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*

BACKGROUNDParkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD.

METHODSThe rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis.

RESULTSL-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test ( P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 ( P < 0.01) and 24:00 ( P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01).

CONCLUSIONSIn the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.

Animals ; Blotting, Western ; Body Weight ; drug effects ; Circadian Rhythm ; drug effects ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Levodopa ; therapeutic use ; Male ; Oxidopamine ; toxicity ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction

In order to observe neuronal toxical effect of Levodopa and investigate if using Levodopa together with Ginkgo Bilobar Extract (EGb) would be an workable method to treat Parkinson disease, rat models of Parkinson disease (PD) were made by injecting 6-OHDA stereotaxically to right side of the mesencephic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Rotational behavioral observation, TUNEL, immunocytochemistry, Nissl's body staining were performed to measure the difference between group treated by Levodopa (50 mg/kg every day for 3 days, 5 days, 7 days, L-dopa group) and group treated by Levodopa combined with EGb (100 mg/kg every day, E-D group). The results showed that in the L-dopa group, the numbers of apoptosis of substantial nigra, rings of rotational behavior were more than those in the E-D group (P < 0.05). The numbers of Nissl's cells in L-dopa group were fewer than in E-D group (P < 0.05). The results suggested that Levodopa had neur toxic effect and EGb may decrease the toxicity of levodopa. The combined use of EGb with Levodopa may be a workable method to treat PD and may be better than using Levodopa alone.
Animals ; Apoptosis ; drug effects ; Dihydroxyphenylalanine ; metabolism ; Drug Interactions ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Ginkgo biloba ; Levodopa ; pharmacology ; therapeutic use ; toxicity ; Male ; Neurons ; drug effects ; Oxidopamine ; Parkinson Disease ; metabolism ; pathology ; prevention & control ; Random Allocation ; Rats ; Rats, Wistar ; Substantia Nigra ; pathology

OBJECTIVETo study the effects of deltamethrin on tyrosine hydroxylase in nigrostriatum of male rats.

METHODSSprague-Dawley rats were daily treated with deltamethrin at 6.25 or 12.5 mg/kg body weight by gavage for 10 days. Then HPLC-fluorescence detection was used to analyze the contents of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homoranillic acid (HVA) in substantial nigra and striatum. The activities of tyrosine hydroxylase (TH) were also detected by HPLC-fluorescence detection. TH mRNA or TH protein levels were measured by RT-PCR and immunohistochemistry method.

RESULTSThe content of DA in striatum was significantly decreased by the treatments, suggesting an inhibition of DA synthesis by deltamethrin. The contents of DA metabolites DOPAC and HVA increased, indicating increased dopamine turnover. Furthermore, deltamethrin significantly decreased the activity, as well as the mRNA and protein levels of TH.

CONCLUSIONSThese findings reveal a novel aspect of deltamethrin neurotoxicity and suggest tyrosine hydroxylase as a molecular target of deltamethin on dopamine metabolism in the nigrostriatal pathway.

3,4-Dihydroxyphenylacetic Acid ; metabolism ; Animals ; Corpus Striatum ; drug effects ; metabolism ; Dopamine ; metabolism ; Gene Expression Regulation, Enzymologic ; Hominidae ; Insecticides ; toxicity ; Levodopa ; metabolism ; Male ; Nitriles ; toxicity ; Pyrethrins ; toxicity ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Substantia Nigra ; drug effects ; metabolism ; Tyrosine 3-Monooxygenase ; genetics ; metabolism

A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND.
Animals ; Apomorphine/pharmacology ; Behavior, Animal/drug effects ; Corpus Striatum/drug effects/pathology ; Disease Models, Animal ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Glucose/metabolism ; Injections, Intraperitoneal ; Levodopa/pharmacology ; Male ; Medial Forebrain Bundle/drug effects/pathology ; Oxidopamine/*toxicity ; Parkinson Disease/metabolism/pathology ; Positron-Emission Tomography ; Quinolinic Acid/*toxicity ; Rats ; Rats, Wistar ; Striatonigral Degeneration/*chemically induced/metabolism/pathology ; Touch/drug effects

To study behavioral character and changes of neuronal activity in the basal ganglia of rat model of levodopa-induced dyskinesia, unilateral 6-hydroxydopamine lesioned rat model of Parkinson disease (PD) was treated with levodopa/benserazide twice daily for 4 weeks and the behavior observed on the 1st, 3rd, 4th, 7th, 9th, 10th, 14th, 21st and 28th day. The animals were sacrificed and immunohistochemical technique was used to measure the changes of Fos expression in the caudate putamen (CPU), globus pallidus (GP) and sensorimotor area of cerebral cortex 2 h after the last treatment. The results showed that pulsatile treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movement (AIM), including stereotypy (limb dyskinesia, axial dystonia and masticatory dyskinesia) towards the side contralateral to the dopamine-denervated striatum and increased contraversive rotation. The motor pattern of each subtype was highly stereotypic across individual rats, and the proportion of each subtype was not consistent among individual rats. Fos positive nuclei in the CPU and GP were increased by levodopa acute administration, and more remarkably in the CPU, but not in the cerebral cortex. After repeated levodopa treatment. Fos positive nuclei were reduced remarkably in the CPU, but were increased in the GP and cerebral cortex. It was concluded that the neural mechanisms underlying levodopa induced AIM in rat model of PD was very similar to those seen in levodopa-induced dyskinesia (LID) in PD patients and MPTP-lesioned monkeys, and increased striatopallidal neuronal activity might be involved in occurrence of LID.
Animals ; Antiparkinson Agents ; toxicity ; Basal Ganglia ; metabolism ; Behavior, Animal ; drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Dyskinesia, Drug-Induced ; etiology ; psychology ; Levodopa ; toxicity ; Male ; Parkinson Disease ; drug therapy ; metabolism ; psychology ; Proto-Oncogene Proteins c-fos ; biosynthesis ; Random Allocation ; Rats ; Rats, Sprague-Dawley