Publications du Neurocentre Magendie

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IF du Neurocentre

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Amphetamine induces a pronounced rotation directed ipsilateral to the lesion and lasting about 2 h in rats bearing a unilateral lesion of the nigrostriatal dopaminergic pathway. Implantation of embryonic dopaminergic neurons into the lesioned striatum leads to a compensation of this rotation. However, graft-bearing animals display a strong biphasic contralateral rotation, lasting up to 5 h. To try to ascertain the mechanisms of this anomalous rotation, two separate experiments were performed. First, we tested whether the contralateral rotation presented by the grafted animals could be correlated to the persistence of the lesion-induced decoupling of striatal D1 and D2 receptors. Lesioned and grafted animals were submitted to a series of four amphetamine (5 mg/kg, i.p.) rotation tests. Preceding each test animals received, in a randomized order, one of four of the following treatments: physiological saline, a D1 receptor blocker (SCH-23390, 0.1 mg/kg, s.c.), a D2 receptor blocker (raclopride, 2.5 mg/kg, i.p.) or the combination of the D1 and D2 antagonists. The ipsilateral rotation observed in the lesioned animals was abolished by the separate blockade of both classes of dopamine receptor as well as by their combined blockade. Grafted animals could be separated into two subgroups, based on the effect of the antagonists during the first 2 h of amphetamine-induced rotation. In one subgroup, antagonists had the same effect on the amphetamine-induced contralateral rotation as they did on the ipsilateral rotation displayed by lesioned animals. In this group, D1 and D2 receptors were therefore recoupled by the implant in the lesioned striatum. In the other subgroup, the contralateral rotation could be antagonized only by the combined D1 and D2 blockade, while the separate blockade of D1 or D2 receptors did not decrease or even increased the amphetamine-induced rotation. This indicates that in this group the lesion-induced decoupling of D1 and D2 receptors persisted. Nevertheless, the characteristics of the amphetamine-induced rotation (magnitude, duration) were the same in the two subgroups. Likewise, hypersensitivities of both D1 and D2 receptors were completely abolished by the graft in both subgroups. From this experiment it is concluded that the amphetamine-induced rotation observed in grafted animals is not correlated with the state of coupling of striatal D1 or D2 receptors. In a second experiment, dopamine release was monitored by microdialysis in the graft-bearing and the contralateral normal striatum of awake, behaving animals following the administration of amphetamine to test whether the observed rotation could be explained by a higher than normal dopamine release from the implanted dopaminergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

This study compares the behavioural efficiency of dopaminergic mesencephalic neurons implanted into the rat neostriatum and/or the nucleus accumbens. The dopaminergic mesotelencephalic pathway was unilaterally destroyed by injection of 6-hydroxydopamine into the medial forebrain bundle at the level of the lateral hypothalamus. Three weeks later, embryonic dopaminergic mesencephalic neurons were implanted into the denervated neostriatum, or the nucleus accumbens or into both locations (double grafts). All animals were tested over a four month period for amphetamine- and apomorphine-induced rotation, apomorphine-induced locomotor activity, and on a skilled paw reaching task. The characteristic ipsilateral rotation induced by amphetamine observed in lesioned animals was significantly reduced by neostriatal and double grafts, but persisted in animals with grafts in the nucleus accumbens alone. Four months after grafting, an overcompensation of rotation was observed for the neostriatal and double grafted animals, which now rotated contralaterally, i.e. away from the grafted side. The rotation induced by apomorphine in lesioned rats was decreased by neostriatal and double grafts and to a lesser extent by grafts implanted into the nucleus accumbens. Apomorphine-induced locomotor hyperactivity in lesioned animals was ameliorated by the nucleus accumbens and by double grafts. In the paw-reaching task, lesioned animals showed severe impairment in the use of the contralateral limb, which none of the grafts alleviated. Pretreatment with amphetamine had variable effects on the paw-reaching task which persisted in subsequent drug-free trials, suggesting that a conditioning mechanism may be involved. These findings suggest that the simultaneous reinnervation of the neostriatum and the nucleus accumbens by dopaminergic transplants is not sufficient to re-establish normal function in more complex behavioural tasks.

The aim of the our experiment was to compare the ability of intrastriatal implants of embryonic dopaminergic neurons to reverse two kinds of postlesion modification in the host brain: the change in the activity level of neurons in the denervated area and morphological modifications, e.g. collateral sprouting. The ascending dopaminergic system of 3-day-old rat pups was unilaterally lesioned by an intrahypothalamic injection of the neurotoxin 6-hydroxydopamine. This lesion has been described previously to induce an increase in the level of activity of striatal enkephalinergic neurons. The same lesion leads also to sprouting of the serotoninergic afferents in the striatum, leading to hyperinnervation of this structure. The existence of these modifications thus offers the possibility of testing the influence of grafts in one structure of the same animal on two lesion-induced reactions of different nature. A cell suspension obtained from mesencephali of embryonic day 14 rats and containing dopaminergic neurons was implanted into the denervated striatum of lesioned animals 5 days after the lesion. Nine months later the animals were killed and immunohistochemistry was performed on striatal sections using antibodies directed against tyrosine hydroxylase, methionine enkephalin and serotonin. Intensity of immunostaining (methionine enkephalin and serotonin) as well as innervation density (serotonin) was quantified through the use of a computer-assisted image analyser. The lesion led to the disappearance of striatal dopaminergic innervation. Implanted dopaminergic neurons were found scattered in the striatum and restored a dopaminergic innervation in a large portion of this structure. There was a marked increase in striatal methionine enkephalin immunostaining in lesioned animals, which was most pronounced in the dorsolateral part of the striatum (+ 150% compared to control values), while in the ventral part it was slight or non-existent. The density of striatal serotoninergic innervation was also increased by approximately 250% relative to control values. In grafted animals striatal enkephalin immunostaining was similar to that observed in control animals. On the other hand, the serotoninergic hyperinnervation was still present in the graft-bearing striata. These results suggest that while intrastriatal implants of embryonic dopaminergic neurons are able to counteract modifications in the functioning of local striatal neuronal systems such as the increase in enkephalinergic activity or receptor hypersensitivity occurring as a result of the lesion, they might be unable to reverse postlesion morphological modifications.

1993 | Exp Brain Res   IF 1.8
Conditioning versus priming of dopaminergic grafts by amphetamine.
Annett LE, Reading PJ, Tharumaratnam D, Abrous DN, Torres EM, Dunnett SB

Previous treatment with amphetamine can influence the rotational response induced by amphetamine in rats with dopaminergic grafts. In order to distinguish whether this is due to graft 'priming' or conditioning effects of the drug, groups of adult rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra, or with the lesion plus grafts of embryonic mesencephalic tissue in the striatum, were exposed to either: (1) amphetamine in the test environment and saline in the home cage; (2) saline in the test environment and amphetamine in the home cage; or (3) saline in the test environment and saline in the home cage. During this conditioning stage of the experiment, rats with the lesion alone rotated ipsilaterally and rats with the lesion plus grafts contralaterally when tested after administration of amphetamine. The rotation sensitized, i.e. the rats with lesions made more ipsilateral and the rats with grafts more contralateral turns, with repeated injections of the drug. On a subsequent no-drug test, only the rats with grafts which had previously experienced amphetamine in the test environment (1) showed conditioned contralateral rotation. Rats with grafts which had received the same number of amphetamine injections, but experienced the effects of the drug in the home cage (2), rotated ipsilaterally on the no-drug test to the same extent as rats with grafts which had received only saline (3). Thus, amphetamine treatment per se did not 'prime' grafts. Rather, the response of the rats with grafts was the result of formation of a conditioned association between the amphetamine and the environment with which it had been paired.(ABSTRACT TRUNCATED AT 250 WORDS)

11/12/1992 | Brain Res   IF 3.1
Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion.
Deroche V, Piazza PV, Casolini P, Maccari S, Le Moal M, Simon H

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.

31/10/1992 | Behav Brain Res   IF 3.2
Unilateral dopamine lesions in neonatal, weanling and adult rats: comparison of rotation and reaching deficits.
Abrous DN, Wareham AT, Torres EM, Dunnett SB

The aim of this study was to compare the functional effects of neonatal, weanling and adult lesions of the dopaminergic (DA) mesencephalic neurones on paw-reaching behaviour. The mesotelencephalic DA pathway was destroyed unilaterally in neonatal (3 and 7 day), weanling (21 day) and adult (2 months) rats by local injection of 6-hydroxydopamine into the medial forebrain bundle at the level of the lateral hypothalamus, followed by behavioural studies conducted 2 months later. Amphetamine and apomorphine induced similar rates of rotation irrespective of the age of the lesion. By contrast skilled reaching with the contralateral paw was profoundly disrupted by lesions made in adult or weanling rats, but a much reduced deficit was observed in neonatally lesioned rats. Tyrosine hydroxylase immunohistochemistry indicated a similar degree of dopamine cell loss from the substantia nigra in all groups. These observations suggest that the host brain undergoes developmental changes 1-3 weeks postnatally that influence the long-term effects of lesions in the nigrostriatal dopamine system.

1. Magnocellular neurosecretory cells (MNCs) were isolated from the supraoptic nucleus of adult Long-Evans rats using an enzymatic procedure. Immunocytochemical staining with antibodies against vasopressin and oxytocin revealed that MNCs can be identified by size. The membrane properties of these cells were examined at 32-34 degrees C using intracellular recording methods. 2. Isolated MNCs displayed a mean (+/- S.E.M.; n = 109) resting membrane potential of -64.1 +/- 1.0 mV, an input resistance of 571 +/- 34 M omega, and a time constant of 8.7 +/- 0.4 ms. Measurements of specific resistivity and input capacitance revealed that the soma of these cells accounts for a mere 20% of their total somato-dendritic membrane in situ. 3. Voltage-current relations measured near -60 mV were linear negative to spike threshold. From more hyperpolarized membrane potentials, voltage responses to depolarizing current steps displayed transient outward rectification and delayed impulse discharge. 4. Action potentials (76.6 +/- 0.9 mV) triggered from an apparent threshold of -59.3 +/- 0.1 mV broadened progressively at the onset of spontaneous or current-evoked spike trains. Steady-state spike duration increased as a logarithmic function of firing frequency with a maximum near 25 Hz. These effects were abolished in Ca(2+)-free solutions. 5. In all cells, evoked spike trains were followed by a prolonged Ca(2+)-sensitive after-hyperpolarization. In contrast, only a small proportion (16%) of MNCs displayed spontaneous bursting activity or depolarizing after-potentials following brief current-evoked bursts. 6. Isolated MNCs responded to amino acids (glutamate and GABA) and to the neuropeptide cholecystokinin, indicating that receptors for these neurotransmitters are expressed postsynaptically by MNCs and are retained following dissociation. 7. Increasing the osmolality of the superfusing solution by 5-30 mosmol kg-1 caused a membrane depolarization associated with a decrease of input resistance and accelerated spontaneous spike discharge in each of thirty-six MNCs tested. Current-clamp analysis suggested that these responses resulted from the activation of a cationic conductance. Excitatory effects of hyperosmolality were not observed in non-magnocellular neurones (n = 6).

17/07/1992 | Brain Res   IF 3.1
Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers.
Deminiere JM, Piazza PV, Guegan G, Abrous N, Maccari S, Le Moal M, Simon H

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.

03/07/1992 | Brain Res   IF 3.1
Repeated corticosterone administration sensitizes the locomotor response to amphetamine.
Deroche V, Piazza PV, Maccari S, Le Moal M, Simon H

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.

Changes in striatal dopamine D2 receptor mRNA levels provoked by unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway were studied by in situ hybridization. The influence of embryonic dopaminergic neurons implanted into the dopamine-depleted striatum on the lesion-induced changes was also examined. Changes in D2 mRNA levels were compared with changes in D2 receptor densities measured in the same animals by receptor autoradiography using [3H]spiperone or [3H]SDZ 205-501 as ligands. The distribution of D2 mRNA in the striatum of control animals closely paralleled that of the D2 receptor itself, as assessed by autoradiography, and the highest density of D2 mRNA occurred in the lateral part of the striatum. One month after lesion, levels of D2 mRNA were 34% higher in the dorsolateral part of the dopamine-depleted striatum than in the corresponding region of the contralateral control striatum. D2 receptor density in this region was increased by 40% relative to the control level. No significant increases could be measured in the medial part of the striatum. The increases in the lateral part were similar at 7 months post-lesion; however, at this time the increase in both D2 mRNA and receptor levels had spread to the medial part of the striatum as well. In the graft-bearing striatum levels of both D2 mRNA and D2 receptors reverted to control levels. This study shows that the post-lesion increase in striatal dopamine receptor and mRNA level is a biphasic phenomenon with a late-occurring component in the medial striatum. It also shows that once the increase in striatal D2 receptor gene expression is accomplished, it is maintained unchanged for long periods, similar to that of D2 receptor levels themselves. Moreover, grafts of embryonic dopaminergic neurons are able to modulate the expression of the dopamine D2 receptor gene.