High frequency stimulation of the subthalamic nucleus increases the extracellular contents of striatal dopamine in normal and partially dopaminergic denervated rats.

The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Manipulations of the STN have been described to compensate for some imbalance in motor output of the basal ganglia in animal models of PD and have been proposed as a potential therapeutic target in humans. Indeed, high frequency stimulation (HFS) (130 Hz) of the STN has beneficial effects in severe parkinsonian patients but the precise mechanisms underlying these clinical results remain to be elucidated. To date, very little is known concerning the effect of HFS-STN on striatal dopaminergic transmission. Since it has been reported that dopaminergic medication may be reduced in PD patients under HFS-STN, our goal was to study the effect of HFS-STN on striatal dopamine (DA) transmission by using intracerebral microdialysis in normal and partially DA denervated rats. Our results show that HFS STN induces a significant increase of extracellular DA in the striatum of normal and partially DA lesioned rats while striatal extracellular levels of DOPAC were not affected. We conclude that HFS-STN acts directly and/or indirectly on striatal DA levels in control or partially DA lesioned rats.

Intrastriatal Dopamine-rich Implants Reverse the Increase of Dopamine D2 Receptor mRNA Levels Caused by Lesion of the Nigrostriatal Pathway: A Quantitative In Situ Hybridization Study.

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.

Increase of striatal methionin enkephalin content following lesion of the nigrostriatal dopaminergic pathway in adult rats and reversal following the implantation of embryonic dopaminergic neurons: a quantitative immunohistochemical analysis.

The aim of the present study was to test whether intrastriatal implants of embryonic dopaminergic neurons are able to normalize the lesion-induced dysfunction of striatal enkephalinergic neurons, one of the major output systems of the striatum. The ascending dopaminergic pathway of adult rats was unilaterally lesioned. Three weeks later a cell suspension obtained from the mesencephali of ED14 rat embryos was implanted into the denervated striatum and striatal methionin enkephalin immunostaining was quantified six months later by the use of an image analyser. Methionin enkephalin immunostaining was unevenly distributed in the striatum of control animals. Besides the classical patch/matrix pattern, a mediolateral gradient was also present and, moreover, immunostaining decreased towards caudal levels. Seven months after the lesion of the nigrostriatal dopaminergic pathway, methionin enkephalin immunostaining was found to be increased in the denervated striatum by about 50%. However, relative increases were more sustained in the areas where basal methionin enkephalin immunostaining were lowest, i.e. the lateral striatum and posterior striatal areas. This resulted in an attenuation of the global gradients seen in the normal striatum. Increased immunostaining was also found in the ipsilateral globus pallidus. The implantation, into the denervated striatum, of embryonic dopaminergic neurons led to a reversal of the lesion-induced increase of striatal and pallidal methionin enkephalin immunostaining six months later. Moreover, this reversal resulted in an overshoot, as the level of immunostaining in the graft-bearing striatum was found to be lower than the levels found in the normal striatum. It is concluded that grafts of embryonic dopaminergic neurons can normalize the function of one of the major output systems of the striatum and, through it, influence more distant targets of this structure. This suggests a physiological basis for the behavioral effects observed previously with such grafts.

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.

Cognitive executive dysfunction in patients with obstructive sleep apnea syndrome (OSAS) after CPAP treatment.

We have previously described impairments of cognitive executive functions in 17 patients with OSAS in comparison with 17 normal controls, as assessed by various frontal-lobe-related tests. In the present study, 10 of these OSAS patients treated with continuous positive airway pressure (CPAP) were reevaluated after 4-6 months of treatment. Neuropsychological tasks explored attention, short-term memory span, learning abilities, planning capacities, categorizing activities, and verbal fluency. Patients were found to have normalized most of their cognitive executive and learning disabilities, but all the short-term memory tests remained unchanged. These findings are discussed in light of the contribution of the frontal-lobe-related systems to short-term memory functions, and the eventual pathogenic role played by sleep fragmentation and nocturnal hypoxemia, which are related to the occurrence of apneic and hypopneic events. In conclusion, short-term memory impairment was persistent in OSAS patients despite CPAP treatment for 4-6 months.

Deficits of cognitive executive functions in patients with sleep apnea syndrome.

Impairment of cognitive executive functions previously has been suspected to occur in association with sleep apnea syndrome (SAS), as suggested by some neuropsychological studies. However, such functions have not been assessed directly. In the present study, 17 patients with SAS were evaluated with various focused frontal lobe-related tests in comparison with 17 normal controls. Such tasks explored attention, short-term memory spans, learning abilities, planning and programming capacities, categorizing activities and verbal fluency. Patients were found to have a significantly decreased ability to initiate new mental processes and to inhibit automatic ones, in conjunction with a tendency for preservative errors. They were also affected with deficits of verbal and visual learning abilities and had reduced memory spans. Such defects were further evaluated via logistic regression against two criteria of the severity of the disease: the number of apneas and hypopneas per hour of sleep and the level of nocturnal hypoxemia. Memory deficits were rather related to the former, whereas typical frontal lobe-related abnormalities seemed rather consistent with the latter. These findings are discussed in light of data from the literature concerning cognitive impairments described for patients with isolated daytime sleepiness versus hypoxemia, as illustrated in other pathological or physiological circumstances.

Time-course of changes in striatal levels of DA uptake sites, DA D2 receptor and preproenkephalin mRNAs after nigrostriatal dopaminergic denervation in the rat.

Changes in striatal dopamine uptake sites, D2 receptor and preproenkephalin (PPE) mRNA levels provoked by unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic (DA) pathway were studied by quantitative autoradiography and in situ hybridization (ISH) in rats sacrificed at different post-lesion delays. The disappearance of DA terminals as visualized with the labelling of dopamine uptake sites with [3H]GBR 12935 became significant 36 h after the lesion and was almost complete at a delay of 7 days. PPE mRNA amounts significantly increase (+24%) already at the shortest delay studied (9 h after the lesion) while the labelling of the uptake sites on DA terminals was not affected. The time course increase of PPE mRNA levels was progressive until 21 days post-lesion where it reached its maximum (+132%) and remained stable up to the latest delay studied (60 days). Conversely D2 mRNA contents remained unchanged up to 5 days post-surgery and then increased relatively quickly since at 7 days post-lesion their levels were near (+21%) the maximum observed which was reached at 21 days post-lesion (+32%). This study suggests a time-dependent differential sensitivity to the degree of DA denervation of both major components implicated in the striatopallidal output.

GDNF: existence of a second transcript in the brain.

The detection of the glial cell-line derived neurotrophic factor (GDNF) mRNA by RT-PCR in dissociated cell culture of rat embryonic or post-natal brain allowed the amplification of a doublet. The major band corresponded to the expected size and the minor one to a shorter product. We cloned and sequenced the latter product, and thus identified a mRNA potentially encoding for an isoform of the initially described precursor protein involved in GDNF synthesis.

Evidence for dopamine D2 receptor mRNA expression by striatal astrocytes in culture: in situ hybridization and polymerase chain reaction studies.

The expression of dopamine D2 receptor mRNA in cultured rat striatal and cerebellar astrocytes was examined by in situ hybridization (ISH) and polymerase chain reaction (PCR). Cells double-labelled for glial fibrillary acidic protein (GFAP) immuno-histochemistry and dopamine D2 receptor mRNA (ISH) provide evidence that striatal but not cerebellar astrocytes express the dopamine D2 gene in vitro. These results were confirmed by polymerase chain reaction studies. As judged by GFAP immunostaining and morphology of the cells, this gene is almost exclusively expressed by astrocytes type 1. The expression of dopamine D2 receptor mRNA by striatal astrocytes in vitro, as found in this study, brings thus evidences for the existence of dopamine D2 receptors in such glial cells. This had been previously suggested from ligand binding studies but the typical dopaminergic nature of the binding to striatal astrocytes was left questionable. Our results with molecular biological techniques thus suggest that striatal dopamine might modulate the functions of striatal astrocytes.

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.

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.

Immunohistochemical study of the catecholaminergic innervation of the spinal cord of the rat using specific antibodies against dopamine and noradrenaline.

We have assessed the relative contributions of dopaminergic and noradrenergic descending systems to the catecholaminergic innervation of the rat spinal cord. Fibres and terminals were labelled with their own neurotransmitter by using specific antibodies raised against dopamine (DA) and noradrenaline (NA) respectively. For this purpose, immunohistochemistry according to the peroxidase anti-peroxidase technique was performed in different experimental conditions. Two group of rats received intracisternal 6-hydroxy-dopamine (6-OHDA) injections either with or without benzatropine pretreatment. Animals of a third group were not pretreated at all. While 6-OHDA induced a complete disappearance of spinal NA-like immunoreactivity (NA-LI), except for scarce residual fibres in the thoracic intermedio-lateral cell column, DA-like immunoreactivity (DA-LI) was unaffected by the lesion. This strongly suggests that the antisera used specifically labelled NA-containing and DA-containing fibres respectively. Spinal DA-LI and NA-LI innervations differed markedly in their topographical distributions and in the morphology of the corresponding fibres. DA-LI innervation was restricted to laminae I, III and IV and to the intermediate zone, especially the autonomic areas. In the ventral horn, it was sparse and more visible after acidification of the fixation solution. NA-LI innervation was much more widely spread. In addition, the organization of NA-LI fibres suggests that the innervation of the whole dorsal horn comes from a group of fibres travelling, at least partially, in the superficial dorsal horn.

Evidence for the existence of L-dopa- and dopamine-immunoreactive nerve cell bodies in the caudal part of the dorsal motor nucleus of the vagus nerve.

The precise neurochemical nature of tyrosine hydroxylase-immunoreactive neurons lying in the caudal part of the dorsal motor nucleus of the vagus nerve of the rat has been identified by immunohistochemistry of the catecholamines themselves. This region corresponds precisely to the area where tyrosine hydroxylase has been previously shown to be colocalized with choline acetyltransferase. Adjacent serial cryostat sections from the medulla oblongata and from the cervical spinal cord were treated either for choline acetyltransferase immunohistochemistry, aromatic L-amino acid decarboxylase and tyrosine hydroxylase immunolabelling or for tyrosine hydroxylase, dopamine, noradrenaline and L-dihydroxyphenylalanine (DOPA) immunostaining. The procedure involved the peroxidase-antiperoxidase method and an intensified diaminobenzidine reaction with imidazole. While no noradrenaline-positive cells were detectable in the dorsal motor vagal nucleus, tyrosine hydroxylase-, dopamine- and DOPA-immunoreactive perikarya were seen in the medial half of this nucleus, caudally the obex level. These results led us to conclude that these tyrosine hydroxylase-positive cells were effectively of dopaminergic nature and therefore that dopamine is a neurotransmitter contained in some neurons of the dorsal motor vagal nucleus. In the light of previous data showing colocalization of tyrosine hydroxylase and choline acetyltransferase in neurons of this portion of the nucleus, colocalization of dopamine with acetylcholine appears most likely. This might shed some light on the physiological consequences of dopamine action at target parasympathetic organs, such as the gastrointestinal tract.

Brain noradrenergic systems modulate the ceco-colonic myoelectric activity in rats.

The role of the brain noradrenergic systems in the control of the ceco-colonic myoelectric activity was investigated in rats following lesions with intracerebroventricular (icv) or intracisternal (ic) injection of 6-hydroxydopamine (6-OHDA). Controls received the vehicle alone. The ceco-colonic myoelectric activity was recorded 3 weeks later in conscious rats chronically fitted with electrodes. After icv injection of 6-OHDA, lesions of rostral and caudal (spinal) noradrenergic systems were observed whereas only spinal noradrenergic systems were lesioned after ic injection. This differential pattern of lesions was followed by a differential pattern of ceco-colonic myoelectric activity. In fasted animals, a significant increase of the long spike burst (LSB) frequency (nb min-1) was observed after icv injection of 6-OHDA whereas no modification was observed after ic injection of the neurotoxic. After a 6-g pelleted rat diet, a significant increase of the LSB frequency was also observed in the icv lesioned group when compared to controls. No modification of the ceco-colonic noradrenergic innervation was observed, thus confirming the central selectivity of these lesions. Lesions of central noradrenergic systems modify the LSB frequency in rats; the rostral noradrenergic systems seem to play the major role.

Fedotozine, a kappa-opioid agonist, prevents spinal and supra-spinal Fos expression induced by a noxious visceral stimulus in the rat.

Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.

Involvement of hypothalamic noradrenergic systems in the modulation of intestinal motility in rats.

Selective lesions of the noradrenergic systems of the paraventricular nucleus (PVN) of the hypothalamus with 6-hydroxydopamine (6-OHDA) lengthen the periodicity of the migrating myoelectric complex (MMC), an index of intestinal motility, in rats. These lengthening effects resemble those obtained after lesions of the locus coeruleus (LC), thus suggesting that noradrenergic terminals from LC to the PVN are involved in this modulation.

Effects of long-term hypoxia on tyrosine hydroxylase protein content in catecholaminergic rat brainstem areas: a quantitative autoradiographic study.

The nucleus tractus solitarius (NTS), the ventrolateral medulla (VLM), the dorsal motor vagus nucleus (DMnX) and the locus coeruleus (LC) are catecholaminergic brainstem areas involved in ventilatory and cardiovascular responses to hypoxia and tyrosine hydroxylation is the rate limiting step of cathecholamine biosynthesis in the central nervous system. The aim of this study was to evaluate the effects of long-term hypoxia on tyrosine hydroxylase (TH) content in these different areas using a quantitative autoradiographic technique. Two experimental groups of rats were studied: Group I (9 males, 8 females) was submitted to normobaric hypoxia (10% O2-90% N2) for 21 days and compared to 12 (6 males, 6 females) normoxic control rats (Group II). Coronal tissue sections from fresh-frozen rat brains, obtained along the caudo-rostral axis, were incubated in the presence of a TH monoclonal antibody, and the reaction was revealed by a 35S-labelled secondary antibody. TH levels were quantified in the NTS, VLM, DMnX and LC by measuring optical density on autoradiographic films using an automatic image analyser system. Regional antigen quantification was assessed by computer-assisted image analysis. Chronic hypoxia led to body weight decrease until day 5, haematocrit increase (65 +/- 2% vs. 44 +/- 2%, P < 0.01) and right ventricle hypertrophy (35 +/- 0.5% vs. 23 +/- 0.1% of the weight of the two ventricles, P < 0.01). TH protein contents expressed as percentage of controls were as follows. In males, in the rostral part of the NTS 132 +/- 9% (P < 0.02), in the caudal part of the NTS, 117 +/- 5% (P < 0.04). In female rats, the TH quantity reached a value of 124 +/- 4% (P < 0.01) in the rostral part and 126 +/- 6% (P < 0.01) in the caudal part of the NTS. In females, TH content was significantly increased in the VLM, 124 +/- 6%, P = 0.01, whereas in males there was only a non-significant trend to increase, 122 +/- 11%. In females, there was a significant increase in the DMnX, 127 +/- 9%, P = 0.05, whereas in males there was only a trend to increase, 120 +/- 5%. This study shows that long-term hypoxia induces a persistent increase in TH protein content both in the caudal and rostral part of the NTS, which are known to receive respectively chemo- and barosensory inputs, and in other catecholaminergic areas involved in baroreflex activity. Our data clearly demonstrate the implication of neurochemical mechanisms in the central relationship between chemo- and baroreflex which are responsible for changes in systemic arterial pressure and oxygen partial pressure as required for maintaining an adequate oxygen supply to the tissues.

Time course of the changes in striatal acetylcholine levels induced by pergolide and haloperidol after lesion of the nigrostriatal dopaminergic pathways in the rat.

Lesion of the nigrostriatal dopaminergic pathway in the rat by 6-hydroxydopamine enhances the ability of pergolide to increase striatal acetylcholine levels and prevents the haloperidol-induced decrease in acetylcholine concentrations. This supersensitive response of striatal cholinergic cells is already maximal 6 days after lesion but tends to decrease thereafter. As the time course of the development of the supersensitivity of cholinergic cells differs from that of increased dopamine binding site density, the two are probably not causally related, the former reflecting rather a change occurring beyond the dopamine recognition site.

Cortical ablation fails to influence striatal dopamine target cell supersensitivity induced by nigrostriatal denervation in the rat.

The possible influence of the corticostriatal (glutamatergic) pathway on denervation-induced striatal dopamine target cell supersensitivity has been investigated in the rat by measuring the changes in striatal acetylcholine levels induced by the dopamine agonist pergolide and the basal dopamine D2-receptor density after combined 6-hydroxydopamine-induced lesion of the substantia nigra and cortical ablation. Lesion of the nigrostriatal dopaminergic pathway alone enhanced the ability of pergolide (0.06-1 mg/kg i.p.) to increase acetylcholine levels and increased the maximal density of [3H]spiperone binding sites in the striatum. Similar changes in these biochemical parameters were observed after combined cortical ablation and nigral lesion. Cortical ablation by itself slightly diminished acetylcholine levels and reduced by 30% [3H]spiperone binding site density in the striatum. These results indicate that the corticostriatal tract does not influence striatal dopamine target cell supersensitivity caused by dopaminergic denervation.

Intraspinal noradrenergic-rich implants reverse the increase of alpha 1 adrenoceptors densities caused by complete spinal cord transection or selective chemical denervation: a quantitative autoradiographic study.

This study examined, in the adult rat, whether the intraspinal transplantation of a cell suspension of embryonic day (ED)13 rat locus coeruleus primordia was able to normalize the lesion-induced increase of spinal alpha 1-adrenoceptors. Two experimental models of spinal denervation were studied. The first model consisted of a complete spinal cord transection (thoracic vertebrae level T8-T9) and 1 week later, the cell suspension was transplanted below the section; the second one was obtained by a selective chemical lesion of the noradrenergic (NA) system and one month later, the cell suspension was implanted at the same level as in transected rats. Five weeks after grafting, all animals were sacrificed and spinal cord tissue sections were processed for immunohistochemical detection of noradrenaline or for quantification of alpha 1-adrenoceptors binding sites densities using [3H]prazosin as a ligand. After 6-OHDA lesion, as well as caudally to the transection, a significant increase by 21% (P < 0.01) to 68% (P < 0.001) of alpha 1-adrenoceptors densities was detected. The implantation of embryonic NA neurons into the denervated spinal cord led to a reversal of the lesion-induced increase of spinal alpha 1-adrenoceptors, five weeks later. Moreover, this reversal seems to be more effective after mechanical than after chemical denervation.