Single administration of GDNF into the striatum induced protection and repair of the nigrostriatal dopaminergic system in the intrastriatal 6-hydroxydopamine injection model of hemiparkinsonism

Purpose: Neurotrophic factor delivery into the brain is a promising approach in the treatment of Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors for dopaminergic neurons. Although multiple injections of GDNF into the brain are commonly performed in experimental studies, the present study investigates the efficacy of using a single injection of GDNF, which may be useful in elinically applying this treatment. Methods: Unilateral 6-hydroxydoparnine (6-OHDA) administration into the striatum was perforrned in Sprague-Dawley rats to create a partial lesion of the nigrostriatal DA system. These parkinsonian model rats received a single injection of human recombinant GDNF into the same portion of the striatum either 24 h before or 4 weeks after 6-OHDA treatrnent. Results: GDNF injected into the striatum before 6-OHDA administration potently protected the dopaminergic system, as shown by the numbers of mesencephalic dopaminergie neuron cell bodies and dopaminergic nerve terminal densities in the striatum. Dopaminergic neuron cell bodies and fiber densities were also significantly restored when GDNF was given after 6-OHDA administration, although the degree of restoration was lower than in the protective experiment. ODNF administration ameliorated apomorphine-induced rotational behavior in animals receiving it either before or after 6-OHDA treatment. However, the degree of improvement was less prominent when GDNF was iniected after 6-OHDA. Conclusion: Intracerebral GDNF adininistration exerts both protective and regenerative effects on the nigrostriatal dopaminergic system, a finding which may have implications for the development of new treatment strategies for Parkinson's disease.     

Retrograde degeneration of nigrostriatal neurons induced by intrastriatal 6-hydroxydopamine injection in rats.

Quantitative receptor autoradiography was used to assess the effects of unilateral intrastriatal injections of 6-hydroxydopamine (6-OHDA) on the distribution of D1 and D2 dopamine (DA) receptors and of DA uptake sites in the mesostriatal pathway. [3H]Mazindol-labeled DA uptake sites were reduced both in the striatum (-97%) and in the substantia nigra pars compacta (SNpc) (-88%) on the injected side. There were also significant decreases of dopamine uptake sites in the nucleus accumbens (NAc) (-73%) and in the ventral tegmental area (VTA) (-70%). Changes in [3H]mazindol binding were also found within the contralateral VTA (-30%) and SNpc (-13%) but not in the contralateral-striatum. [3H]SCH23390-labeled D1 receptors were significantly reduced in the dorsomedial (-18%) and ventromedial (-14%) aspects of the striatum ipsilateral to the side of the lesions. In contrast, the concentration of [3H]spiperone-labeled D2 receptors was not altered. There were also significant decreases in D1 (-18%) and of D2 (-27%) receptors in the SNpc and of D1 (-10%) in the SN pars reticulata (SNpr). These results suggest that oxyradical-induced damage in striatal DA terminals could lead to retrograde changes in the SNpc. In addition, the data indicate that unilateral striatal damage can result in bilateral changes in the SNpc, thus confirming the interdependence of the two nigrostriatal pathways in rats.     

Lack of permanent nigrostriatal dopamine deficit following 6-hydroxydopamine injection into the rat striatum

Summary The lesion caused by a single 6-hydroxydopamine injection into rat striatum was evaluated. In vivo positron emission tomography using a dopamine reuptake tracer revealed no consistent reduction in striatal dopamine transporter. Amphetamine rotation test was negative up to 18 weeks. A 21% reduction in striatal dopamine seen at 11 weeks was not detectable at 18 weeks. Tyrosine hydroxylase-positive neurone counts showed no decline in substantia nigra. Our results suggest that this lesion may be subject to compensation and therefore should be used with caution in studies on neuroprotective treatments of Parkinson' disease.     

Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system.

The neurotoxic specificity of injections of 6-hydroxydopamine (6-OHDA) into areas containing either dopamine (DA) cell bodies (substantia nigra) or DA axon terminals (striatum) was studied. This selective effect was compared to the unspecific effects of copper sulfate (CuSO4) injection and electrocoagulation. One to two days after unilateral nigral injection of 2 mug of either 6-OHDA or CuSO4 into the nigra the volume of the unspecific lesions around the tip of the cannula was very similar. Only the 6-OHDA-induced lesions were associated with elective degeneration of the nigral DA neurons. Ten days after the administration of the same compounds the gliosis in the substantia nigra was much more extensive in CuSO4-than in 6-OHDA-treated rats; however, the reduction of DA concentrations in the ipsilateral striatum was only noticeable after 6-OHDA (-62%). A somewhat similar decrease of striatal DA levels (-52%) was observed after large electrocoagulation of the substantia nigra. Ten days after 6-OHDA (8mug) or electrolytic lesion of the striatum the Km for DA, serotonin and choline uptakes were similar in the striata of both sides, suggesting that the uptake process in the non-damaged neurons of the lesioned side was functionally normal. Following electrolytic lesion of the striatum, serotonin and choline Vmax values were decreased to about the same extent as the striatal reduction in weight and DA levels. When directly administered into the striatum 6-OHDA also produced a decline in DA concentration and Vmax but in contrast did not affect serotonin and choline uptake (Vmax), suggesting that the drug specifically destroyed dopaminergic neurons. The present data confirm that selective DA denervation can be achieved when appropriate amounts of the drug are injected into brain tissue in order to limit the unspecific lesion.     

Long-term protection of the rat nigrostriatal dopaminergic system by glial cell line-derived neurotrophic factor against 6-hydroxydopamine in vivo

Glial cell-line-derived neurotrophic factor (GDNF) has been shown to enhance the survival of dopaminergic neurones both in vitro and in vivo , and to protect the rodent dopaminergic system from neurotoxic damage. However, most previous studies have only examined the short-term protective effects of GDNF. We have investigated the long-term effects of GDNF on a 6-hydroxydopamine (6-OHDA)-induced lesion of the rat medial forebrain bundle (MFB), which results in complete and irreversible destruction of the nigrostriatal pathway, and is a robust model of Parkinson's disease.
GDNF was administered ipsilaterally above the substantia nigra and into the lateral ventricle immediately before a unilateral 6-OHDA injection into the MFB. The effects of GDNF were examined in vivo by behavioural testing and positron emission tomography (PET) at weekly intervals, for 12 weeks. GDNF prevented the development of amphetamine-induced rotations at all time-points. PET studies, using [¹¹C]-RTI-121 as a tracer for the dopamine transporter, indicated that GDNF prevented 6-OHDA-induced reduction of dopamine reuptake sites in the ipsilateral striatum. Post-mortem neurochemical analysis at 13 weeks after surgery found that GDNF significantly inhibited 6-OHDA-induced loss of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the ipsilateral striatum. Immunocytochemistry showed that GDNF reduced 6-OHDA-induced loss of tyrosine hydroxylase-positive neurones in both the substantia nigra pars compacta and ventral tegmental area. We have shown that a single treatment with GDNF can confer long-term protective effects against a 6-OHDA lesion, which suggests that this factor may be useful for the treatment of Parkinson's disease.     

The intrastriatal 6-hydroxydopamine model of hemiparkinsonism: quantitative receptor autoradiographic evidence of correlation between circling behavior and presynaptic as well as postsynatic nigrostriatal markers in the rat

Unilateral injections of 6-hydroxydopamine into the striatum resulted in almost immediate ipsilateral amphetamine (AMPH)- and delayed contralateral apomorphine (APO)-induced circling behavior in rats. APO-induced rotation correlated positively with that caused by AMPH. In these animals, there was al almost complete disappearance of dopamine uptake sites as well as increases in DA D₂ receptors in specific subdivision of the ipsilateral caudate-putamen CPu). Both the rate of AMPH- and APO-induced rotation correlated with the percentage of DA terminal loss in the total aspect and in various quadrants of the striatum. In contrast, AMPH- and APO-induced rotation correlated with the percentage increase in striatal D₂ receptors only in the dorsolateral (DL) aspect of the CPu. These results indicate that both AMPH- and APO-induced rotation can be sued to determine the extent of DA terminal loss in the rat basal ganglia. The positive correlation of circling behavior to only changes in DA D₂ receptors observed in the DL striatal subdivision provides further evidence for the heterogeneity of the basal ganglia. This model of hemiparkinsonism in the rat which uses a distant intrastriatal approach to the destruction of nigral DA cell bodies may be a more appropriate model to study the regenerative properties of the nigrostriatal DA system. This approach could also be used to more specifically localize peptidergic receptors on midbrain dopamine cell bodies     

Single or continuous injection of glial cell line-derived neurotrophic factor in the striatum induces recovery of the nigrostriatal dopaminergic system

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor beta superfamily and acts as a neurotrophic factor for the nigrostriatal dopaminergic system. GDNF at a dose of 100 micrograms was injected stereotactically into the striatum of Sprague-Dawley rats that had been treated with intrastriatal 6-hydroxydopamine (6-OHDA) injection four weeks earlier. Immunocytochemical and behavioral analyses showed significant recovery of the nigrostriatal dopaminergic system after a single GDNF injection or continuous GDNF injection. Immunocytochemical and behavioral study showed that there was no significant difference between the results obtained from the two different injection methods. This result demonstrates the potential usefulness of GDNF for the treatment of Parkinson's disease.     

Single or continuous injection of glial cell line-derived neurotrophic factor in the striatum induces recovery of the nigrostriatal dopaminergic system

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor fi superfamily and acts as a neurotrophic factor for the nigrostriatal dopaminergic system. GDNF at a dose of 100 jig was injected stereotactically into the striatum of Sprague-Dawley rats that had been treated with intrastriatal 6-hydroxydopamine (6-OHDA) injection four weeks earlier. Immunocytochemical and behavioral analyses showed significant recovery of the nigrostriatal dopaminergic system after a single GDNF injection or continuous GDNF injection. Immunocytochemical and behavioral study showed that there was no significant difference between the results obtained from the two different injection methods. This result demonstrates the potential usefulness of GDNF for the treatment of Parkinson’s disease. [Neurol Res 2000; 22: 832-836]     

The intrastriatal 6-hydroxydopamine model of hemiparkinsonism: quantitative receptor autoradiographic evidence of correlation between circling behavior and presynaptic as well as postsynaptic nigrostriatal markers in the rat.

Unilateral injections of 6-hydroxydopamine into the striatum resulted in almost immediate ipsilateral amphetamine (AMPH)- and delayed contralateral apomorphine (APO)-induced circling behavior in rats. APO-induced rotation correlated positively with that caused by AMPH. In these animals, there was an almost complete disappearance of dopamine uptake sites as well as increases in DA D2 receptors in specific subdivisions of the ipsilateral caudate-putamen (CPu). Both the rate of AMPH- and APO-induced rotation correlated with the percentage of DA terminal loss in the total aspect and in various quadrants of the striatum. In contrast, AMPH- and APO-induced rotation correlated with the percentage increase in striatal D2 receptors only in the dorsolateral (DL) aspect of the CPu. These results indicate that both AMPH- and APO-induced rotation can be used to determine the extent of DA terminal loss in the rat basal ganglia. The positive correlation of circling behavior to only changes in DA D2 receptors observed in the DL striatal subdivision provides further evidence for the heterogeneity of the basal ganglia. This model of hemiparkinsonism in the rat which uses a distant intrastriatal approach to the destruction of nigral DA cell bodies may be a more appropriate model to study the regenerative properties of the nigrostriatal DA system. This approach could also be used to more specifically localize peptidergic receptors on midbrain dopamine cell bodies.     

Fibroblast growth factor-2-producing fibroblasts protect the nigrostriatal dopaminergic system from 6-hydroxydopamine

We tested the hypothesis that fibroblasts, which had been genetically engineered to produce fibroblast growth factor-2 (FGF-2), can protect nigrostriatal dopaminergic neurons. Three groups of rats received either a burr hole only (n=5) or implantation of fibroblasts, which had been genetically engineered to produce beta-galactosidase (beta-gal) (n=8) or FGF-2 (n=8), at two sites in the right striatum. Two weeks later, the animals received an injection of 25 microg of 6-hydroxydopamine hydrobromide (6-OHDA) midway between the two implant sites. The group that received FGF-2-fibroblasts had significantly fewer apomorphine-induced rotations than the groups that received a burr hole only or beta-gal-fibroblasts at weeks 2 and 3 following lesioning with 6-OHDA. Testing for amphetamine-induced rotation revealed a mild reduction in rotation in the beta-gal-fibroblast group compared to the burr hole only group, but a striking attenuation of amphetamine-induced rotation in the FGF-2-fibroblast group. There was also preservation of TH-IR neurons on the lesioned side relative to both control groups. The size of the grafts and the gliosis surrounding the injection sites did not differ between the FGF-2-fibroblast and beta-gal-fibroblast groups. To further characterize the production of FGF-2 by the FGF-2-fibroblasts, we implanted FGF-2-fibroblasts and beta-gal-fibroblast into the striatum of rats but did not lesion the animals with 6-OHDA. The animals were then sacrificed at 1, 2 and 5 weeks following implantation. Prior to implantation the FGF-2 fibroblasts contained 148 ng/mg of FGF-2-immunoreactive (FGF-2-IR) material per mg of protein of cell lysate. After implantation FGF-2-IR material was noted in the grafts of FGF-2-fibroblasts, most conspicuously at 1 and 2 weeks following implantation. We also noted FGF-2-IR material in the nuclei of reactive astrocytes adjacent to the implants, and OX-42-immunoreactive (OX-42-IR) cells adjacent and occasionally within the implants. Our work indicates that fibroblasts genetically engineered to produce FGF-2 and implanted in the striatum can protect the nigrostriatal dopaminergic system and may be useful in the treatment of Parkinson's disease.     

Curcumin protects nigrostriatal dopaminergic neurons and reduces glial activation in 6-hydroxydopamine hemiparkinsonian mice model

This study investigated the effects of curcumin on nigrostriatal dopaminergic (DA) neurons and glial response in 6-hydroxydopamine (6-OHDA) hemiparkinsonian mice. Following unilateral intrastriatal 6-OHDA injection, mice were daily injected with curcumin for seven days, beginning on the day of lesion. Seven days after 6-OHDA lesioning, sections from the striatum and the substantia nigra pars compacta (SNpc) were collected and immunohistochemically stained for DA neurons and reactive glia. Curcumin decreased 6-OHDA-induced loss of nigral tyrosine hydroxylase-immunoreactive (TH-IR) neurons and striatal TH-IR fibers. The neuroprotection was coincided with a significant attenuation of microglial and astroglial reaction in the SNpc and the striatum. These results suggest that the neuroprotective effects of curcumin in 6-OHDA-lesioned mice may be mediated through its anti-inflammatory properties or direct protection on nigral DA neurons, thereby reducing neuronal injury-induced glial activation.     

Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor

Here we studied whether glial cell line-derived neurotrophic factor (GDNF), given as a single bolus injection before an intrastriatal 6-hydroxydopamine (6-OHDA) lesion, can protect the nigrostriatal dopamine neurons against the toxin-induced damage and preserve normal motor functions in the lesioned animals. GDNF or vehicle was injected in the striatum (25 microg), substantia nigra (25 microg) or lateral ventricle (50 microg) 6 h before the 6-OHDA lesion (20 microg/3 microL). Motor function was evaluated by the stepping and drug-induced motor asymmetry tests. Lesioned animals given vehicle alone showed a clear ipsilateral-side bias in response to amphetamine (13 turns/min), a moderate contralateral-side bias to apomorphine (4.5 turns/min) and a moderate to severe stepping deficit on the contralateral forepaw (three to four steps, as compared with 11-13 steps on the unimpaired side). Injection of GDNF into the striatum had a significant protective effect both on nigrostriatal function (1-2 turns/min in the rotation tests and seven to eight steps in the stepping test), and the integrity of the nigrostriatal pathway, seen as a protection of both the cell bodies in the substantia nigra and the dopamine innervation in the striatum. Injection of GDNF in the nigra had a protective effect on the nigral cell bodies, but not the striatal innervation, and failed to provide any functional benefit. In contrast, intranigral GDNF had deleterious effects on both the striatal TH-positive fibre density and on drug-induced rotation tests. Intraventricular injection had no effect. We conclude that preservation of normal motor functions in the intrastriatal 6-OHDA lesion model requires protection of striatal terminal innervation, and that this can be achieved by intrastriatal, but not nigral or intraventricular, administration of GDNF.     

Experimental torticollis in the marmoset produced by injection of 6-hydroxydopamine into the ascending nigrostriatal pathway

Torticollis was observed in the marmoset following interruption of the ascending nigrostriatal dopaminergic pathway by injection of the specific catecholamine neurotoxin, 6-hydroxydopamine. It was possible to either accentuate or reverse the torticollis by manipulation of the relative dopamine activity of the two striata. The relationship between these findings and the etiology of torticollis in the primate is discussed.     

L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson's disease: relation to motor and cellular parameters of nigrostriatal function

In order to assess the role of striatal dopamine (DA) afferents in L-DOPA-induced dyskinesia, we have studied a large series of rats sustaining 2, 3, or 4 unilateral injections of 6-hydroxydopamine (6-OHDA) in the lateral striatum. This type of lesion produced a dose-dependent depletion of DA fibers in the caudate-putamen, which was most pronounced in the lateral aspects of this structure. An additional group of rats was injected with 6-OHDA in the medial forebrain bundle to obtain complete DA denervation on one side of the brain. During a course of chronic L-DOPA treatment, rats with intrastriatal 6-OHDA lesions developed abnormal involuntary movements (AIMs), which mapped onto striatal domains exhibiting at least approximately 90% denervation, as judged by DA transporter autoradiography. The denervated areas showed local upregulation of preproenkephalin and prodynorphin mRNA, and FosB-like immunoreactivity, which were highly correlated with the rats' AIM scores. When compared to completely DA-denervated animals, the rats with intrastriatal 6-OHDA lesions showed an overall lower incidence, lower severity and different topographic distribution of AIMs. The involvement of proximal limb and axial muscles in the abnormal movements was proportional to the spreading of the lesion from lateral towards medial aspects of the caudate-putamen. Locomotive AIMs were only seen in rats with complete lesions, but not in any of the animals with intrastriatal 6-OHDA (which showed > 5% DA fiber sparing in the medial striatum). Intrastriatally 6-OHDA-lesioned rats had a larger therapeutic window for L-DOPA than did rats with complete bundle lesions, since they exhibited an overall lower predisposition to dyskinesia but a similar degree of drug-induced motor improvement in a test of forelimb stepping. Our results are the first to demonstrate that selective and partial DA denervation in the sensorimotor part of the striatum can confer cellular and behavioral supersensitivity to L-DOPA, and that the phenomenology of L-DOPA-induced rat AIMs can be accounted for by the topography of DA denervation within the caudate-putamen.     

Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration

Animal models reproducing early stages of striatonigral degeneration (SND), the core pathology underlying parkinsonism in multiple system atrophy, are lacking. We have developed a new model of early-stage SND by using a simultaneous unilateral administration of quinolinic acid (QA) and 6-hydroxydopamine (6-OHDA) into the putaminal equivalent of the rat striatum. Spontaneous and drug-induced behavior, thigmotactic scanning, paw reaching deficits, and histopathology were studied in rat groups: group 1 (control), group 2 (QA), group 3 (6-OHDA), and group 4 (QA + 6-OHDA). The double toxin administration resulted in reduction of the spontaneous and the amphetamine-induced ipsiversive bias in the 6-OHDA group and in a reduction of the apomorphine-induced ipsiversive rotations in the QA group. Simultaneous QA and 6-OHDA also reduced the thigmotactic bias observed in the 6-OHDA rats. Combined toxin elicited a nonsignificant contralateral deficit in paw reaching but a significant deficit on the ipsilateral side. Histopathology revealed a significant reduction of the lesioned striatal surface (-27%) with neuronal loss and increased astrogliosis in group 4 compared to group 2, consistent with an exacerbation of QA toxicity by additional 6-OHDA. By contrast, the mean loss of the TH-positive neurons in the ipsilateral substantia nigra pars compacta (SNc) of group 4 was less marked (-15%) than in the 6-OHDA group (-36%), indicating a possible protective action of intrastriatal QA upon 6-OHDA retrograde SNc degeneration. This study shows that a combined unilateral intrastriatal administration of QA and 6-OHDA may serve as a model of early stage SND which is more suitable for early therapeutic interventions.     

Degeneration of the nigral dopamine neurons after 6-hydroxydopamine injection into the rat striatum

6-Hydroxydopamine (6-OHDA) was injected into the rat striatum unilaterally. After 2-4 weeks, a marked decrease in the number of tyrosine hydroxylase-immunoreactive neuronal perikarya and dendrites was observed in the substantia nigra (SN) ipsilateral to the injection. Nissl staining showed a severe cell loss in the same region and electron microscopy revealed neuronal perikarya under degenerating process in the SN. The results showed a retrograde cytotoxic effect of 6-OHDA from the striatal terminals to their dopaminergic neuronal perikarya in the SN, and suggest the possibility that the striatum may be a primary locus in the degeneration process in Parkinson's disease.     

Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: new clues from an old model

Despite the progressive development of innovative animal models for Parkinson's disease, the intracerebral infusion of neurotoxin 6-hydroxydopamine (6-OHDA) remains the most widely used means to induce an experimental lesion of the nigrostriatal pathway in the animal, due to its relatively low complexity and cost, coupled with the high reproducibility of the lesion obtained. To gain new information from such a classic model, we studied the time-course of the nigrostriatal damage, metabolic changes in the basal ganglia nuclei (cytochrome oxidase activity) and behavioural modifications (rotational response to apomorphine) following unilateral injection of 6-OHDA into the corpus striatum of rat, over a 4-week period. Striatal infusion of 6-OHDA caused early damage of dopaminergic terminals, followed by a slowly evolving loss of dopaminergic cell bodies in the substantia nigra pars compacta, which became apparent during the second week post-injection and peaked at the 28th day post-infusion; the rotational response to apomorphine was already present at the first time point considered (Day 1), and remained substantially stable throughout the 4-week period of observation. The evolution of the nigrostriatal lesion was accompanied by complex changes in the metabolic activity of the other basal ganglia nuclei investigated (substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus and subthalamic nucleus), which led, ultimately, to a generalized, metabolic hyperactivity, ipsilaterally to the lesion. However, peculiar patterns of metabolic activation, or inhibition, characterized the post-lesional responses of each nucleus, in the early and intermediate phases, with peculiar response profiles that varied closely related to the functional position occupied within the basal ganglia circuitry.     

EEG modifications in the cortex and striatum after dopaminergic priming in the 6-hydroxydopamine rat model of Parkinson's disease

In rats bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, a single administration of a dopamine receptor agonist (priming) sensitizes the behavioral motor responses to a dopaminergic agonist, administered 3 days after priming. In this study, changes in the electroencephalogram (EEG) frequency spectra were evaluated during priming in unilaterally 6-OHDA-lesioned rats, implanted bilaterally with electrodes both in the somatosensory cortex and striatum. Two weeks after 6-OHDA lesion, rats were primed with apomorphine (0.2 mg/kg) and received a challenge with the D(1) agonist SKF 38393 (3 mg/kg) 3 days later. 6-OHDA lesion modified the EEG pattern mainly in the beta(1) frequency band, in both cortex and striatum. Apomorphine priming produced a power decrease in the beta(1) frequency band, more pronounced in the cortex than in the striatum, as compared to saline-treated rats. Antagonism of NMDA receptor with MK-801, a treatment known to block the development of priming, increased apomorphine inhibitory effect mainly in the striatum, producing the same degree of inhibition in the two structures. Administration of SKF 38393, 3 days after priming, caused a power decrease in beta(1) frequency band of the cortex and striatum, which was more pronounced in apomorphine-primed as compared to drug-naive rats. The inhibitory effect of SKF 38393 was enhanced in rats primed with MK-801 plus apomorphine, particularly in the striatum. The results of this study suggest that long-term changes in the electrical activity of cortex and striatum after priming, might contribute to the development of the behavioral sensitization observed after priming. Development of priming might be related to the degree and cortical/striatal ratio of EEG power inhibition produced by dopamine agonists.     

Effects of anaesthetics on the loss of nigrostriatal dopaminergic neurons by 6-hydroxydopamine in rats

Summary. Various studies use ketamine/xylazine, fentanyl/medetomidine, etorphine/methotrimeprazine, and isoflurane anaesthesia for creating the 6-hydroxydopamine (6-OHDA)-lesion rat model of Parkinson’s disease. As these anaesthetics are known to modulate uptake and turnover of dopamine and that 6-OHDA-induced neurotoxicity is also dependents on uptake/turnover, we studied the effects of these anaesthetics on the extent of nigrostriatal dopaminergic damage caused by 6-OHDA. Infusion of 8 μg of 6-OHDA into the medial forebrain bundle significantly reduced the numbers of dopaminergic cells in nigra and striatal concentrations of dopamine in animals anaesthetized with fentanyl/medetomidine, etorphine/methotrimeprazine and isoflurane but not with ketamine/xylazine. In the latter group, however, increasing the dose of 6-OHDA to 10 and 12 μg resulted in a moderate (15 and 29%), but significant loss of dopaminergic cells. A severe loss of dopaminergic cells (59% and 81%) was seen with these doses in isoflurane-anaesthetized animals, but with only 8 μg in etorphine/methotrimeprazine-anaesthetized animals. Thus, these results suggest that the extent of nigrostriatal dopaminergic neuronal loss with 6-OHDA seems to be influenced by anaesthetic used during the surgery.