increased the locomotor response to morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which corticosterone secretion was blocked. These results suggest that corticosterone secretion is required for the expression of the enhanced locomotor response to opioids induced by isolation. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings suggest a role for glucocorticoids in the vulnerability to the reinforcing effects of opioids.

Adrenalectomy↗

PubMed1994

Modulation of immune reactivity by unilateral striatal and mesolimbic dopaminergic lesions.

Asymmetrical modulation of immune reactivity by central dopaminergic pathways was suggested by previous reports which described an association between alterations of immune response and peculiar patterns of dopamine asymmetries in pathological and physiological situations. In the present experiments, we studied the respective roles of the nigrostriatal and mesolimbic dopaminergic networks in the asymmetrical modulation of immune responses. Lymphocyte proliferation as well as natural killer (NK) cell activity were analysed in mice, 2 weeks after unilateral lesions of dopaminergic projections by in situ injection of 6-hydroxydopamine in the striatum or the nucleus accumbens. After lesions of the striatum, proliferation of splenic lymphocytes was impaired only in the right-lesioned group. Left-lesions appeared to not modify T lymphocyte reactivity. After lesions of the nucleus accumbens, no modification of T lymphocyte mitogenesis was observed but splenic NK cell activity was depressed in left-lesioned mice as compared with controls or right-lesioned animals. Proliferation of B lymphocytes was not affected by striatal or mesolimbic dopaminergic lesions. It was concluded that both striatal and mesolimbic dopaminergic pathways are asymmetrically involved in neuro-immunomodulation. These dopaminergic regions appear to function independently as the effective side as well as the immune parameters that were altered differ according to the structure lesioned.

Animals↗

PubMed1994

Maturation of the behavioral and neuroendocrine differences between the Roman rat lines.

The behavioral and/or neuroendocrine reactivity to psychological (open-field exposure) and physiological (CRF challenge) stimulations, as well as adrenal tyrosine hydroxylase (TH) and phenylethanolamine N-methyl transferase (PNMT) activities were measured, at different ages, in the Roman high avoidance (RHA) and Roman low avoidance (RLA) rat lines that have been genetically selected on the basis of their divergent active avoidance behavior. The highest locomotor activity in the open field, associated to blunted prolactin and renin reactivity to an emotional stress and lower specific TH and PNMT activities, characterized the RHA rats of all ages. HPA axis reactivity to psychological and/or physiological stimulations was identical in young animals (14 weeks old) of the two lines. Nevertheless, it displayed with age maturation processes, since the amplitude of postopen-field secretion peak for ACTH was larger in RLA rats from 20 weeks on, the response to CRF being not increased until 42 weeks. These maturation processes could result from genetically influenced changes related to environmental stimulations. Therefore, the Roman lines may be an excellent model to study the interactions between the genetic and developmental factors controlling the coupling between both behavioral and neuroendocrine functions.

Adrenocorticotropic Hormone↗

PubMed1994

Lateralized interdependence between limbicotemporal and ventrostriatal dopaminergic transmission.

The antipsychotic effects of dopaminergic antagonists suggest dopaminergic hyperactivity plays a role in schizophrenia. However, an elevated number of D2 dopamine receptors in the left putamen of non-treated schizophrenics has been reported which is consistent with a diminution of dopaminergic transmission in the ventral striatum. Morphological and functional studies have shown marked alterations in the left medial temporal lobe (entorhinal cortex, hippocampus, parahippocampus gyrus) of schizophrenics. As the entorhinal cortex and the ventral hippocampus project to the ventral striatum, the functional relationship between left temporal structures and the left ventral striatum may be impaired in schizophrenics. To assess the validity of this hypothesis, we investigated the existence of a preferentially left hemispheric interdependency between dopaminergic pathways in male rats. We found that dopaminergic projections in the entorhinal cortex and the ventral hippocampus regulate dopaminergic transmission in the nucleus accumbens, particularly in the left hemisphere. Temporal D2 dopamine receptors seem to be primarily involved in this effect. This lateralized interdependent functioning appears structurally based. These results may provide new insights into the pathophysiology of schizophrenic psychoses.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

The D1 dopamine agonist SKF 38393, but not the D2 agonist LY 171555, decreases the affinity of type II corticosteroid receptors in rat hippocampus and ventral striatum.

Type I and type II brain corticosteroid receptors are regulated by adrenal hormones as well as being under neural control. Recent studies have indicated that neurotransmitters such as serotonin and noradrenaline are also involved in the regulation of corticosteroid receptors. In a previous study, we showed that dopamine also modulates activity of the corticosteroid receptor system. In the present study, we examined the roles of the dopamine D1 and D2 receptor subtypes in the regulation of corticosteroid receptors. Adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone replacement implants, were injected intraperitoneally with the D1 agonist SKF 38393 or the D2 agonist LY 171555. Corticosteroid receptors were assayed in the ventral striatum and hippocampus. We have shown that the D1 agonist SKF 38393 decreased type II receptor affinity in both regions, whereas the D2 agonist LY 171555 had no effects. The results show that the influence of the dopaminergic system on corticosteroid receptors appears to be mediated by D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats.

Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring.

Aging↗

PubMed1994

Corticosterone circadian secretion differentially facilitates dopamine-mediated psychomotor effect of cocaine and morphine.

Studies of intravenous self-administration and psychomotor effects of drugs have recently suggested that stress-induced corticosterone secretion may be an important factor determining vulnerability to drugs of abuse. In this report, we studied if basal physiological corticosterone secretion modulates sensitivity to cocaine and morphine, and if changes in the reactivity of mesolimbic dopaminergic (DA) neurons, one of the principal substrates of drug-reinforcing effects, are involved. For this purpose we determined the psychomotor effects of these drugs in animals in which corticosterone secretion was suppressed by adrenalectomy and in adrenalectomized animals submitted to different corticosterone replacement therapies designed to mimic (1) only the diurnal levels of the hormone, obtained by the subcutaneous implantation of 50 mg corticosterone pellets; (2) only the nocturnal levels, obtained by adding corticosterone (50 micrograms/ml) to the drinking solution during the dark period; and (3) the entire circadian fluctuation, obtained by combining the two previous treatments. Locomotor response to cocaine and morphine was studied after both systemic and central injections, into the nucleus accumbens for cocaine and into the ventral tegmental area for morphine. These sites were chosen because stimulant effects of cocaine and morphine injected in these structures are dopamine dependent. Our results show that suppression of corticosterone by adrenalectomy reduced the locomotor response to cocaine and morphine, injected both systemically and centrally. The reinstatement of diurnal levels of corticosterone totally reversed adrenalectomy's effects on the behavioral response to cocaine, whereas the reestablishment of the entire corticosterone circadian fluctuation (diurnal plus nocturnal levels) was necessary to reverse the response to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗