OBJECTIVE: It was hypothesized that dopamine agonist administration and subthalamic nucleus (STN) lesion in the rat might have a synergistic effect on the neuronal activities of substantia nigra pars reticulata (SNpr) as observed in patients with Parkinson's disease. The effects of SKF38393 (a D1 receptor agonist) and Quinpirole (a D2 receptor agonist) were compared in parkinsonian rat models with 6- hydroxydopamine (6-OHDA) after STN lesion. METHODS: SKF38393 and Quinpirole were consecutively injected intrastriatally. SNpr was microrecorded to ascertain the activity of the basal ganglia output structure. The effect of SKF38393 or Quinpirole injection on the firing rate and firing patterns of SNpr was investigated in medial forebrain bundle (MFB) lesioned rats and in MFB+STN lesioned rats. RESULTS: The administration of SKF38393 decreased SNpr neuronal firing rates and the percentage of burst neurons in the MFB lesioned rats, but did not alter them in MFB+STN lesioned rats. The administration of Quinpirole significantly decreased the spontaneous firing rate in the MFB lesioned rats. However, after an additional STN lesion, it increased the percentage of burst neurons. CONCLUSION: This study demonstrated that dopamine agonists and STN lesion decreased the hyperactive firing rate and the percentage of burst neurons of SNpr neurons in 6-OHDA lesioned rats, respectively. Quinpirole with STN lesion increased a percentage of burst neurons. To clear the exact interactive mechanism of D1 and D2 agonist and the corresponding location, it should be followed a study using a nonselective dopamine agonist and D1, D2 selective antagonist.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine ; Animals ; Basal Ganglia ; Dopamine Agonists ; Dopamine* ; Fires ; Humans ; Hydroxydopamines ; Kainic Acid ; Medial Forebrain Bundle ; Models, Animal ; Neurons* ; Oxidopamine ; Parkinson Disease ; Quinpirole ; Rats* ; Substantia Nigra* ; Subthalamic Nucleus*

No abstract available
Dopamine*

L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD.
Animals ; Basal Ganglia ; Dopamine ; Dyskinesias* ; Extremities ; Forelimb ; Humans ; Levodopa ; Mice* ; Oxidopamine ; Parkinson Disease ; Phosphorylation ; Receptors, Dopamine D1 ; Serotonin*

The present study was to evaluate the protective effects of bromocriptine, which is known as D2 dopamine receptor agonist and used for the treatment of patients with Parkinson's disease (PD), on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro and in vivo. Lipid peroxidation product (malondialdehyde; MDA) produced by the administration of 6-OHDA was profoundly reduced following the treatment of bromocriptine in a dose-dependent manner in rabbit brain homogenate. Quinone formation by 6-OHDA autoxidation was also attenuated, and its effect was as potent as other antioxidants. Pretreatment of bromocriptine reduced the cytotoxicity of 6-OHDA on SH-SY5Y neuroblastoma cell lines dose-dependently. The loss of striatal dopamine and its metabolite, DOPAC (dihydroxyphenylacetic acid) as well as increase of MDA production caused by intrastriatal injection of 6-OHDA was significantly recovered following the treatment of bromocriptine. The present study clearly showed that bromocriptine had a protective action against 6-OHDA-induced neurotoxicity. These results suggest that bromocriptine has the antioxidant properties, which could be another advantage for delaying the progress of Parkinson's disease.
3,4-Dihydroxyphenylacetic Acid ; Antioxidants ; Brain ; Bromocriptine* ; Cell Line ; Dopamine ; Dopamine Agonists ; Humans ; Lipid Peroxidation* ; Neuroblastoma ; Oxidopamine ; Parkinson Disease

The globus pallidus occupies a critical position in the indirect pathway of the basal ganglia circuit, which regulates movement under both normal and pathological conditions. Previous studies have shown that the globus pallidus receives dopaminergic innervation from the axonal collaterals of nigrostriatal fibers. Both dopamine Dand Dlike receptors are expressed in the globus pallidus. The present study was aimed to investigate the direct in vivo electrophysiological effects of dopamine Dlike receptors in the globus pallidus of both normal and parkinsonian rats. Extracellular recordings of multi-barreled microelectrode were used in the present study. In normal rats, micro-pressure ejection of dopamine Dlike receptor agonist quinpirole induced different effects on the firing rate of globus pallidus neurons. In 24 out of the 61 pallidal neurons, quinpirole significantly increased the firing rate by (62.7 ± 11.2)%. In another 16 neurons, quinpirole decreased the spontaneous firing rate by (37.5 ± 2.9)%. Furthermore, co-application of dopamine Dlike receptor antagonist, sulpride, blocked quinpirole-induced modulation of the firing rate of pallidal neurons. On the 6-hydroxydopamine (6-OHDA) lesioned side of parkinsonian rats, quinpirole increased the firing rate in 25 out of the 47 pallidal neurons by (64.2 ± 10.1)%, while decreased the firing rate in 11 neurons by (51.9 ± 6.2)%. Our findings suggest that activation of pallidal dopamine Dlike receptors may bidirectionally modulate the spontaneous firing of globus pallidus neurons in both normal and parkinsonian rats.
Animals ; Disease Models, Animal ; Dopamine ; Globus Pallidus ; metabolism ; Male ; Neurons ; Oxidopamine ; Parkinsonian Disorders ; metabolism ; Rats ; Receptors, Dopamine D1 ; metabolism ; Receptors, Dopamine D2 ; metabolism

Recently the reports of the autologous grafting of adrenal medullary tissue into the brain of parkinsonian patient have given the wide attention to the neurosurgeons as well as other clinicians, because the current therapeutic modalities are either imperfect or palliative. Although neural grafting of adrenal medullary tissue of fetal brain which can supply the dopamine seems to be a ideal form of treatment theoretically, many problems must be overcome for this approach to be a routine procedure. Authors made the rat parkinsonian model by destroying the substantia nigra and nigrostriatal fiber selectively with 6-OHDA. And abnormal behaviors and growth patterns were observed and studied using rotometry, T-maze and metabolic cage. With the results, some parameters which would be useful in further experiments could be established.
Animals ; Brain ; Dopamine ; Humans ; Oxidopamine ; Parkinson Disease ; Rats* ; Substantia Nigra ; Transplants

The frontal cortex of rat is innervated by dopaminergic pathway(mesocortical pathway) arising from ventral tegmental area. Several studies have suggested that mesocortical dopaminergic neurons may modulate the function of dopaminergic neurons at subcortical sites. The effect of lesions of the dopaminergic nerve terminals in the medial prefrontal cortex of the rat on dopamine D1 and D2 receptors within the striatum and olfactory tubercle has been investigated. Bilateral 6-hydroxy-dopamine lesions were stereotaxically placed in the medial prefrontal cortex. Animal were pretreated with desipramine to block the uptake of neurotoxin into noradrenergic terminals and to make it more selective for dopamine terminal. After 2weeks later, we examined the changes of D1 and D2 receptors in caudate-putamen and nucleus accumbens by quantitative autoradiography using the specific D1 antagonist [3H]SCH23390 and D2 antagonist [3H]spiperone. The results shows that D1 receptor at striatum was up regulated 2weeks after destruction of dopamine terminals within medial prefrontal vortex of the rat. This findings suggest that frontal cortical dopamine system may regulate the dopamine system in corpus striatum.
Animals ; Autoradiography ; Corpus Striatum ; Desipramine ; Dopamine* ; Dopaminergic Neurons ; Nucleus Accumbens ; Olfactory Pathways ; Oxidopamine* ; Prefrontal Cortex* ; Rats* ; Receptors, Dopamine* ; Ventral Tegmental Area

L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D₂ receptor (D₂R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D₂R⁺ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D₂R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D₂-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D₂R⁺ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D₂R⁺ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D₂R⁺ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D₂R⁺ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Rats ; Animals ; Levodopa/toxicity* ; Dopamine ; Parkinsonian Disorders/drug therapy* ; Oxidopamine ; Dyskinesia, Drug-Induced ; Corpus Striatum/metabolism* ; Neurons/metabolism* ; Receptors, Dopamine D2/metabolism* ; Antiparkinson Agents/toxicity*

There are several methods with which 6-hydroxy-dopamine is injected into the nigrostriatal pathway in rats for making models of Parkinson's disease. One is a complete lesion model in which A9 and A10 dopamine cells are destroyed, and the other one is a partial lesion model in which only A9 dopamine cells are destroyed. The aim of this study is to establish the model most suitable for transplantation of neural tissue. First, the behavioral change was investigated after dopamine releasing(amphetamine) or dopamine agonist(apomorphine) substances were injected. And then, immunohistochemical staining for tyrosine hydroxylase(TH) of the striatum and the substantia nigra was performed. Sixteen complete lesion models of Brundin, 4 complete lesion models of Perese, and 5 partial lesion models of Perese were made. The rotation response to amphetamine injection(5mg/kg, intraperitoneally) was checked 2 weeks after lesion making. For 6 rats, which showed rotation more than 7 turns/minute with amphetamine, the rotation response to subcutaneous injection of apomorphine was examined. Five complete lesion model of Brundin, 1 partial lesion model of Perese and 4 complete lesion model of Perese demonstrated rotation above 7 turns/minute in amphetamine test. Immunohistochemical staining of substantia nigra and corpus striatum for TH was faint on the lesioned side in rats which showed rotation above 7 turns/min in amphetaine-induced rotation test, irrespective of the kinds of model, while those ares of the normal side showed dense staining for TH. However, the results of immunohistochemical staining did not coincide with the results of rotation test by apomorphine.
Amphetamine ; Animals ; Apomorphine ; Corpus Striatum ; Dopamine ; Injections, Subcutaneous ; Models, Animal* ; Oxidopamine* ; Parkinson Disease* ; Rats* ; Substantia Nigra ; Tyrosine

OBJECTIVE: Recently, the serotonin-dopamine interaction is being regarded as a possible mechanism for both less extrapyramidal symptoms and good therapeutic effect on negative symptoms which are outstanding advantages of atypical antipsychotics. The goal of the study was to further define serotonin dopamine interaction in three different brain area of rats ; prefrontal cortex, striatum and nucleus accumbens. METHOD: The rats used in this study weighed 150-300gm. Under the aesthesia with pentothal sodium(25 mg/kg), stainless steel cannula was inserted in the right substantia nigra according to atlas(Paxinous and Watson) and 6-OHDA was injected at the rate of 1 mul/min to make a unilateral substantia nigra lesion. A week later, apomorphine (s. c. 0.1 mg/kg) was injected through the cannula and the rats with circling behavior counting more than 200 for an hour were selected for the study. Three weeks after that, the rats were further divided into 3 groups according to the brain area that permanent stainless steel cannula was implanted : prefrontal cortex group, striatum group and nucleus accumbens group. Within each group comparison was done between the number of circling behavior obtained by the injection of vehicle plus apomorphine and the one obtained by the injection of ritanserin plus apomorphine. Wilcoxon signed ranks test was used in data-analysis. RESULTS: The effect of ritanserin on the circling behavior in prefrontal cortex was absent but in striatum and nucleus accumbens, increasing effect was noted. CONCLUSIONS: It might be suggested that serotonin has an inhibitory control on dopaminergic function in striatum and nucleus accumbens.
Animals ; Antipsychotic Agents ; Apomorphine ; Brain ; Catheters ; Dopamine ; Nucleus Accumbens ; Oxidopamine ; Prefrontal Cortex ; Rats* ; Ritanserin* ; Serotonin ; Stainless Steel ; Substantia Nigra ; Thiopental