Parkinson’s disease (PD) is a debilitating movement disorder associated with the death of dopaminergic nigrostriatal neurons. In addition to dopamine deficiency, abnormalities in glutamate and other receptors at striatal synapses have been reported. Synapse associated protein 97 (SAP97) is involved in regulation of glutamate receptor function. In the striatum of unilaterally-lesioned 6-OHDA rat model of PD, SAP97 levels are decreased in post synaptic density fraction, as well as in the whole striatum. I hypothesize that changes in striatal levels and subcellular distribution of SAP97 are responsible for abnormal neurotransmission in striatum and the motor symptoms of PD. GFP-tagged wild type SAP97 and SAP97 mutants were over-expressed in the striatum of 6-OHDA-lesioned rat model of PD. A single 6.5 mg/kg dose of L-DOPA eliminated parkinsonism in 6-OHDA-lesioned rats over-expressing SAP97-GFP, whereas, three 6.5 mg/kg doses of L-DOPA negated parkinsonism in 6-OHDA-lesioned rats over-expressing SAP97-GFP and SAP97∆1-65-GFP. The over-expression of SAP97∆1-65-GFP enhanced parkinsonism in 6-OHDA-lesioned rats and blocked the antiparkinsonian effect of L-DOPA.

Parkinson’s disease (PD) is a debilitating movement disorder associated with the death of dopaminergic nigrostriatal neurons. In addition to dopamine deficiency, abnormalities in glutamate and other receptors at striatal synapses have been reported. Synapse associated protein 97 (SAP97) is involved in regulation of glutamate receptor function. In the striatum of unilaterally-lesioned 6-OHDA rat model of PD, SAP97 levels are decreased in post synaptic density fraction, as well as in the whole striatum. I hypothesize that changes in striatal levels and subcellular distribution of SAP97 are responsible for abnormal neurotransmission in striatum and the motor symptoms of PD. GFP-tagged wild type SAP97 and SAP97 mutants were over-expressed in the striatum of 6-OHDA-lesioned rat model of PD. A single 6.5 mg/kg dose of L-DOPA eliminated parkinsonism in 6-OHDA-lesioned rats over-expressing SAP97-GFP, whereas, three 6.5 mg/kg doses of L-DOPA negated parkinsonism in 6-OHDA-lesioned rats over-expressing SAP97-GFP and SAP97∆1-65-GFP. The over-expression of SAP97∆1-65-GFP enhanced parkinsonism in 6-OHDA-lesioned rats and blocked the antiparkinsonian effect of L-DOPA.

Sustained gastroesophageal reflux (GER) causes airway inflammation and can be considered as a potential trigger of asthma. There are complex neural innervations and reflex mechanisms between trachea and esophagus, and close proximity between them also provide a chance that trachea and esophagus could heavily interact with each other. The studies of the interactions between trachea and esophagus began early, but how gastric contents in the esophagus cause airway inflammation are still not completely understood. In this study, we will observe the extent of airway inflammatory response of the Long Evans rats induced by intraesophageal infusion of different inflammatory agents. We simulated the condition of inflammatory substances in the esophagus by intraesophageal infusion of either capsaicin or 6-hydroxydopamine (6-OHDA). At the different time point after infusion of inflammatory substances, rats were sacrificed for the analysis of the amount of the plasma leakage in the lower airways and esophagus. The amount of plasma leakage was expressed by the area density of India ink-labeled leaky blood vessels in tissue whole mounts. From the previous studies, we realize that neural reflexes played an important role in GER-induced airway inflammation. In this research, we further studied whether vagus nerves were involved in this neural reflex pathway by the pretreatment of bilateral vagotomy. Free radicals generated by the oxidation of 6-OHDA and capsaicin damage the airway epithelium, and lead to the liberation of cellular contents and cytokines that will augment the inflammatory response. Free radicals also activate NF-£eB pathway and will further enhance the inflammatory response. We evaluate the extent of these free radicals involved in GER-induced airway inflammation, by pretreatment with a hydroxyl radical scavenger -dimethylthiourea (DMTU). Our results showed that plasma leakage in the airway increased time-dependently from 5 to 15 min after the infusion of 5 £gg/ml/kg of capsaicin. This response peaked at 15 min, and gradually diminished after 30 min of capsaicin application. Plasma leakage in the airways caused by the application of 10 mg/ml/kg of 6-OHDA also increased time-dependently and peaked at 30 min. We also demonstrated that the vagus nerve played an important role in GER-induced airway inflammation. Because bilateral vagotomy significantly alleviated the airway inflammatory response caused by the application of capsaicin. Free radicals also involved in this process, because pretreatment with (2.25 g/kg, i.v.) DMTU significantly lowered the amount of plasma leakage caused by capsaicin and 6-OHDA.

Vagal and spinal sensory afferent innervation are responsible for to regulation of neurogenic inflammation in the airways. Neurogenic inflammation is a complex process involving vasodilatation,plasma protein extravasation and edema,glandular secretion and immunoinflammatory cell chemotaxis and activation. Plasma extravasation is the result of the activation of sensory nerve endings and the subsequent prodution of neuropeptides, namely, tachykinins such as substance P, neurokinin A and neurokinin B. SP was more potent than NKA or NKB in increasing microvascular permeability, which indicate that tachykinin NK-1 receptors are mainly involved in neurogenic inflammation in the airways of rat. When 6-hydroxydopamine¡]6-OHDA¡^was infused into the tracheal lumen,it causes plasma extravasation in the tracheal mucosa mediated by sensory nerve axons. Local application of 6-OHDA to stellate ganglion, had no effect on neurogenic inflammation and SP-IR innervation in the airways.The present study was to investigate the effect of intravenous injection of 6-OHDA on plasma leakage in the airways.This study also used the NK-1 receptor antagonist L-732,138 to investigate if 6-OHDA-induced plasma leakage in the airways was related to NK-1 receptors. India ink was used as tracer dye to label the leaky microvessels to evaluate the magnitude of inflammation . We found that 6-OHDA in the doses of 25 mg/kg and 50 mg/kg caused an extensive increase in plasma extravasation in the trachea and bronchi. But the vehicle¡]1 ¢ML-ascorbic acid and 0.4 ¢MNaCl, pH 3.4¡^caused a slight plasma leakage. Intravenous administration of L-732,138 decrease 6-OHDA induced plasma leakage. But one week after vagal transection, 6-OHDA-induced plasma extravasation in the ipsilateral airways was not significatly reduced. It is suggested that intravenous 6-OHDA stimulated bronchopulmonary C-fibers and resulted in vagal C-fiber release of tachykinins that produced acute inflammation in the lower airways. Intravenous application of L-732,138 significantly reduced the 6-OHDA-induced plasma leakage, suggesting that NK-1 receptors in the venular endothelial cells mediate the inflammatory response in the layynx,trachea,bronchi.and esophagus of the rat .

Várias evidências têm caracterizado os efeitos benéficos do gangliosídeo GM1 no tratamento de lesões neurológicas. O GM1 também foi estudado para o tratamento de doenças neurodegenerativas, principalmente em relação ao seu papel na neuroplasticidade e neuroproteção. O objetivo deste estudo foi analisar os possíveis efeitos de GM1 em modelo de doença de Parkinson induzida pela injeção intraestriatal unilateral de 6-hidroxidopamina (6-OHDA) em ratos. O GM1 foi injetado em conjunto com 6-OHDA e sete dias após a cirurgia os cérebros foram coletados para análise. Os resultados bioquímicos mostraram que o tratamento com GM1 intraestrial atenua aspectos inflamatórios e reduz os indicadores de morte neuronal, tal como evidenciado pela manutenção dos níveis de GFAP, OX-42 e caspase-3 em níveis de controle. A melhoria no tratamento por GM1 foi também demonstrada com a preservação de um fator neurotrófico derivado do encéfalo (BDNF) e os níveis de tirosina hidroxilase após 6-OHDA. A análise comportamental corrobora os achados bioquímicos, demonstrando que o GM1 possui a capacidade de preservação dos movimentos, visto pelo teste de cilindro. Sugerimos que o GM1 exerce neuroproteção no modelo de 6-OHDA, quando administrado por uma via local. Isto poderia representar um meio viável para transpor as barreiras farmacocinéticos que afetam a entrega de uma concentração apropriada da droga para áreas do cérebro / Several evidences have characterized the beneficial effects of ganglioside GM1 in the treatment of neurological lesions. GM1 has also been studied for the treatment of neurodegenerative diseases, mainly in relation to its role in neuroplasticity and neuroprotection. The objective of this study was to analyze the possible effects of GM1 on a model of Parkinson\'s disease induced by unilateral intra-striatal injection of 6-hydroxydopamine (6-OHDA) in rats. The GM1 was injected together with 6-OHDA and seven days after surgery the brains were collected for analysis. Biochemical results showed that treatment with intra-striatal GM1 attenuates inflammatory aspects and reduces the indicators of neuronal death, as evidenced by maintaining levels of GFAP, OX-42 and caspase-3 at control levels. Improvement after GM1 treatment was also demonstrated by the preservation of a brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase levels after 6-OHDA. The behavioral analysis corroborates the biochemical findings, demonstrating that GM1 has the ability to preserve movements, as seen by the cylinder test. We suggest that GM1 exerts neuroprotection in the 6-OHDA model when administered by a local route. This could represent a viable means of overcoming the pharmacokinetic barriers affecting the delivery of an appropriate concentration of the drug to areas of the brain

A doença de Parkinson (DP) é considerada a segunda doença neurodegenerativa mais comum em idosos e é caracterizada pela presença de disfunções motoras decorrentes da redução de neurônios dopaminérgicos na substância negra pars compacta (SNpc). Uma das principais neurotoxinas utilizadas para o estudo de DP em modelos animais é a 6-hidroxidopamina (6-OHDA), que possui como mecanismo de neurotoxicidade a formação de espécies reativas de oxigênio (EROs). A liberação de EROs pela NADPH oxidase (Nox) e a ativação microglial constituem os eventos iniciais da neurodegeneração induzida pela 6-OHDA. A Nox2 está relacionada com a modulação dos fenótipos microgliais e encontra-se superativada na DP, levando a um desequilíbrio redox e a danos celulares. A microglia é o principal componente da defesa imune no sistema nervoso central (SNC) e é dependente do receptor fator 1 estimulador de colônias (CSF1R) para a sobrevivência. O inibidor de CSF1R é utilizado como método para depletar microglia em modelos de neurodegeneração e, consequentemente, compreender o impacto da sua eliminação no processo da doença. Baseado nisso, foram propostas duas abordagens para compreender o papel da microglia na progressão da DP induzida pela 6-OHDA, sendo que o primeiro investigou a modulação da ativação microglial pela Nox2 em camundongos nocautes para a subunidade gp91phox, enquanto que o segundo avaliou o impacto da depleção por meio do tratamento com 1200mg/Kg de PLX5622, um tipo de inibidor de CSF1R. Os animais naïves gp91phox-/- apresentaram aumento da proliferação de microglias e da expressão da enzima iNOS. Quando submetidos à 6-OHDA, os nocautes não apresentaram declínio motor em função do tempo avaliado pelo teste do cilindro, devido à maior sobrevivência de neurônios dopaminérgicos na SN em relação aos selvagens (WT). Um dos possíveis fatores relacionados à perda expressiva de neurônios nos WT foi a indução precoce da enzima iNOS, sugerindo que a ativação de Nox2 conjuntamente com iNOS na microglia aumenta os níveis de EROs tornando os neurônios mais susceptíveis à morte celular. Também foram observadas modulações temporais distintas entre os grupos com relação à expressão de CD86 e Arginase-1, além dos nocautes apresentarem baixos níveis de lesões oxidativas no DNA mitocondrial quando comparado com os WT. Assim, a ativação da Nox2 e da iNOS parecem atuar em sinergia no processo neurodegenerativo causado pela 6-OHDA. Por outro lado, os resultados com PLX5622 mostraram que a depleção microglial acelera o comprometimento da coordenação motora e da bradicinesia avaliado pelo teste do poste, bem como reduz o número de neurônios dopaminérgicos na SNpc. Além disso, a redução de células postivas para GFAP, do marcador CD68 e da regulação de genes ligados a microglia foram observados. O gene MeCP2, que está relacionado à via nigroestriatal e que consiste em um importante modulador da expressão de TH, está pouco expresso no grupo submetido à depleção microglial e a 6-OHDA. Esses achados sugerem que a deficiência na comunicação entre microglias e astrócitos, bem como a redução do nível de transcritos do gene MeCP2 causados pela depleção microglial, podem contribuir para a aceleração do processo neurodegenerativo causado pela 6-OHDA. / Parkinson\'s disease (PD) is considered the second most common neurodegenerative disease in elderly people and is characterized by the presence of motor impairment, which is a consequence of dopaminergic neuron loss in the substantia nigra pars compacta (SN). A major neurotoxin used for PD study in animal models is 6-hydroxydopamine (6-OHDA), which exerts neurotoxic effects through the production of reactive oxygen species (ROS). ROS release by the enzyme NADPH oxidase (Nox) and microglial activation are early events of neurodegeneration induced by 6-OHDA. Nox2 is related to modulation of microglia phenotypes and is overactivated in PD, which can lead to redox imbalance and cellular damage. Microglial cells are the main components of immune defense in the central nervous system and are dependent upon Colony-stimulating factor 1 receptor (CSF1R) for survival. The CSF1R inhibitor is used with a tool to deplete microglia in models of neurodegenerative diseases and, consequently, to understand the impact of its elimination in the disease process. Based on that, we proposed two approaches to evaluate the microglial role in the PD progression induced by 6-OHDA, in which the first one investigated the modulation of microglial activation by Nox2 in gp91phox knockout mice, whereas the second one evaluated the impact of microglial depletion through a treatment with 1200 mg/Kg of PLX5622, one type of CSF1R inhibitor. The gp91phox-/- naïve mice showed an increase of microglia proliferation and in the iNOS expression. When the knockout mice were submitted to 6-OHDA, they did not have motor impairments as a function of toxin exposure as evaluated by cylinder test. This result is due to the increase number of dopaminergic neurons survival in SNpc compared to wild type (WT). One of the possible factors involved in neurons death in WT was the early iNOS induction, which indicates that Nox2 and iNOS simultaneous activation in microglial cells enhance ROS levels, leading to neurons more vulnerable to cell death. Moreover, the expression of CD86 and Arginase-1 have differences in temporal modulation between both groups, as well as knockout mice showed lower levels of oxidative damage in mitochondrial DNA when compared with WT. Thus, the activation of Nox2 and iNOS could act sinergically in the neurodegenerative process caused by 6-OHDA.On the other hand, results with PLX5622 indicated that the microglial depletion aggravates the impairment of bradykinesia and motor coordination evaluated by pole test, as well as the reduction of tyrosine hydroxylase (TH) positive neurons in the SNpc. Moreover, the decrease of GFAP positive cells, of CD68 marker and regulation of genes linked to microglia were observed. The MeCP2 gene, related to the nigrostriatal pathway and an important modulator of TH expression, is down-regulated in the group with microglial elimination and submitted to 6-OHDA. These findings suggest that the deficiency of crosstalk between astrocytes and microglia, as well as the reduced MeCP2 transcript levels may contribute to the acceleration of neurodegenerative process initiated by 6-OHDA.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A DoenÃa de Parkinson (DP) à uma desordem neurodegenerativa caracterizada pela perda de neurÃnios dopaminÃrgicos na substancia nigra (SN). Estudos epidemiolÃgicos sugerem uma associaÃÃo entre estresse, depressÃo e DP. Agentes antioxidantes tem sido relatados como capazes de mudar o curso da doenÃa, bloqueando a neurodegeneraÃÃo dopaminÃrgica. Com a finalidade de estudar os efeitos neuroprotetores da catequina, um flavonÃide encontrado na Camelia sinensis, o presente trabalho avaliou os efeitos deste composto no comportamento motor, memÃria, avaliaÃÃo imunohistoquÃmica e bioquÃmica em um modelo de DP induzido em ratos pela 6-OHDA. Em uma outra etapa do trabalho tambÃm avaliou-se os efeitos da associaÃÃo do estresse com a DP sobre estes mesmos parÃmetros, usando um modelo animal de estresse de imobilizaÃÃo subcrÃnico (11d/6hrs). Os animais (ratos Wistar machos, 200-250g) foram tratados com catequina (10 e 30 mg/kg i.p.) diariamente por 16 dias, iniciando-se na ocasiÃo da lesÃo estriatal pela 6-OHDA (21Âg/ 3ÂL). Os resultados obtidos demonstram que a 6-OHDA aumentou o nÃmero de rotaÃÃes contralaterais à lesÃo induzida por apomorfina e a catequina nas duas doses foi capaz de reverter esse dano motor. Houve uma recuperaÃÃo da atividade exploratÃria e memÃria de trabalho promovido pela catequina nas doses testadas. A 6-OHDA diminuiu a imunorreatividade para tirosina hidroxilase (TH) e transportador de dopamina (DAT) no corpo estriado e mesencÃfalo, alÃm de promover uma diminuiÃÃo nos nÃveis de GSH. A catequina nas duas doses em animais lesionados pela 6-OHDA foi capaz de recuperar a imunorreatividade para TH e DAT, alÃm de aumentar significativamente os nÃveis de GSH em relaÃÃo aos animais lesionados pela 6-OHDA. A 6-OHDA promoveu a morte neuronal demonstrada pela diminuiÃÃo nos nÃveis de catecolaminas, a catequina, por sua vez, foi capaz de reverter esses nÃveis. O estresse de imobilizaÃÃo subcrÃnico nÃo reverteu o nÃmero de rotaÃÃes contralaterais induzidas pela apomorfina, nem melhorou a memÃria de trabalho dos danos pela 6-OHDA, mas foi capaz de melhorar a atividade locomotora e a memÃria aversiva. O estresse subcrÃnico levou os animais a um estado depressivo no teste de nado forÃado, o que nÃo foi observado em animais que sofreram apenas a lesÃo estriatal. Houve uma diminuiÃÃo no ganho de peso nos animais submetidos ao estresse. AlÃm disso, houve uma aumento discreto da imunorreatividade para a TH e DAT em animais submetidos ao estresse e lesÃo pela 6-OHDA. Em relaÃÃo Ãs catecolaminas, houve uma reversÃo parcial nos nÃveis de noradrenalina e serotonina pelo efeito do estresse. Os resultados do presente trabalho demonstram que tanto a catequina, quanto estresse de imobilizaÃÃo foram neuroprotetores neste modelo experimental da DP. A catequina na dose de 30mg demonstrou um efeito prÃ-oxidante. O estresse de imobilizaÃÃo parece ter exercido um condicionamento fisiolÃgico nos animais, protegendo, de certa maneira, dos efeitos tÃxicos da 6-OHDA. / Parkinsonâs disease (PD) is a neurodegenerative disorder reported since antiquity and characterized for neuronal dopaminergic loss mainly in the substantia nigra (SN). Epidemiological studies suggest association between depression and PD and stress has been implicated in causing depression. The currently available therapies can not prevent the progression of PD, but are able to contain the symptoms. Neuroprotective agents have been reported as able to change the course of the disease, stopping dopaminergic neurodegeneration. Many of these agents are derived from plants with antioxidant actions, as catechin, a flavonoid found in green tea. In order to study the neuroprotective effects of catechin, the present study evaluated the effects of this compound on motor behavior, memory, Immunohistochemistry, biochemical evaluation and determination of catecholamines in an animal model of PD by 6-OHDA. Another stage of the study also evaluated the effects of stress associated with PD on the same parameters, in an animal model of subchronic restraint stress (11d/6hrs). Animals (male Wistar rats, 200-250g) were treated with catechin (10 and 30mg/kg ip) daily for 16 days, starting at the time of injury by striatal 6-OHDA. Results show that 6-OHDA increased the number of rotations contralateral to the lesion induced by apomorphine and catechin in the two doses was able to reverse the 6-OHDA damage. There was a recovery of exploratory activity and working memory promoted by catechin in both doses. Catechin in a dose of 30mg worsened the aversive memory. 6-OHDA decreased the immunoreactivity for tyrosine hydroxylase (TH) and dopamine transporter (DAT) in striatum and midbrain, and promote a decrease in GSH levels. Catechin in two doses in animals injured by 6-OHDA was able to increase the immunoreactivity for TH and DAT, significantly increasing the levels of GSH compared to lesioned animals by 6-OHDA. 6-OHDA caused neuronal death demonstrated by decreasing levels of catecholamines, catechin, in turn, was able to reverse these levels. The subchronic restraint stress did not reverse the number of contralateral rotations induced by apomorphine, neither improved the working memory of the damage by 6-OHDA, but was able to increase the number of crossings and improve the aversive memory. Stressed subchronic animals led to an increase in immobilization time in the forced swimming test, which was not observed in animals that were only striatal injury. There was a decrease in weight gain in animals subjected to stress. There was a slight increase of immunoreactivity for TH and DAT in animals subjected to stress and injury by 6-OHDA. In relation to catecholamines, there was a partial reversal in the levels of noradrenaline and serotonin by the effect of stress. Results of this study demonstrate that both catechin and immobilization stress were neuroprotective in this experimental model of PD. The catechin in a dose of 30mg was both oxidant and pro-oxidant. Restraint stress appears to have exerted a priming in animals, protecting, in a way, the toxic effects of 6-OHDA.

Methylphenidate (MPH) is the most commonly-prescribed medication for treating ADHD. Despite high prescription rates among kindergarten-aged children, MPH was not approved for use in children younger than nine, and research into its long-term consequences is lacking. Here, we examined the effects of early-life MPH exposure on anxiety-like behaviors in adulthood in normal rats and rats with dysfunctional central dopamine. On postnatal day (PD) 3, male and female rat pups were injected intracisternally with 6-OHDA or vehicle to generate normal and dopamine-deficient groups. In an initial pair of experiments, 6-OHDA (50, 100 and 150 µg/10µL infusion) was assessed for its ability to induce an ADHD-like phenotype. Subsequently, rats were lesioned with 6-OHDA (100 µg/infusion) or vehicle on PD3 and given MPH (0, 0.5, 2 or 5 mg/kg, i.p.) once daily for 10 days, starting on PD11. On PD60, anxiety-like behavior was assessed with light/dark box or social interaction tests. On PD65, all rats were tested on the elevated plus maze (EPM). Rats with neonatal 6-OHDA lesions exhibited anxiety-like behavior in the light/dark box test and on the EPM. However, there was a complex interaction between sex, lesion, and drug dose in the social interaction test. Pretreatment with 2 mg/kg MPH increased investigatory behaviors in non-lesioned females and decreased investigatory behaviors in lesioned females, suggesting that the long-term effects of early-life MPH in females depend on normal dopamine levels. Together, these experiments support the efficacy of preclinical ADHD models and diverse measures of anxiety-like behaviors when studying the effects of early-life MPH exposure.

The purpose of this study was to investigate whether locomotor training, in the form of treadmill training, could ameliorate neurochemical changes and behavioural deficits in the 6-hydroxydopamine (6-OHDA) rat model of Parkinsons disease. It has been recently demonstrated that rehabilitative forelimb motor training can attenuate dopamine loss and some deficits in forelimb movements in this animal model. In addition, brief locomotor treadmill training has been shown to attenuate forelimb deficits in 6-OHDA treated rats. However, it is not known whether locomotor training could result in an amelioration of locomotor deficits in these animals. Rats were lesioned with 6-OHDA injected intracerebrally. Lesioned rats were randomly assigned to one of 3 groups: early treadmill trained, late treadmill trained and untrained. Animals in the treadmill groups were trained to trot on a moving treadmill for 2 x 20 minute sessions daily for 30 days, beginning either 24 hours or 7 days after 6-OHDA injection. Untrained animals were exposed to a stationary treadmill for the same time periods. All animals were assessed on their abilities to perform several behavioural tasks designed to test locomotor and forelimb movement abilities prior to 6-OHDA injection and again at 3 and 6 weeks post-injection. These tests included measurement of ground reaction forces during overground locomotion, paw placements during a ladder crossing task, forelimb useage during exploratory behaviour and ability to initiate forelimb stepping movements. In addition, assessments of dopamine depletion in the striatum were carried out first in vivo, by measuring apomorphine-induced rotations at 2 weeks post 6-OHDA injection, and subsequently by post-mortem analysis of dopamine levels in the striatum using HPLC at the conclusion of the study. Treadmill training resulted in attenuation of dopamine depletion compared to non-treadmill trained animals, as measured by both apomorphine injection and HPLC. However, treadmill training produced no difference in behavioural deficits on a variety of tests compared to untrained animals. In some cases, early treadmill trained animals tended to display more severe behavioural deficits compared to untrained animals. Late treadmill training had a similar but smaller effect compared to early treadmill training. We conclude that treadmill training does not ameliorate locomotor deficits, in the 6-OHDA model of Parkinsons disease, even though this same training results in attenuation of dopamine loss in the striatum.

The purpose of this study was to investigate whether locomotor training, in the form of treadmill training, could ameliorate neurochemical changes and behavioural deficits in the 6-hydroxydopamine (6-OHDA) rat model of Parkinsons disease. It has been recently demonstrated that rehabilitative forelimb motor training can attenuate dopamine loss and some deficits in forelimb movements in this animal model. In addition, brief locomotor treadmill training has been shown to attenuate forelimb deficits in 6-OHDA treated rats. However, it is not known whether locomotor training could result in an amelioration of locomotor deficits in these animals. Rats were lesioned with 6-OHDA injected intracerebrally. Lesioned rats were randomly assigned to one of 3 groups: early treadmill trained, late treadmill trained and untrained. Animals in the treadmill groups were trained to trot on a moving treadmill for 2 x 20 minute sessions daily for 30 days, beginning either 24 hours or 7 days after 6-OHDA injection. Untrained animals were exposed to a stationary treadmill for the same time periods. All animals were assessed on their abilities to perform several behavioural tasks designed to test locomotor and forelimb movement abilities prior to 6-OHDA injection and again at 3 and 6 weeks post-injection. These tests included measurement of ground reaction forces during overground locomotion, paw placements during a ladder crossing task, forelimb useage during exploratory behaviour and ability to initiate forelimb stepping movements. In addition, assessments of dopamine depletion in the striatum were carried out first in vivo, by measuring apomorphine-induced rotations at 2 weeks post 6-OHDA injection, and subsequently by post-mortem analysis of dopamine levels in the striatum using HPLC at the conclusion of the study. Treadmill training resulted in attenuation of dopamine depletion compared to non-treadmill trained animals, as measured by both apomorphine injection and HPLC. However, treadmill training produced no difference in behavioural deficits on a variety of tests compared to untrained animals. In some cases, early treadmill trained animals tended to display more severe behavioural deficits compared to untrained animals. Late treadmill training had a similar but smaller effect compared to early treadmill training. We conclude that treadmill training does not ameliorate locomotor deficits, in the 6-OHDA model of Parkinsons disease, even though this same training results in attenuation of dopamine loss in the striatum.