Biomedical subjects

D N Abrous

Publications and source records attributed to D N Abrous.

At least 19 recordsLinked 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

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↗

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↗

PubMed1996

Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission.

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg/kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.

Adrenalectomy↗

PubMed1996

Administration of amphetamine does not increase the functional efficacy of dopaminergic grafts made in infancy.

Previous reports have evoked the possibility that a priming stimulation of grafted dopaminergic (DA) neurones by amphetamine enhances their efficacy in behavioural tests performed several days later. The present study was designed to test this hypothesis. Five days after the unilateral destruction of the DA mesotelencephalic system of 3-day-old rat pups, DA grafts were implanted into the denervated neostriatum of half of the lesioned pups. At adulthood, lesion and graft groups were subdivided into 4 subgroups which received one of the following treatments: saline or amphetamine injection in an environment where the behavioural test was subsequently conducted (paired environment) or in an unrelated environment (unpaired environment). Five days later, rotational response to a tail-pinch stress was tested in the paired environment. In these conditions, we found no evidence for a priming effect of amphetamine. Animals that received amphetamine or saline in the unpaired environment displayed the same rotational response to the tail-pinch stress. On the other hand, a conditioning influence of the environment was detected. Thus, the effect previously described might have been caused by a conditioning effect and/or might be due to differences in the experimental conditions. This suggests that 'priming' the graft with amphetamine does not provide a general strategy to enhance the functional efficacy of DA grafts.

Amphetamine↗

PubMed1996

Changes in striatal immediate early gene expression following neonatal dopaminergic lesion and effects of intrastriatal dopaminergic transplants.

To evaluate the functional integration of neonatal dopaminergic transplants within host brain we studied the postsynaptic effects induced by their stimulation by following the expression of immediate early genes c-fos, c-jun and egr-1. This study was conducted nine months after the intrastriatal implantation of embryonic mesencephalic neurons to rat pups having sustained a unilateral lesion of the nigrostriatal dopaminergic system. We examined whether, when challenged with d-amphetamine: (1) dopaminergic grafts transplanted into the previously denervated neonatal neostriatum lead to a normal activation of postsynaptic striatal neurons in term of immediate early genes activation; and (2) whether this activation is related to the action of the dopamine released from the grafts using a dopaminergic D1 antagonist. Following a mild stress-injection of saline-c-fos expression was high in the lesioned neostriatum when compared with control animals. This effect was only partially counteracted by a pre-treatment with the D1 antagonist SCH 23390, but was abolished by the graft. Administration of d-amphetamine increased c-fos expression in the neostriatum and the globus pallidus of the control group. This activation was partially blocked by the lesion. The transplant reversed the effect of the lesion and, moreover, led to a c-fos over-expression in the dorsolateral neostriatum and the globus pallidus. These overcompensations positively correlated with the abnormal rotation induced by d-amphetamine in the same animals. Pre-treatment with SCH 23390 blocked the effect of d-amphetamine on c-fos expression in control and grafted animals. Similar results were found for egr-1 but not c-jun expression. It is concluded that the neonatal lesion of the nigrostriatal dopaminergic pathway, in contrast to the adult-stage lesion, modifies the reactivity of c-fos in the neostriatum to stress, presumably in relation with compensatory reorganizations occurring following the neonatal lesion. Grafts made into neonates, when challenged with amphetamine, induce an abnormal c-fos expression which can predict the degree of overshoot observed for rotation activity. This over-expression, which depends upon the stimulation of D1 receptors, indicate an abnormal activation of postsynaptic target cells by the grafts.

Amino Acid Sequence↗

PubMed1996

Phenotype of striatal cells expressing c-Fos following amphetamine treatment of rats with intrastriatal dopaminergic grafts.

Activation of the nigrostriatal dopaminergic system by psychostimulants such as amphetamine increases c-Fos expression in the striatum, mostly in the striatonigral substance P-ergic pathway. This effect is greatly reduced in the neostriatum deprived of dopaminergic afferents. Dopaminergic grafts implanted into the denervated neostriatum restore the reactivity of the striatum to amphetamine. However, the number of striatal neurons expressing c-Fos is greatly increased in the graft-bearing striatum compared with the normal striatum. We examined whether this increase in the number of c-Fos-expressing neurons corresponds to the recruitment of a new neuron population, or whether it reflects an increase in the proportion of substance P-ergic neurons exhibiting activation of c-Fos. Adult rats received a unilateral 6-hydroxydopamine lesion of the ascending dopaminergic mesotelencephalic pathway, and a suspension of embryonic mesencephalic neurons was subsequently implanted into the denervated neostriatum. Three months after implantation, animals were injected with d-amphetamine (5 mg/kg) and killed 2 h later. In the first experiment, striatal sections were processed to visualize both c-Fos protein, by immunohistochemistry, and preproenkephalin A or substance P, by in situ hybridization. In the second experiment, c-Fos and neuropeptide Y were visualized on the same sections. In addition, some sections incubated with anti-c-Fos antibody were counterstained with toluidine blue in order to determine whether cholinergic neurons were expressing c-Fos following amphetamine treatment. The density of neurons expressing c-Fos following amphetamine treatment was three-fold higher in the graft-bearing striata than in the striata of control animals. Approximately 75% of the c-Fos expressing cells were substance P-ergic in control animals whereas 6% were enkephalinergic and only a few were neuropeptide Y-ergic or cholinergic. Similar proportions were found in the graft-bearing striatum, signifying that the pattern of activation of c-fos following amphetamine administration is not changed by the graft. Thus, the increased expression of c-Fos predominantly reflects a graft-induced increase in the proportion of neurons expressing c-Fos within the same population of neurons which normally expresses c-Fos in the striatum, i.e. the striatonigral substance P-ergic neurons; there is no recruitment of a new neuronal population. This increased activation of the striatonigral substance P-ergic pathway may underlie the abnormal behavioural reactions brought about by amphetamine-induced stimulation of the implanted dopaminergic neurons.

Amphetamine↗

PubMed1995

The neonatal lesion of the meso-telencephalic dopaminergic pathway increases intrastriatal D2 receptor levels and synthesis and this effect is reversed by neonatal dopaminergic rich-graft.

The ascending dopaminergic pathway of 3-day-old rats has been unilaterally destroyed by the injection of 6-hydroxydopamine into the lateral hypothalamus. Five days later, a suspension containing embryonic dopaminergic neurones was injected in the lesioned neostriatum. Rotational responses to dopaminergic agonists were tested eight months after grafting and animals were killed one month later. Neostriatal dopaminergic D1 and D2 receptors were examined using autoradiography while changes in D2 receptor mRNA levels were studied by in situ hybridization. The lesion induced a behavioural hypersensitivity - as manifested in contralateral rotations - to dopaminergic D1 (SKF 38393) or D2 (LY 171555) agonists which was abolished by the graft. Density of D1 receptors was not affected by the lesion while D2 receptors density was increased by 20-25% in the more rostral part of the neostriatum. Changes in D2 mRNA after the lesion paralleled those observed for D2 receptor density, i.e. D2 mRNA level was increased by 15-19% in the rostral neostriatum. The graft did not influence D1 receptor densities but reversed the post-lesion increase of D2 receptors associated parameters. It is concluded that dopaminergic grafts implanted in neonatal hosts are able to normalise the density of D2 receptors by an action on their synthesis.

Animals↗

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↗

PubMed1993

Intrastriatal transplants of embryonic dopaminergic neurons counteract the increase of striatal enkephalin immunostaining but not serotoninergic sprouting elicited by a neonatal lesion of the nigrostriatal dopaminergic pathway.

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.

Animals↗

PubMed1993

Conditioning versus priming of dopaminergic grafts by amphetamine.

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)

Amphetamine↗

PubMed1993

Transplantation of fetal nigral cells reverses the increase of preproenkephalin mRNA levels in the rat striatum caused by 6-OHDA lesion of the dopaminergic nigrostriatal pathway: a quantitative in situ hybridization study.

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine (DA) pathway causes a significant increase of preproenkephalin (PPE) messenger RNA (mRNA) levels in the DA-depleted striatum in rat brain. Using an in situ hybridization (ISH) technique and computer-assisted microdensitometry, we quantified the changes in PPE mRNA levels in the striatum. Seven months after lesion, levels of PPE mRNA were 75% higher in the DA-depleted striatum than in the contralateral control striatum of the same animal or in the striatum of sham control animals. The implantation of embryonic dopaminergic neurons into the denervated striatum led to a complete reversal of this increase and, in grafted animals, levels of PPE mRNA were at control values. Moreover, this reversal extended beyond the areas reinnervated by the grafted dopaminergic neurons.

Animals↗

PubMed1993

Dopaminergic grafts implanted into the neonatal or adult striatum: comparative effects on rotation and paw reaching deficits induced by subsequent unilateral nigrostriatal lesions in adulthood.

We have examined whether dopaminergic mesencephalic grafts implanted into neonates can provide more extensive protection against deficits induced by a subsequent unilateral lesion of the mesotelencephalic dopaminergic pathway than when the grafts are implanted in adulthood. A dopamine-rich neuronal cell suspension obtained from embryonic day 14 mesencephali was injected unilaterally into the neostriatum of otherwise intact neonatal or adult rats at one day or two months of age, respectively. Two months later, the ipsilateral mesotelencephalic dopaminergic pathway was destroyed by unilateral injection of 6-hydroxydopamine. The behavioural effects of the grafts were evaluated in tests of drug-induced rotation and skilled paw reaching. After completion of the behavioural testing, animals were killed and brains were processed for tyrosine hydroxylase immunohistochemistry. In rats receiving transplants as adults, grafts were compact and located in the neostriatum. In contrast, in rats receiving transplants neonatally, fewer dopaminergic neurons survived and they were dispersed over a large area of the host neostriatum and nucleus accumbens. After lesioning, all animals manifested strong rotation in response to amphetamine: this was not initially prevented by the grafts, made at either age, up to three months following the lesion, but was reduced in both groups of grafted rats by seven months after lesioning. This prolonged period for the development of recovery contrasts markedly with the rapid recovery obtained when similar grafts are implanted into the denervated neostriatum of adult rats that had received a prior 6-hydroxydopamine lesion. The development of apomorphine rotation, thought to reflect the development of receptor supersensitivity following lesions, was partially blocked to a similar extent by the grafts in both age groups. In contrast to their effects in the rotation tests, the dopaminergic grafts had no detectable effect on the profound contralateral deficit induced by the lesions in the paw-reaching test, whether implanted into neonatal or adult brains. Thus, whereas the age of the host at the time of implantation can markedly influence the gross morphological organization of dopaminergic grafts implanted into the neostriatum, the functional effects were similar, whether the grafts were implanted into neonatal or adult hosts.

Aging↗

PubMed1993

Effects of intracerebral dopaminergic grafts on behavioural deficits induced by neonatal 6-hydroxydopamine lesions of the mesotelencephalic dopaminergic pathway.

The functional capabilities of dopamine neuron-rich grafts implanted into the accumbens and striatal regions in neonatal rats were evaluated in a series of behavioural tests. The ascending mesotelencephalic dopaminergic system of three-day-old rat pups was bilaterally lesioned by injecting 6-hydroxydopamine at the level of the lateral hypothalamus. Five days later a suspension containing dopaminergic neurons obtained from embryonic day 14 mesencephali was injected bilaterally into the striatal complex. The functional effects of such grafts were evaluated using behavioural tests for which it was known that the performance of the animals is changed following the lesion of the mesotelencephalic pathway and for which the influence of dopaminergic grafts implanted into adult hosts have previously been described. The dopamine-rich grafts compensated for the modifications of the locomotor responsiveness to amphetamine and apomorphine induced by neonatal dopamine depletion. However, the grafts were unable to restore more complex behaviours such as hoarding for food pellets, schedule-induced polydipsia and learning behaviours. Moreover, the neonatal transplants induced additional deficits such as catalepsia, nocturnal hyperactivity and day-time hyperactivity during food deprivation. It was concluded that, at least in the present paradigm, the implantation into neonatal brain does not lead to any greater functional recovery than that observed after implantation during adulthood.

Animals↗

PubMed1993

Dopamine-rich grafts in the neostriatum and/or nucleus accumbens: effects on drug-induced behaviours and skilled paw-reaching.

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.

Amphetamine↗

PubMed1993

Mechanisms of amphetamine-induced rotation in rats with unilateral intrastriatal grafts of embryonic dopaminergic neurons: a pharmacological and biochemical analysis.

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)

Amphetamine↗

PubMed1992

Unilateral dopamine lesions in neonatal, weanling and adult rats: comparison of rotation and reaching deficits.

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.

Aging↗

PubMed1992

Intrastriatal dopamine-rich grafts induce a hyperexpression of Fos protein when challenged with amphetamine.

The aim of the present experiment was to characterize the effect of intrastriatal grafts of embryonic dopaminergic neurones on the expression of Fos protein in the striatum when challenged with amphetamine. Unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were made in adult rats and grafting was performed 3 weeks later. The numbers of Fos-positive nuclei in the ipsi- and contralateral striata were counted on coronal sections following immunohistochemical staining 5 months after grafting. Administration of d-amphetamine induced an increase in the density of Fos-positive nuclei in the intact striatum. This stimulatory effect of amphetamine on c-fos expression was blocked by 6-hydroxydopamine hydrobromide lesions and was restored in the striata bearing transplants. However, an overshoot was observed as the density of Fos-positive cells within the grafted striatum was larger than that observed within the intact striatum. This hyperexpression of Fos-positive nuclei was correlated with the exaggerated compensation of amphetamine-induced rotation in the same animals.

Animals↗