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Biomedical subjects

M Le Moal

Publications and source records attributed to M Le Moal.

At least 73 records · Page 4Linked to original sources
PubMed1998

Behavioural recovery after unilateral lesion of the dopaminergic mesotelencephalic pathway: effect of repeated testing.

Functional recovery following a complete unilateral lesion of the nigrostriatal pathway in adult rats was studied. We examined the effect of training on the spontaneous or induced postural bias following the lesion. Two tasks measuring lateralization were used to assess the lesion-induced postural bias: spontaneous asymmetry was evaluated in the Y-maze, whereas induced body bias was measured by hanging the rat by its tail. Recovery was assessed at three different times following the lesion. The effects of lesion in adult rats in the short, medium and long term were evaluated and compared with the effects of dopaminergic transplants. In adult lesioned rats, destruction of dopaminergic innervation of the neostriatum induced initially an ipsilateral bias as measured in the "tail hang test" and the Y-maze. Recovery of function was observed in the tail hang test as ipsilateral bias declined on repeated testing. Apart from this effect, there was a post-lesion interval effect, since the postural bias disappeared more rapidly on repeated testing in the long-term lesioned rats. This spontaneous recovery was impaired by intrastriatal dopaminergic grafts. Furthermore, no spontaneous recovery was observed in the Y-maze test. These observations show that repeated testing can influence the long-term effects of damage to the nigrostriatal dopamine system.

Animals↗
PubMed1998

Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory systems.

Mechanisms underlying the development of acute tolerance to the analgesic effect of opiates were investigated. In the rat tail-flick test, administration of naloxone (1 mg/kg, s.c.) 40 min after heroin (1 mg/kg, s.c.) was shown to induce hyperalgesia, indicative of a short-onset, opiate-activated pain facilitatory systems masking the opiate analgesia. Pretreatment with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate blocked, in a dose-dependent manner, the naloxone-induced hyperalgesia and potentiated the heroin-induced analgesia. Using a schedule of two successive injections of 1 mg/kg heroin, acute tolerance was indicated by a marked reduction (-52%) in analgesia induced by the second dose. After pretreatment with dizocilpine maleate, the acute tolerance was abolished and the analgesic effects of both injections of heroin were strongly potentiated. These observations indicate that acute tolerance appears after the first exposure to opiates and stems from opiate activation of N-methyl-D-aspartate-dependent pain facilitatory systems.

Analgesics, Opioid↗
PubMed1998

The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory.

The effects of an infusion (5 ng) of the neurosteroid pregnenolone sulfate into the nucleus basalis magnocellularis on acetylcholine release in the frontoparietal cortex and basolateral amygdala were evaluated during the 130 min post-injection in male Sprague-Dawley rats using in vivo microdialysis coupled "on line" with high performance liquid chromatography detection. One week later, the same animals were tested for spatial memory after another infusion of pregnenolone sulfate (5 ng) into the nucleus basalis. Results show that pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline concentrations in the two structures relative to a control injection. The duration of this effect was longer in cortex (130 min) than in amygdala (30 min). Furthermore, pregnenolone sulfate improved memory performance in a task based upon spatial recognition of a familiar environment. A significant positive correlation (r=0.49) was found between the recognition score in the spatial memory test and the levels of acetylcholine release in the frontoparietal cortex but not in the basolateral amygdala. Therefore, our results suggest that the nucleus basalis magnocellularis-cortical pathway could be in part responsible for the promnesic effect of pregnenolone sulfate. This neurosteroid acts as a negative modulator of the GABA(A) receptor complex and positively modulates the N-methyl-D-aspartate receptor, possibly resulting in a global stimulatory effect on central cholinergic neurotransmission.

Acetylcholine↗
PubMed1998

Neuropeptide FF in the rat adrenal gland: presence, distribution and pharmacological effects.

Neuropeptide FF (NPFF, FLFQPQRFamide) is an FMRFamide-like octapeptide exhibiting antiopiate activity. The presence of both NPFF-immunoreactivity (NPFF-IR) and NPFF-specific receptors has been described in the mammalian central nervous system (CNS). The peripheral effects of NPFF indicate that NPFF-IR material is present outside the CNS. Biochemical and immunohistochemical methods enabled us to determine the presence and distribution of NPFF-IR in the rat adrenal gland. The amount of NPFF-IR material in whole gland was estimated by radioimmunoassay to be 19.00 +/- 4.00 fmol/gland. High performance liquid chromatography analysis of adrenal extracts revealed a single molecular form which coeluted with authentic NPFF. Demedullation decreased adrenal NPFF-IR content, indicating that NPFF-IR was present in both cortex and medulla. Light microscopy revealed NPFF-IR in beaded fibers confined in the outer part of the cortex and in medullary cells. Double-labeling with antityrosine-hydroxylase and anti-NPFF antibodies showed NPFF-IR in cortical catecholaminergic postganglionic fibers restricted to the subcapsular and glomerulosa zonae. NPFF-IR was also located in medullary chromaffin cells and in rays and islets of chromaffin cells dispersed throughout the cortex. Insulin-induced hypoglycemia did not alter NPFF-IR content. Denervation lowered adrenal NPFF-IR content. These data indicate that this peptide is present in nerve fibers of extrinsic origin. In vitro approaches using adrenal slices have shown that NPFF inhibited aldosterone release in a dose-dependent manner. Taken together, these data suggest that NPFF may participate in the control of aldosterone production and adrenal blood supply.

Adrenal Cortex↗
PubMed1998

Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time.

Acute dependence, defined as a precipitation of somatic signs by an antagonist, may occur after a single administration of an opiate drug. Because hyperalgesia is a consistent sign of the withdrawal syndrome, we tested the effectiveness of heroin, an opiate used by addicts, to induce pain facilitation even after a first exposure to the drug. In opiate-naive rats, subcutaneous injection of heroin induced analgesia followed by allodynia, a decrease in pain threshold. This latter phenomenon was observed in the absence of noxious stimuli and lasted several days. An N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 prevented such long-lasting allodynia. These results suggest that allodynia is an early sign reflecting neural plasticity associated with the development of dependence.

Animals↗
PubMed1998

Complex regulation of the expression of the polysialylated form of the neuronal cell adhesion molecule by glucocorticoids in the rat hippocampus.

The gyrus dentatus is one of the few areas of the brain that continues to produce neurons after birth. The newborn cells differentiate into granule cells which project axons to their postsynaptic targets. This step is accompanied by the transient expression of the polysialylated isoforms of neuronal cell adhesion molecules (PSA-NCAM) by the developing neurons. Glucocorticoid hormones have been shown to inhibit neurogenesis. We noted a functional correlation between PSA-NCAM expression and glucocorticoid action after manipulation of corticosterone levels in the adrenalectomized rat. Adrenalectomy increased neurogenesis, evaluated from the incorporation of 5-bromo-2'-deoxyuridine in neuronal precursors, as well as PSA-NCAM expression. The increase in PSA-NCAM-immunoreactive (IR) cells in the gyrus dentatus, evidenced 72 h following adrenalectomy, persisted for at least a month. It was accompanied by enhanced dendritic arborization of PSA-NCAM-IR cells in the gyrus dentatus and by an increase in number of PSA-NCAM-IR fibres in the CA3 subfield. Neurogenesis was normalized by restitution of diurnal or nocturnal levels of corticosterone, whereas normalization of PSA-NCAM expression was only observed after simulation of the complete circadian fluctuation of the hormone. Our findings reveal the complex action of corticosterone in modulating the expression of PSA-NCAM in the gyrus dentatus of the hippocampal formation. They also highlight the importance of corticosterone fluctuations in the control of neurogenesis and plasticity in this structure.

Adrenalectomy↗
PubMed1998

Neurochemical characterization of individual vulnerability to addictive drugs in rats.

Rats exposed to a low-light, low-noise, novel environment exhibit differences in individual locomotor response to the novelty stressor. The categorization of rats in a locomotor screening procedure as low- (LR) or high-responders (HR), where LRs are in the low locomotor range while HRs belong to the high locomotor range, is significant in that HRs show higher activity in mesencephalic dopaminergic projection neurons, and also show a higher propensity to self-administer psychostimulants and other drugs of abuse compared with LRs. In this study, we examined the neurobiological basis of dopaminergic hyperactivity by comparing in HRs and LRs the steady-state differences in regulatory inputs to mesencephalic (substantia nigra and ventral tegmental area: VTA) dopaminergic neurons. In particular, using in situ hybridization, we studied levels of mRNA for tyrosine hydroxylase (TH) and cholecystokinin (CCK) in the mesencephalon, and for preprodynorphin (DYN), preproenkephalin (PPE), and preprotachykinin (PPT) in the striatum and nucleus accumbens (Acb). We also evaluated TH levels by radioimmunocytochemistry (TH-RIC) in striatal, accumbal and mesencephalic regions. HRs versus LRs had lower levels of neurochemicals belonging to the intrinsic inhibitory input to dopaminergic neurons in the VTA, e.g. lower TH-RIC (-25%) and CCK-mRNA (-48%). In contrast, HRs showed higher levels of parameters belonging to extrinsic facilitating inputs, e.g. higher PPE-mRNA (+37%). In addition, HRs had higher DYN-mRNA in Acb (+61%), which has been shown to be positively correlated with higher dopaminergic activity. These results enhance our knowledge of the neurobiological correlates of individual rats' propensities to develop drug-intake and provide some putative mechanisms for the dopaminergic hyperactivity that characterizes drug-prone animals.

Animals↗
PubMed1998

Pharmacological stimuli decreasing nucleus accumbens dopamine can act as positive reinforcers but have a low addictive potential.

Opioid peptides, through mu and delta receptors, play an important part in reward. In contrast, the role of kappa receptors is more controversial. We examined the possible positive reinforcing effects of a selective kappa agonist, RU 51599, by studying intravenous self-administration in the rat. The effect of RU 51599 on dopamine release in the nucleus accumbens was also studied, as opioids and dopamine seem to interact in the mediation of reward. The behavioural and dopaminergic effects of RU 51599 were compared with those of the mu agonist heroin. Rats self-administered both RU 51599 (6.5, 20 and 60 microg/inj) and heroin (30 microg/inj) at low ratio requirement. When the ratio requirement, i.e. the number of responses necessary to receive one drug infusion, was increased, self-administration of RU 51599 rapidly extinguished, whereas self-administration of heroin was maintained. Intravenous infusion of RU 51599 (100, 200 and 400 microg) dose-dependently decreased (25, 30 and 40%, respectively) extracellular concentrations of dopamine, as measured by means of microdialysis in freely moving rats. In contrast, heroin increased accumbens dopamine (130% over baseline). These results indicate that kappa receptors, similarly to mu ones, can mediate positive reinforcing effects of opioid peptides. However, the strength of the reinforcement is very low for kappa receptors. This suggests that changes in accumbens dopamine do not correlate with the capacity of a stimulus to induce reward or aversion. In contrast, a parallel seems to exist between an increase in accumbens dopamine and the drive to reach or obtain a positive reinforcer.

Animals↗
PubMed1998

Individual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone.

Stressful experiences, glucocorticoids hormones and dopaminergic neurons seems to interact in determining a higher propensity to develop drug abuse. In this report, we studied the acute interaction between these three factors. For this purpose, we compared stress-induced dopamine release in intact rats and in rats in which stress-induced corticosterone secretion was experimentally blocked. Ten-minute tail-pinch was used as a stressor and dopamine release estimated in the nucleus accumbens by using the microdialysis technique. Individual differences were also taken into account by comparing rats identified as either predisposed (HRs) or resistant (LRs) to develop self-administration of drugs of abuse, on the basis of their locomotor response to novelty. It was found that suppression of stress-induced corticosterone secretion significantly decreased stress-induced dopamine release. However, such an effect greatly differed between HR and LR rats. When corticosterone secretion was intact HR animals had a higher and longer dopamine release in response to stress than LRs. The blockade of stress-induced corticosterone secretion selectively reduced the dopaminergic response of HRs that did not differ from LRs anymore. These findings strength the idea that glucocorticoids could be involved in determining propensity to develop drug self-administration. In particular, these hormones could play a role in determining the higher dopaminergic activity that characterizes drug proned individuals.

Adrenalectomy↗
PubMed1998

Corticotropin-releasing factor administered centrally, but not peripherally, stimulates hippocampal acetylcholine release.

In addition to corticotropin-releasing factor's well-known role in mediating hormonal and behavioral responses to stress, this peptide also reportedly affects arousal and cognition, processes that classically have been associated with forebrain cholinergic systems. Corticotropin-releasing factor stimulation of cholinergic neurons might thus provide a mechanism for this peptide's cognitive effects. To examine this possibility, the present experiments characterize the effect of corticotropin-releasing factor on cholinergic neurotransmission, using in vivo microdialysis to measure hippocampal acetylcholine release. Corticotropin-releasing factor (0.5-5.0 microg/rat intracerebroventricularly) was found to increase dialysate concentrations of acetylcholine in a dose-dependent manner in comparison with a control injection, the ovine peptide having a greater effect than the same dose of the human/rat peptide. This effect was found to be centrally mediated, independent of the peripheral effects of an exogenous corticotropin-releasing factor injection; subcutaneous injections of the peptide increased plasma concentrations of corticosterone, the adrenal hormone ultimately secreted in the rat's stress response, to the same level as did the central injections, without affecting hippocampal acetylcholine release. These results demonstrate that corticotropin-releasing factor, acting centrally, regulates hippocampal cholinergic activity, and suggest that corticotropin-releasing factor/acetylcholine interactions may underlie some of the previously identified roles of these neurotransmitters in arousal, cognition, and stress.

Acetylcholine↗
PubMed1998

The neurosteroid pregnenolone sulfate increases cortical acetylcholine release: a microdialysis study in freely moving rats.

The effects of pregnenolone sulfate (Preg-S) administrations (0, 12, 48, 96, and 192 nmol intracerebroventricularly) on acetylcholine (ACh) release in the frontal cortex and dorsal striatum were investigated by on-line microdialysis in freely moving rats. Following Preg-S administration, extracellular ACh levels in the frontal cortex increased in a dose-dependent manner, whereas no change was observed in the striatum. The highest doses (96 and 192 nmol) induced a threefold increase above control values of ACh release, the intermediate dose of 48 nmol led to a twofold increase, whereas after the dose of 12 nmol, the levels of ACh were not different from those observed after vehicle injection. The increase in cortical ACh reached a maximum 30 min after administration for all the active doses. Taken together, these results suggest that Preg-S interacts with the cortical cholinergic system, which may account, at least in part, for the promnesic and/or antiamnesic properties of this neurosteroid.

Acetylcholine↗
PubMed1997

Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.

Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22-24 month-old) male Sprague-Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a gamma-aminobutyric acid antagonist and a positive allosteric modulator at the N-methyl-D-aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and/or treatment of age-related memory disorders.

Aging↗
PubMed1997

Drug abuse: hedonic homeostatic dysregulation.

Understanding the neurobiological mechanisms of addiction requires an integration of basic neuroscience with social psychology, experimental psychology, and psychiatry. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug-taking. Sensitization and counteradaptation are hypothesized to contribute to this hedonic homeostatic dysregulation, and the neurobiological mechanisms involved, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems, are beginning to be characterized. This framework provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and to relapse in individuals with a history of addiction.

Adaptation, Physiological↗
PubMed1997

Prenatal stress induces a phase advance of circadian corticosterone rhythm in adult rats which is prevented by postnatal stress.

Prenatal and postnatal stressors can have different long-term neuroendocrine effects including modifications of stress-induced corticosterone secretion. However, very little is known about the possible long-term effects of prenatal or postnatal stress on the rhythmicity of basal corticosterone secretion in adult offspring. Corticosterone levels were thus determined at six different time points over 24 h in adult rats whose mothers had undergone restraint stress manipulations. The results demonstrate that prenatal stress induces a phase advance in the evening increase of corticosterone levels, and that this change is prevented by postnatal stress. It thus appears that the circadian system governing the HPA axis is modifiable by a prenatal stress, and remains susceptible to compensatory changes during the postnatal period.

Age Factors↗
PubMed1997

Inter-individual differences in the effects of acute stress on the sleep-wakefulness cycle in the rat.

It has been described that an acute immobilization stress (IS) modifies subsequent paradoxical sleep (PS). However, its effects are complex because some subjects remain unaffected. This discrepancy might result from constitutive inter-individual psychobiological differences. In order to test this hypothesis, an inter-individual analysis of sleep patterns and their modifications after 60 min IS has been performed. Even though global analysis showed a PS increase after IS, inter-individual analysis evidenced different PS reactivity; subjects which had the least PS during control recordings were those with the largest PS increase. Unlike global analysis, an inter-individual study evidenced different modifications of wakefulness and slow wave sleep according to individuals. Subjects presenting the highest amount of wakefulness in control conditions (the lowest amount of slow wave sleep) decreased their wakefulness amount, while subjects with the lowest amount of wakefulness increased it. Thus, individual characteristics of the sleep-wakefulness cycle should be considered while studying its modifications induced by different treatments.

Animals↗
PubMed1997

Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion.

It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.

Analysis of Variance↗
PubMed1997

Decrease in highly polysialylated neuronal cell adhesion molecules and in spatial learning during ageing are not correlated.

Age-dependent spatial memory impairments have been related to a decline in hippocampal plasticity. Highly polysialylated neuronal cell adhesion molecules (PSA-NCAM) show a strong expression during adulthood within regions associated with neuroplastic events. Furthermore, NCAM molecules have been proposed to mediate neuronal plasticity during learning and memory. The aim of the present study was to examine the effect of ageing on the expression of PSA-NCAM within the hippocampus. To investigate whether age-dependent changes in expression of PSA-NCAM were accentuated in aged rats with learning impairment, animals were in a first step assessed for their cognitive abilities using a Morris water maze. Seven-month-old and 24-month-old-rats were tested for their performance in the Morris water maze. The animals were sacrificed and brain sections were processed for PSA-NCAM immunohistochemistry. Ageing was accompanied by an overall decrease in PSA-NCAM-immunoreactivity (-IR) within the forebrain, presenting a important decrease of the number of PSA-NCAM-IR perikarya within the hippocampus. These results were confirmed by Western blot analysis. No difference in PSA-NCAM immunoreactivity was observed in aged rats with or without spatial learning impairment. It is concluded that although changes in PSA-NCAM accompanied the decrease in cognitive abilities, our data did not evidence a causal relationship between these two parameters.

Aging↗