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*

Adult ; Aged ; Antipsychotic Agents ; adverse effects ; Child ; China ; epidemiology ; Combined Modality Therapy ; Drugs, Chinese Herbal ; therapeutic use ; Dyskinesia, Drug-Induced ; drug therapy ; epidemiology ; Female ; Humans ; Male ; Middle Aged ; Phytotherapy ; Prevalence

OBJECTIVETo investigate the relationship between efficacy of Chaihu Taoren Decoction (CTD) and the polymorphism of valine-alanine missense mutation of 9th codan (Val9Ala, T1183C) of superoxide dismutase (SOD) in patients with tardive dyskinesia (TD).

METHODSSeverity of TD was assessed by abnormal involuntary movement scale (AIMS), and the psychologic symptoms were rated by the positive and negative symptoms scale (PANSS). The sample size consisted of 119 patients with TD assigned to the TD group, 129 patients of chronic schizophrenia with the general condition matched strictly with that of the enrolled TD patients assigned to the non-TD group, and 148 healthy persons assigned to the normal group. The gene distribution rate of Val9Ala gene was analyzed using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis, and the therapeutic effect of CTD on 36 patients with TD was observed after 12 weeks treatment.

RESULTSThere was no significant difference in genotype and allelic gene frequency of SOD Val9Ala among the TD, non-TD and normal groups (P > 0.05). Comparison of the AIMS score in TD patients with various Val9Ala genotypes showed that the difference of AIMS scores in patients with TT and CT genotype was not significant (P > 0.05), but CTD did show a better efficacy in TD patients with CT heterozygote than in those with TT homozygote (P < 0.05).

CONCLUSIONThe CTD could effectively relieve the symptoms of TD, its efficacy might be related with the genotype of SOD, and 9Ala is considered to be a protective factor for the susceptibility to TD.

Adolescent ; Adult ; Capsules ; Drugs, Chinese Herbal ; therapeutic use ; Dyskinesia, Drug-Induced ; drug therapy ; etiology ; genetics ; Female ; Humans ; Male ; Middle Aged ; Phytotherapy ; Polymorphism, Genetic ; genetics ; Superoxide Dismutase ; genetics ; Valine ; genetics ; Young Adult

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

PURPOSE: To evaluate the effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on levodopa-induced peakdose dyskinesia in patients with Parkinson's disease (PD). MATERIALS AND METHODS: A retrospective review was conducted on patients who underwent STN DBS for PD from May 2000 to July 2012. Only patients with levodopa-induced dyskinesia prior to surgery and more than 1 year of available follow-up data after DBS were included. The outcome measures included the dyskinesia subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV (items 32 to 34 of UPDRS part IV) and the levodopa equivalent daily dose (LEDD). The patients were divided into two groups based on preoperative to postoperative LEDD change at 12 months after the surgery: Group 1, LEDD decrease >15%; Group 2, all other patients. Group 2 was further divided by the location of DBS leads. RESULTS: Of the 100 patients enrolled, 67 were in Group 1, while those remaining were in Group 2. Twelve months after STN DBS, Groups 1 and 2 showed improvements of 61.90% and 57.14%, respectively, in the dyskinesia subscore. Group 1 was more likely to experience dyskinesia suppression; however, the association between the groups and dyskinesia suppression was not statistically significant (p=0.619). In Group 2, dyskinesia was significantly decreased by stimulation of the area above the STN in 18 patients compared to stimulation of the STN in 15 patients (p=0.048). CONCLUSION: Levodopa-induced dyskinesia is attenuated by STN DBS without reducing the levodopa dosage.
Aged ; Aged, 80 and over ; Antiparkinson Agents/administration & dosage/*adverse effects ; *Deep Brain Stimulation ; Dyskinesia, Drug-Induced/*therapy ; Female ; Humans ; Levodopa/administration & dosage/*adverse effects ; Male ; Middle Aged ; Outcome Assessment (Health Care) ; Parkinson Disease/*drug therapy ; Postoperative Period ; Retrospective Studies ; Subthalamic Nucleus ; Treatment Outcome

OBJECTIVETo further investigate whether the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD.

METHODSThe patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis.

RESULTSThe genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P<0.05) in the patients with TD, compared against those in patients without TD. There were no differences in the distributions of the allelic frequencies and genotypes of Taq I. A polymorphism in DRD2 gene, of Ser/Gly polymorphism in DRD3 gene, and of Ala-9Val polymorphism in MnSOD gene between the TD group and non-TD group (P>0.05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0.05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups.

CONCLUSIONThe excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD.

Aged ; Alleles ; Antipsychotic Agents ; adverse effects ; therapeutic use ; Dyskinesia, Drug-Induced ; etiology ; genetics ; Female ; Gene Frequency ; Genetic Variation ; Genotype ; Glycine ; genetics ; Haplotypes ; Humans ; Male ; Middle Aged ; Mutation ; Receptor, Serotonin, 5-HT2C ; Receptors, Dopamine D2 ; genetics ; Receptors, Dopamine D3 ; Receptors, Serotonin ; genetics ; Schizophrenia ; drug therapy ; Superoxide Dismutase ; genetics ; Valine ; genetics