PubMed Health⌕ Search

Biomedical subjects

M Le Moal

Publications and source records attributed to M Le Moal.

At least 19 recordsLinked to original sources
PubMed1992

Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion.

Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and 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, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. 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 point to a role for glucocorticoids in the susceptibility to drug abuse.

Adrenal Glands↗
PubMed1992

Corticotropin-releasing factor induces a place aversion independent of its neuroendocrine role.

The purpose of the present experiment was to test the hypothesis that corticotropin-releasing factor (CRF), a polypeptide of 41 amino acids, when administered either intracerebroventricularly (i.c.v.) or subcutaneously (s.c.), has aversive properties in the conditioned place-preference paradigm. Five doses of CRF (0, 0.005, 0.05, 0.5, 5 micrograms) were tested. i.c.v. CRF induced a specific dose-dependent reduction of the amount of time spent in the environment previously paired with the administration of CRF. Furthermore, this CRF-induced place aversion was prevented by pretreatment with alpha-helical-CRF(9-41), a specific CRF antagonist, administered i.c.v. In order to test whether the aversive effects induced by i.c.v. CRF could result from the stimulation of the HPA axis accompanying i.c.v. CRF injection, the reinforcing properties of s.c. CRF were studied using the same dose range. Only the higher s.c. dose was effective in producing a place aversion suggesting that the aversive effects of CRF could not be due solely to the stimulation of the pituitary-adrenocortical system, measured by plasmatic levels of adrenocorticotropic hormone (ACTH) and corticosterone, because the lower doses consistently activate the pituitary-adrenocortical system without producing any behavioral changes. Altogether, these data indicate that the non-neurosecretory CRF neurons may mediate the aversive state occurring during stress.

Animals↗
PubMed1992

Cognitive enhancing properties of beta-CCM infused into the nucleus basalis magnocellularis of the rat.

Peripheral administration of various benzodiazepine derivatives or beta-carbolines (inverse agonists at benzodiazepine receptors), has been shown to affect memory. In this study, the effect of local infusion of a beta-carboline-methyl beta carboline-3-carboxylate (beta-CCM) into the nucleus basalis magnocellularis (NBM) of rats was examined in a two-trial recognition task. The results show that beta-CMM (3 micrograms/0.5 microliter) enhances recognition performance when injected both before or immediately after the acquisition trial. These effects appear to be mediated by a benzodiazepine (BZD) receptor since they were blocked by pretreatment with Ro 15-1788, a BZD receptor antagonist. This study supports the involvement of the NBM in cognitive processes, and demonstrates that these processes can be influenced by alteration of GABAergic neurotransmission.

Animals↗
PubMed1992

A two-trial memory task with automated recording: study in young and aged rats.

A two-trial recognition task, based on place or object exploration in a Y-maze, was developed to study memory in adult and aged rats. This paradigm avoids the use of electric shocks or deprivation that may have non-specific influences on the responses, and the task does not require learning of a rule. A number of behavioral parameters in several animals could be recorded automatically. These behavioral parameters were found to be differently influenced both by the type of recognition (place vs. object) and by the inter-trial interval (recognition retention time). Impaired recognition was also detected in 18-months-old rats. This recognition task which combines simplicity, sensitivity and high specificity may thus be a useful adjunct to our current battery of memory tasks.

Aging↗
PubMed1992

Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers.

It is suggested that drug addiction is more likely to develop in individuals who are particularly sensitive to the reinforcing effects of drugs. Animal studies of intravenous drug self-administration (SA) have shown that rats display a large range of individual differences in the propensity to develop drug-seeking. Predisposed animals are characterized by a higher locomotor reactivity to both novelty and psychostimulants. In this report, we show that prenatal stress (restraint of the mother during the last week of pregnancy) may contribute to an individual's vulnerability to develop amphetamine self-administration. The adult offspring of stressed mothers exhibited: (i) a higher locomotor response to novelty and to an injection of amphetamine (0.3 mg/kg, i.v.); (ii) a higher level of amphetamine self-administration. The data indicate that individual predisposition to drug-seeking in the adult may be induced by prenatal events.

Amphetamine↗
PubMed1992

Repeated corticosterone administration sensitizes the locomotor response to amphetamine.

Repeated exposures to stressful situations has been shown to increase individual reactivity to psychostimulants, although the biological factors involved in such stress-induced changes are still poorly understood. In this study, we investigated the role of corticosterone in the effects of stress on the response to psychostimulants. We found that repeated corticosterone administration (both 1.5 mg/kg, intraperitoneally and 50 micrograms/ml in drinking water, once per day for 15 days) increased the locomotor response to amphetamine (1.15 mg/kg, i.p.). At the doses used in these experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those induced by stress. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress increases the behavioral responses to amphetamine. Since an enhanced reactivity to psychostimulants has been found to be an index of a propensity for drug self-administration and a model of certain psychopathological conditions, these findings point to a role for glucocorticoids in such abnormal states.

Amphetamine↗
PubMed1992

Early effects of unilateral lesions of substantia nigra on immune reactivity.

It has recently been demonstrated that central dopaminergic pathways are asymmetrically involved in the modulation of the immune response. Mitogen-induced proliferation of T lymphocytes was shown to be enhanced 4-6 weeks after right lesion of the substantia nigra (SN) in mice, when compared to left lesioned and control animals. In order to study the involvement of post lesion neuronal reorganization in these results, the same immunological parameters were determined as early as 2 weeks after right or left lesion of the SN. We showed that the lymphoproliferation induced by alpha CD3 and concanavalin A was decreased in both lesioned groups, but phytohemagglutinin-induced mitogenesis was more impaired in the right than in the left lesioned animals. Hence, the time course effects of the right lesions of SN shifted from depression to enhancement of the T lymphocyte responsiveness. This shift appeared to occur around the two weeks period following the lesion. These immunomodulatory effects of unilateral SN lesioning, which depended on time and side of lesion, were similar to those observed after hemidecortication. Based on these findings, it is reasonable to suggest that asymmetry in brain immunomodulation involves functionally related dopaminergic and cortical networks.

Animals↗
PubMed1992

Prolonged increase of corticosterone secretion by chronic social stress does not necessarily impair immune functions.

The influence of a chronic social stress upon immunity was investigated in Wistar rats, submitted for four weeks to two different behavioral situations, balanced in a factorial design: housing with three females and membership rotation. The combination of these two factor led to adrenal enlargement (43.3%), thymus involution (39.5%) and increased basal corticosterone levels, all indices of activation of the hypothalamic-hypophysis-adrenal axis. However, neither natural killer cell activity, splenocyte reactivity to mitogen nor the rate of spontaneous development of antibodies against Mycoplasma pulmonis, a common pathogen of the respiratory tract, were changed in the endocrine activated animals. Analysis of the data on kinetics of stress at 1, 7 and 28 days after the initial mixing of the animals gave the same results. These data question the immunosuppressant activity usually conferred to corticosteroids, at least when adrenal hyperactivity is induced by chronic environmental stressors.

Adrenal Glands↗
PubMed1992

Intrastriatal dopamine-rich implants reverse the changes in dopamine D2 receptor densities caused by 6-hydroxydopamine lesion of the nigrostriatal pathway in rats: an autoradiographic study.

The aim of the present study was to test whether intrastriatal implants of embryonic dopaminergic neurons are able to normalize the lesion-induced hypersensitivity of striatal dopaminergic receptors. The ascending dopaminergic pathway of adult rats was unilaterally lesioned using 6-hydroxydopamine. Three weeks later a cell suspension obtained from the mesencephali of ED 14 rat embryos was implanted into the denervated striatum. Rotational responses to dopaminergic agonists were tested five months after implantation. One month later animals were killed and striatal dopaminergic receptor densities were quantified using autoradiography, the dopaminergic reinnervation of the host striatum being visualized with [3H]GBR 12935, a ligand labelling dopamine uptake sites. The lesion induced a behavioural hypersensitivity to dopaminergic agonists and lesioned animals displayed a strong rotation contralateral to the lesion in response to a test dose of the D1 agonist compound SKF 38393 (2.5 mg/kg) or of the D2 agonist LY 171555 (0.15 mg/kg). These responses were completely abolished by the graft. The normal distribution of D1 and D2 dopaminergic receptors in the rat striatum was similar to that described previously. Seven months after the lesion of the nigrostriatal dopaminergic pathway, the density of D1 receptors was not significantly affected while the density of D2 receptors was increased by about 25-50%. The implantation of embryonic dopaminergic neurons into the denervated striatum led to a slight decrease of D1 receptor densities and to a reversal of the lesion-induced increase of striatal dopaminergic D2 receptors six months later. Moreover, this reversal concerned not only the reinnervated striatal region but also extended into non-reinnervated areas of the striatum. It is concluded that grafts of embryonic dopaminergic neurons can normalize the density of dopaminergic D2 receptors.

Animals↗
PubMed1991

Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration.

Individual vulnerability to the reinforcing effects of drugs appear to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with higher locomotor responses to novelty (High Responders, HR) tend to acquire amphetamine SA, while animals with the lower responses (Low Responders, LR) do not. In this study, we examined whether activity of dopaminergic (DA) and serotoninergic (5-HT) systems differed between HR and LR animals. These transmitter systems are thought to be involved in the reinforcing effects of psychostimulants. Animals from both groups were sacrificed under basal conditions and after exposure for 30 or 120 min to a novel environment, and the DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) contents were determined in the prefrontal cortex, nucleus accumbens and striatum. The HR rats displayed a specific neurochemical pattern: a higher DOPAC/DA ratio in the nucleus accumbens and striatum and a lower one in the prefrontal cortex. Furthermore, HR animals had lower overall 5-HT and 5-HIAA levels, corresponding to the mean of these compounds for the three structures studied over the three environmental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Suppression of noradrenergic innervation compensates for behavioral deficits induced by lesion of dopaminergic terminals in the lateral septum.

Spontaneous alternation which is disrupted by lesion of septal dopaminergic (DA) afferents was chosen as a behavioral marker for the study of functional interactions between DA and noradrenergic (NA) innervation of the lateral septum. Three groups of rats were studied: a solvent group which received only vehicle injection, and two lesioned groups, one with DA lesion and the second with simultaneous DA + NA lesion of the septal innervation. DA lesion was produced by infusing 6-hydroxydopamine (6-OHDA) into the lateral septum after pretreatment with desmethylimipramine (DMI) injected intraperitoneally. The DA + NA lesion was produced by infusing 6-OHDA without DMI pretreatment. The lesion of DA innervation alone led to a disturbance of alternation behavior in a Y-maze, but performance was not affected by the combined DA + NA lesion. The group with septal DA lesion was then injected with 6-OHDA into the pedunculus cerebellaris superior (PCS) in order to destroy NA efferents from the locus coeruleus. The two other groups were sham-operated. After post-operative recovery, the rats were retested for spontaneous alternation. The rats with the PCS NA lesion subsequent to the DA septal lesion displayed normal alternation behavior. Their performance was not different from that of animals with both NA and DA lesions in the septum. Thus the NA lesion appears to prevent the alternation deficits induced by the DA septal lesion, and also abolishes the deficits induced by the prior DA lesions. These results may have therapeutic implications.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Anatomical and behavioral comparison of unilateral dopamine-rich grafts implanted into the striatum of neonatal and adult rats.

The anatomical and functional characteristics of dopamine neuron-rich grafts implanted into rat pups were compared with those of identical grafts implanted into adult hosts. The host nigrostriatal dopaminergic pathway was unilaterally destroyed by an intrahypothalamic injection of 6-hydroxydopamine. This was followed five days later by the implantation of a cellular suspension obtained from rat embryonic mesencephali. Identical operations were carried out on adult and infant (PD3) rats. The survival rate of implanted tyrosine hydroxylase-positive cells was lower in the neonates. On the other hand, in the neonate hosts, surviving immunoreactive cells migrated extensively throughout the host striatum coursing preferentially below the corpus callosum and towards the subependymal zone. The structural integrity of the host parenchyma was well maintained after the neonatal implantation, in contrast to that observed in the adults. Despite a difference in the cell survival rate, there was no major difference in reinnervation density between the two types of host. The functional capacities of the implants were evaluated by measuring the rotational responses of the animals to dopaminergic agonists. The implants compensated the lesion-induced contralateral rotational response to the mixed agonist apomorphine and the D1 agonist SCH-38393 in both neonates and adults. However, the response to the D2 agonist LY-171555 was not significantly attenuated by the implant. The ipsilateral rotational response to amphetamine observed in the lesioned animals was also compensated and even reversed by the graft. It is concluded that with respect to rotational behavior, similar functional benefits were observed following adult stage or neonatal implantation, despite differences in their anatomical development.

Amphetamine↗
PubMed1979

Peripheral auditory input to the midbrain limbic area and related structures.

The effect of peripherally applied auditory stimulation on unit activity in midbrain limbic and related regions was investigated in the freely behaving rat. Two pure tones (1 and 10 kHz) and a noise generated by the discharge of a solenoid were used as stimuli presented randomly with 1 min mean interval between presentations. Computer-aided analysis of unit activity indicated that (1) a high proportion of neurons in the limbic midbrain region give excitatory responses to the three stimuli; (2) a majority of the responses have short latencies, especially in the dorsal raphe nucleus; (3) frequency and physical properties of the stimuli seemed not crucial for eliciting responsiveness; (4) habituation to repeated presentation of stimuli was not characteristic of the excitatory responses in the limbic midbrain region. These results are discussed in the light of possible functions of this region.

Acoustic Stimulation↗