ABSTRACT
BACKGROUND AND OBJECTIVES: All US Food and Drug Administration-approved medications for Tourette syndrome are antipsychotics, and their use is limited by the risk of weight gain, metabolic changes, and drug-induced movement disorders. Several small trials suggest that ecopipam, a first-in-class, selective dopamine 1 receptor antagonist, reduces tics with a low risk for these adverse events. This trial sought to further evaluate the efficacy, safety, and tolerability of ecopipam in children and adolescents with moderate to severe Tourette syndrome. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial. Subjects aged ≥6 to <18 years with a baseline Yale Global Tic Severity Score Total Tic Score of ≥20 were randomly assigned 1:1 to ecopipam (n = 76) or placebo (n = 77). The primary endpoint was mean change over 12 weeks in the Yale Global Tic Severity Score Total Tic Score. The Clinical Global Impression of Tourette Syndrome Severity was the secondary endpoint. Safety and tolerability were evaluated at each study visit. RESULTS: Total tic scores were significantly reduced from baseline to 12 weeks in the ecopipam group compared with placebo (least squares mean differences -3.44, 95% confidence interval -6.09 to -0.79, P = .01). Improvement in Clinical Global Impression of Tourette Syndrome Severity was also greater in the ecopipam group (P = .03). More weight gain was seen in subjects assigned to placebo. No metabolic or electrocardiogram changes were identified. Headache (15.8%), insomnia (14.5%), fatigue (7.9%), and somnolence (7.9%) were the most common adverse events. CONCLUSIONS: Among children and adolescents with TS, ecopipam reduces tics to a greater extent than placebo, without observable evidence of common antipsychotic-associated side effects.
Subject(s)
Antipsychotic Agents , Tics , Tourette Syndrome , Adolescent , Child , Humans , Tourette Syndrome/drug therapy , Tourette Syndrome/chemically induced , Tourette Syndrome/complications , Tics/chemically induced , Tics/complications , Tics/drug therapy , Treatment Outcome , Antipsychotic Agents/adverse effects , Double-Blind Method , Weight Gain , Severity of Illness IndexABSTRACT
BACKGROUND: Tourette syndrome is characterized by chronic motor and vocal tics. There is preliminary evidence of benefit from cannabis products containing Δ9-tetrahydrocannabinol (THC) and that coadministration of cannabidiol (CBD) improves the side-effect profile and safety. METHODS: In this double-blind, crossover trial, participants with severe Tourette syndrome were randomly assigned to a 6-week treatment period with escalating doses of an oral oil containing 5 mg/ml of THC and 5 mg/ml of CBD, followed by a 6-week course of placebo, or vice versa, separated by a 4-week washout period. The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range, 0 to 50 [higher scores indicate greater severity of symptoms]). Secondary outcomes included video-based assessment of tics, global impairment, anxiety, depression, and obsessive-compulsive symptoms. Outcomes were correlated with plasma levels of cannabinoid metabolites. A computerized cognitive battery was administered at the beginning and the end of each treatment period. RESULTS: Overall, 22 participants (eight female participants) were enrolled. Reduction in total tic score (at week 6 relative to baseline) as measured by the YGTSS was 8.9 (±7.6) in the active group and 2.5 (±8.5) in the placebo group. In a linear mixed-effects model, there was a significant interaction of treatment (active/placebo) and visit number on tic score (coefficient = −2.28; 95% confidence interval, −3.96 to −0.60; P=0.008), indicating a greater decrease (improvement) in tics under active treatment. There was a correlation between plasma 11-carboxy-tetrahydrocannabinol levels and the primary outcome, which was attenuated after exclusion of an outlier. The most common adverse effect in the placebo period was headache (n=7); in the active treatment period, it was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration (n=8). CONCLUSIONS: In severe Tourette syndrome, treatment with THC and CBD reduced tics and may reduce impairment due to tics, anxiety, and obsessive-compulsive disorder; although in some participants this was associated with slowed mentation, memory lapses, and poor concentration. (Funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically-funded research organization at the University of Sydney, Australia; Australian and New Zealand Clinical Trials Registry number, ACTRN12618000545268.)
Subject(s)
Cannabidiol , Tics , Tourette Syndrome , Humans , Tourette Syndrome/chemically induced , Tics/chemically induced , Dronabinol/adverse effects , Severity of Illness IndexABSTRACT
Tourette syndrome (TS) is a neurodevelopmental movement disorder characterized by multiple motor and vocal tics. In this study, we used a TS rat model induced by 3,3'-iminodipropionitrile (IDPN) and aimed to investigate the expression change of Syntaxin 1A (STX1A). Rats in the control group received intraperitoneal injection of normal saline, and TS rats were injected with IDPN (150 mg/kg/day). After 7 days of treatment, the stereotypic behaviors were assessed. Next, rats were sacrificed; brains were removed for RNA extraction and Western blotting analysis and fixed in 4% paraformaldehyde for immunofluorescence analysis. After 7 days of IDPN administration, stereotypic behaviors were successfully induced. The IDPN group exhibited more counts in biting, putting forepaws around mouth, licking, head twitching, shaking claws, body raising, and episodic utterance. The striatal STX1A mRNA, protein, and STX1A expression in striatal dopaminergic neurons were investigated. As expected, the total STX1A mRNA and protein levels were decreased in the TS model rats. In the striatal dopaminergic neurons, the IDPN group showed a slightly decreased STX1A/TH double positive area, but no statistical significance was found. Additionally, we assessed the expression of some genes closely related to STX1A, such as SNAP25, SY, and gephyrin, and no differences were found between the two groups. Together, reduced STX1A expression is associated with IDPN-induced TS development. Our findings suggested that decreased striatal STX1A expression is associated with the development of TS in the IDPN-induced rat model.
Subject(s)
Tourette Syndrome , Animals , Disease Models, Animal , Nitriles/toxicity , RNA , RNA, Messenger , Rats , Saline Solution , Syntaxin 1/genetics , Tourette Syndrome/chemically induced , Tourette Syndrome/geneticsABSTRACT
There may be immunologic alternations during Tourette syndrome (TS) development. This study aimed to determine the immune function changes in different aspects (spleen or thymus index, plasma cytokines, and T cell) in an 3,3'-iminodipropionitrile (IDPN)-induced rat model of TS. Male Sprague-Dawley rats were assigned to control and TS groups. The control group received intraperitoneal infections of normal saline (5 ml kg-1 day-1 ), and the TS rats were injected with IDPN (150 mg kg-1 day-1 ). The spleen and thymus indices were calculated. The expression of anti-inflammatory cytokines and inflammatory cytokines TNF-α, in peripheral blood were measured by ELISA and Western blotting. The proportion of CD3+, CD4+, CD8+, Treg, Th1, and Th2 cells were determined by fluorescence-activated cell sorting analysis. After 1 week of IDPN treatment, TS rats had decreased spleen and thymus weights versus control. The plasma levels of IL-4, IL-10, IL-12, IFN-γ, and TNF-α were significantly increased, while no significant difference in TGF-ß was found. Flow cytometry analysis demonstrated that TS rats had significantly reduced CD3+ and CD4+ cells in spleen, without any change in the proportion of CD8+ cells. Furthermore, the ratio of Treg cells (CD4+/CD25+/FoxP3+) was decreased in TS rats; simultaneously, Th1 cells (CD4+/IFN-γ+) and Th2 cells (CD4+/IL4+) were dramatically increased. Together, IDPN can trigger immune dysfunction through impairment of matured Th cells, in particular for the Treg subset.
Subject(s)
Cytokines/blood , Lymphocytes/immunology , Tourette Syndrome/immunology , Animals , Male , Nitriles , Rats , Rats, Sprague-Dawley , Spleen , Thymus Gland , Tourette Syndrome/blood , Tourette Syndrome/chemically inducedABSTRACT
Background: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder defined by motor and phonic tics. Sensory stimuli can trigger tics, which suggests that GTS is a disorder of perception-action processing rather than a pure motor disorder. Case report: We describe a GTS patient that developed exacerbation of tics after transcutaneous electro-myo-stimulation (YGTSS pre-EMS 27/100, post-EMS 69/100). Discussion: If behaviorally irrelevant stimuli exacerbate tics, there might be a high readiness of the motor system to respond to any stimulus in these patients. In addition to tighter binding between previously established perception-action links, the likelihood for the formation of automatic perception-action links might also be higher in GTS.
Subject(s)
Electric Stimulation Therapy/adverse effects , Muscle, Skeletal , Tourette Syndrome/physiopathology , Adult , Disease Progression , Humans , Male , Tourette Syndrome/chemically inducedABSTRACT
Tourette's syndrome (TS) is an inherited neurologic disorder characterized by involuntary stereotyped motor and vocal tics. Its pathogenesis is still unclear and its treatment remains limited. Recent research has suggested the involvement of immune mechanisms in the pathophysiology of TS. Microglia are the brain's resident innate immune cells. They can mediate neuroinflammation and regulate brain development and homeostasis. A traditional Chinese medicine (TCM), Ningdong granule (NDG), has been found to be efficacious in the treatment of TS while causing few adverse reactions. In the current study, a rat model of 3,3'-iminodipropionitrile (IDPN)-induced TS was used to explore the regulating effects and mechanisms of NDG on microglia-mediated neuroinflammation. IDNP led to robust pathological changes and neurobehavioral complications, with activation of microglia in the striatum of rats with TS. After activation by IDNP, microglia strongly responded to this specific injury, and TNF-α, IL-6, and MCP-1 were released in the striatum and/or serum of rats with TS. Interestingly, NDG inhibited the activation of microglia and decreased the abnormal expression of TNF-α, IL-6, and MCP-1 in the striatum and/or serum of rats with TS, thus controlling tics. However, there were no significant changes in the striatum and/or serum of rats with TS after treatment with haloperidol. The anti-TS action of haloperidol might occur not through microglial activation and neuroinflammation but through the DAT system, thus controlling tics. In conclusion, microglia might play key roles in mediating neuroinflammatory responses in TS, triggering the release of TNF-α, IL-6, and MCP-1.NDG inhibited tics in rats with TS, and this mechanism may be associated with a reduction in the increased number of activated microglia and a decrease in the expression of pro-inflammatory cytokines and chemokines in the striatum and/or serum.
Subject(s)
Corpus Striatum/drug effects , Drugs, Chinese Herbal/pharmacology , Microglia/drug effects , Tourette Syndrome/drug therapy , Animals , Chemokine CCL2/blood , Chemokine CCL2/metabolism , Corpus Striatum/cytology , Corpus Striatum/immunology , Corpus Striatum/pathology , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Haloperidol/pharmacology , Haloperidol/therapeutic use , Humans , Interleukin-6/blood , Interleukin-6/metabolism , Male , Microglia/immunology , Microglia/metabolism , Nitriles/toxicity , Rats , Rats, Wistar , Tourette Syndrome/chemically induced , Tourette Syndrome/immunology , Tourette Syndrome/pathology , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND Anxiety is one of the common comorbidities of Tourette syndrome (TS). The serotonin (5-HT) system is involved in both TS and anxiety. Jian-pi-zhi-dong decoction (JPZDD) is widely used. However, the mechanism remains unknown. In this study, a rat model of TS and comorbid anxiety was used to evaluate the effect of JPZDD on 5-HT and its receptor. MATERIAL AND METHODS 48 rats were divided into 4 groups randomly (n=12). The model was established by empty water bottle stimulation plus iminodipropionitrile injection for 3 weeks. Then the control and model groups were gavaged with saline, while the treatment groups were gavaged with fluoxetine hydrochloride (Flx) or JPZDD. Body weights were measured, and behavioral tests were evaluated with stereotypy and elevated plus maze. The morphologic characters were observed by hematoxylin and eosin staining. The content of 5-HT was detected by enzyme-linked immunosorbent assay and high-performance liquid chromatography. The expression of 5-HT2C receptor was detected by western blot and quantitative polymerase chain reaction. RESULTS The stereotypy score was lower and the time spent in the open arm was longer in the JPZDD group compared with the model group. After the treatment of Flx or JPZDD, the structure of neurons became gradually normal and the cells were arranged neatly. The contents of 5-HT in the treatment groups were higher compared with the model group in the striatum. The expression of 5-HT2C mRNA in the striatum of JPZDD and Flx groups decreased compared with the model group, and the JPZDD group was lower than the Flx group. CONCLUSIONS JPZDD alleviated both tic and anxiety symptoms and the mechanism may be via reducing the expression of 5-HT2C mRNA in the striatum, increasing the concentration of 5-HT, and enhancing the activity of the 5-HT system, which in turn exerts neuro-inhibition.
Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Anxiety/drug therapy , Drugs, Chinese Herbal/pharmacology , Receptor, Serotonin, 5-HT2C/genetics , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Tourette Syndrome/drug therapy , Animals , Anxiety/chemically induced , Anxiety/genetics , Anxiety/physiopathology , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Disease Models, Animal , Fluoxetine/pharmacology , Gene Expression , Humans , Male , Maze Learning/drug effects , Nitriles/administration & dosage , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin/metabolism , Tourette Syndrome/chemically induced , Tourette Syndrome/genetics , Tourette Syndrome/physiopathology , Treatment OutcomeABSTRACT
The aim of this study was designed to investigate the effects of rhynchophyllin (RH) on neuroinflammation in Tourette syndrome (TS) rats. TS model was established in rats by the injection of selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Behavior in DOI-induced rats was tested. Inflammatory cytokines levels such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum and striatum were detected. The expression levels of janus kinase 2 (JAK2)/signal transducer and transcription activator 3 (STAT3) and nuclear factor (NF)-κB pathways in striatum were measured by Western blot. Data indicated that RH can significantly reduce the numbers of nodding experiment of TS rats. RH significantly decreased IL-6, IL-1ß, and TNF-α in serum and striatum of TS rats, with altered expression of P-JAK2, P-STAT3, P-NF-κBp65, and P-IκBα in TS rats, as evidenced by Western blot analysis and immunohistochemistry, suggesting that the regulation of JAK2/STAT3 and NF-κB pathways might be involved in the mechanism of RH on TS.
Subject(s)
Corpus Striatum/immunology , Drugs, Chinese Herbal/administration & dosage , Janus Kinase 2/immunology , Oxindoles/administration & dosage , Tourette Syndrome/drug therapy , Uncaria/chemistry , Animals , Corpus Striatum/drug effects , Humans , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Janus Kinase 2/genetics , Male , NF-kappa B/genetics , NF-kappa B/immunology , Propane/adverse effects , Propane/analogs & derivatives , Rats , Rats, Wistar , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/immunology , Signal Transduction/drug effects , Tourette Syndrome/chemically induced , Tourette Syndrome/genetics , Tourette Syndrome/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Dysfunctions in dopamine (DA) and serotonin (5HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micropositron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5HT2A receptors (5HT2ARs) and 5HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.
Subject(s)
Dopaminergic Neurons/metabolism , Drugs, Chinese Herbal/pharmacology , Serotonergic Neurons/metabolism , Tourette Syndrome/drug therapy , Animals , Corpus Striatum/metabolism , Corpus Striatum/physiology , Disease Models, Animal , Dopamine/genetics , Dopamine Plasma Membrane Transport Proteins/genetics , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Humans , Medicine, Chinese Traditional , Nitriles/toxicity , Rats , Receptor, Serotonin, 5-HT2A/genetics , Receptors, Dopamine D2/genetics , Serotonergic Neurons/drug effects , Serotonergic Neurons/pathology , Serotonin/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Synaptic Transmission/drug effects , Synaptic Transmission/genetics , Tourette Syndrome/chemically induced , Tourette Syndrome/genetics , Tourette Syndrome/pathologyABSTRACT
Tourette syndrome (TS) is a chronic neuropsychiatric disorder with clinical manifestations of involuntary and repeated muscle twitching and vocal twitching. The drugs used to treat TS are relatively limited. The aim of this study was to investigate the effects of rhynchophylline (RH) and the underlying mechanism in 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced neurotoxicity in a TS rat model. A TS model was induced with DOI. The rats were divided into control, TS, TS + tiapride (25 mg/kg), and TS + RH (20 and 40 mg/kg) groups. Behavioral tests were performed 24 h after the last administration by nodding and stereotype experiments. Interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) levels in striatum and serum were detected with an enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to detect the expression levels of Toll-like receptor (TLR)/nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3)/nuclear factor kappa B (NF-κB) signal proteins in the striatum. The expression of TLR2 and NF-κB p65 subunit was detected with immunohistochemical analysis. RH may significantly improve behavioral changes in rats with DOI-induced TS and reduce the levels of inflammatory factors in serum and striatum. RH inhibited the activation of TLR/NLRP3/NF-κB signaling proteins in the striatum of TS rats. In BV2 cells, DOI-induced inflammation mediated through TLR/NLRP3/NF-κB was significantly inhibited following RH administration. The therapeutic effect of RH in TS was studied and its mechanism of action mediated via the TLR/NLRP3/NF-κB pathway was clarified in vitro and in vivo.
Subject(s)
Amphetamines/toxicity , Corpus Striatum/drug effects , Oxindoles/administration & dosage , Tourette Syndrome/chemically induced , Tourette Syndrome/drug therapy , Animals , Behavior, Animal/drug effects , Cell Line , Cell Survival/drug effects , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/metabolism , Encephalitis/chemically induced , Encephalitis/metabolism , Male , Rats, Sprague-Dawley , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: Tourette syndrome (TS) is a chronic neuropsychiatric disorder. Its clinical manifestations are involuntary and recurrent muscle twitch, resulting in motor twitch and occurrence twitch. Traditional Chinese medicine has obvious advantages in treating TS. The aim of this study was to investigate the effects and mechanism of gastrodin on 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced TS in rats. METHODS: TS model was induced by DOI. Behaviors in TS rats were detected. The striatum, serum inflammatory factors interleukin-6, interleukin-1ß, and tumor necrosis factor-a were detected by enzyme-linked immunosorbent assay. Western blot technique was used to detect the expressions of TLR/NF-κB and TLR/MAPK signaling pathways in the striatum. RESULTS: Gastrodin can significantly improve behavioral changes of TS rats induced by DOI, reduce inflammatory factors in serum and striatum in TS rats, and inhibit activation of TLR/NF-κB and TLR/MAPK signaling in striatum in TS rats. CONCLUSION: Gastrodin can significantly relieve the TS induced by DOI in rats. Its mechanism is related to the inhibition of striatal TLR/NF-κB and TLR/MAPK signaling activation.
Subject(s)
Amphetamines/toxicity , Behavior, Animal/drug effects , Benzyl Alcohols/pharmacology , Glucosides/pharmacology , MAP Kinase Signaling System/drug effects , Tourette Syndrome/drug therapy , Animals , Cytokines/metabolism , Disease Models, Animal , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Male , Rats , Rats, Sprague-Dawley , Tourette Syndrome/chemically induced , Tourette Syndrome/metabolism , Tourette Syndrome/pathologyABSTRACT
Tourette syndrome (TS) is a neurological disorder characterized by highest familial recurrence rate among neuropsychiatric diseases with complicated inheritance. Recurrence of Tourette syndrome was frequently observed in clinical. Unexpectedly, the mechanism of recurrence of Tourette syndrome was failure to elucidate. Here, we first shown that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome. The TS model in rats was induced by DOI (the selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl) -2- aminopropane). The rats were randomly divided into 4 groups:(1)Control;(2) Control + LPS; (2)TS; (3)TS + LPS. The results demonstrated that the LPS treatment significantly increased stereotypic score and autonomic activity. LPS treatment also significantly increased inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in serum and striatum. Also, highly expressed TLR4, MyD88, P-NF-κBp65, P-IκBα in TS rats were increased respectively by LPS treatment as indicted in western blot analysis and immunohistochemistry analysis. Thus, it was supposed that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome and its mechanism was related to TLR/NF-κB pathway.
Subject(s)
Corpus Striatum/metabolism , Indophenol/analogs & derivatives , Lipopolysaccharides , Serotonin Receptor Agonists , Tourette Syndrome/chemically induced , Animals , Cytokines/metabolism , Disease Models, Animal , Male , Rats , Rats, Wistar , Recurrence , Tourette Syndrome/metabolismSubject(s)
Antipsychotic Agents/adverse effects , Aripiprazole/adverse effects , Pimozide/adverse effects , Tics/chemically induced , Tourette Syndrome/chemically induced , Adolescent , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/therapeutic use , Aripiprazole/administration & dosage , Humans , Male , Pimozide/administration & dosage , Tourette Syndrome/drug therapyABSTRACT
Dopamine (DA) is a key neuromodulator in the brain that supports motor and cognitive functions. Here, we use apomorphine (Apo) and 3,3'-iminodipropionitrile (IDPN) to develop two rat models of Tourette's syndrome (TS), a common neuropsychiatric disorder characterized by stereotyped repetitive involuntary tics. The models enabled the assessment of unique ameliorative effects of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation dedicated to the treatment of TS, on the striatal DA content of rats. By using high-performance liquid chromatography (HPLC), we found that long-term administration of NDG could, at least partially, restore the striatal dopamine alterations, either by increasing them after IDPN treatment or by decreasing them after Apo treatment. Taken together, our data indicated that NDG could ameliorate the abnormal striatal DA content dually, and the unique therapeutic property may be meaningful for the treatment of TS.
Subject(s)
Apomorphine , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , Nitriles , Tourette Syndrome/drug therapy , Animals , Behavior, Animal/drug effects , Chromatography, High Pressure Liquid , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/analysis , Drugs, Chinese Herbal/pharmacology , Male , Rats , Rats, Wistar , Receptors, Dopamine D2/metabolism , Tourette Syndrome/chemically induced , Up-Regulation/drug effectsABSTRACT
INTRODUCTION: Gilles de la Tourette syndrome (GTS) is characterized by abnormal movements (tics) often associated with behavioural disorders. Neuropathological data from GTS patients have suggested that aberrant activation of distinct striatal functional territories could produce a large spectrum of GTS symptoms. In a monkey model, injections of GABA-antagonist into the striatum enabled us to produce tic-like movements, hyperactivity and stereotyped behaviours. These effects had similarities with simple motor tics, hyperactivity and compulsive behaviours observed in GTS patients. In this study, we first aimed to identify the neuronal circuits involved in the different behavioural effects using anatomical antero/retrograde tracer in monkeys. We also compared the neuronal circuits thus obtained with the available neuro-anatomical data on GTS patients. METHODS: Using injections of axonal tracer into different functional parts of the striatum of eight monkeys, we identified cortical, thalamic and basal ganglia regions related to the expression of tic-like movements, hyperactivity and stereotyped behaviours induced in response to microinjection of GABA-antagonist. RESULTS: In this monkey model, different anatomical circuits involving distinct cortical and thalamic areas and sub-territories of the basal ganglia underpinned movement and behavioural disorders. Thus, tic-like movements were associated with neuronal labelling within the sensorimotor network, mostly in the medial and lateral premotor cortex and sensorimotor parts of the basal ganglia. Neuronal labelling in the prefrontal dorso-lateral cortex and associative territories of the basal ganglia was related to hyperactivity disorder and stereotyped behaviours were linked to the orbitofrontal cortex and limbic part of the basal ganglia. CONCLUSIONS: These results support the hypothesis that different behavioural effects could arise from distinct but inter-digitated neuronal circuits. As these behavioural disorders shared some similarities with simple motor tics, hyperactivity and compulsive behaviours observed in GTS patients, this model could be a good tool for future studies involving the modulation of neuronal circuits, such as deep brain stimulation.
Subject(s)
Neostriatum/physiopathology , Tourette Syndrome/psychology , Afferent Pathways/pathology , Afferent Pathways/physiopathology , Animals , Axons/physiology , Behavior, Animal/drug effects , Bicuculline/administration & dosage , Bicuculline/pharmacology , Chlorocebus aethiops , Disease Models, Animal , Efferent Pathways/pathology , Efferent Pathways/physiopathology , GABA Antagonists/administration & dosage , GABA Antagonists/pharmacology , Macaca fascicularis , Macaca mulatta , Male , Microinjections , Stereotyped Behavior , Tourette Syndrome/chemically induced , Tourette Syndrome/pathologyABSTRACT
Tardive Tourette syndrome is characterized by the occurrence of multiple motor and vocal tics in patients on long-term neuroleptic, antiepileptic medication or stimulants, and was first reported by Golden in 1974 and was given its name in 1980 by Steven Stahl who linked it to tardive dyskinesia. The Medline was searched with the combination of the words 'tardive' or 'induced' or 'late' and 'Tourette' or 'Tourettism' and 375 papers were indentified; 42 of them were judged to be relevant. Forty-one cases were identified, caused by antipsychotics, antiepileptics, stimulants and other medication. A number of treatment options are reported in the literature but no systematic study of the syndrome has been done yet.
Subject(s)
Movement Disorders/diagnosis , Tourette Syndrome/chemically induced , Tourette Syndrome/diagnosis , Animals , Anticonvulsants/adverse effects , Antipsychotic Agents/adverse effects , Central Nervous System Stimulants/adverse effects , Dyskinesia, Drug-Induced/diagnosis , Dyskinesia, Drug-Induced/physiopathology , Humans , Movement Disorders/physiopathology , Syndrome , Tourette Syndrome/physiopathologyABSTRACT
Gastrodin is used in traditional Chinese medicine to treat Tourette's syndrome (TS). This study evaluated the effects of gastrodin on the dopamine system. TS rat models were established by intraperitoneal injection of apomorphine. After intervention by gastrodin, stereotyped behaviors of TS rats were significantly inhibited and levels of homovanillic acid (HVA) were significantly increased. We conclude that gastrodin effectively inhibited stereotyped behaviors and controlled TS symptoms by promoting dopamine metabolism, thereby increasing levels of HVA in sera.
Subject(s)
Benzyl Alcohols/therapeutic use , Dopamine/metabolism , Glucosides/therapeutic use , Tourette Syndrome/drug therapy , Animals , Apomorphine/pharmacology , Benzyl Alcohols/administration & dosage , Glucosides/administration & dosage , Homovanillic Acid/blood , Injections, Intraperitoneal , Male , Medicine, Chinese Traditional , Rats , Tourette Syndrome/blood , Tourette Syndrome/chemically induced , Tourette Syndrome/pathologySubject(s)
Antipsychotic Agents/adverse effects , Clozapine/adverse effects , Schizophrenia/drug therapy , Tourette Syndrome/chemically induced , Agranulocytosis/chemically induced , Antipsychotic Agents/therapeutic use , Clozapine/therapeutic use , Disease Progression , Dose-Response Relationship, Drug , Haloperidol/therapeutic use , Humans , Male , Tourette Syndrome/drug therapy , Young AdultABSTRACT
OBJECTIVE: To develop a mouse model to mimic the behavioral and neurochemical changes of Tourette syndrome (TS) by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induction and to investigate the effects of fluoxetine and haloperidol on head twitch response (HTR) induced by DOI. METHODS: 1) Preparation of mouse model of TS: Forty mice were randomly divided into experimental and control groups (n=20 each). DOI (1 mg/kg) was administered by peritoneal injection in the experimental group. The control group was injected with normal saline. The levels of dopamine (DA) and homovanillic acid (HVA), the metabolite of DA, in both groups were measured by high performance liquid chromatography and electrochemical detection. 2) Effects of fluoxetine and haloperidol on HTR: Eighty mice were randomly administered with either fluoxetine (2 mg/kg), haloperidol (0.8 mg/kg), fluoxetine + haloperidol or normal saline. DOI (1 mg/kg) was peritoneally injected 20 minutes later (acute trial) or 18-20 hrs after a 21 days injection of fluoxetine or haloperidol (chronic trial). The frequency of DOI induced HTR was observed immediately after DOI injection. RESULTS: The levels of DA and HVA in the experimental group were significantly lower than those in the control group (DA: 45.00 +/-11.24 ng/mg vs 58.16 +/-14.51 ng/mg; HVA:10.54 +/-1.86 ng/mg vs 12.82 +/-2.66 ng/mg). In both acute and chronic trials, the frequency of DOI-induced HTR decreased significantly in mice administered with haloperidol alone or together with fluoxetine (P < 0.05), but it did not change significantly in mice administered with fluoxetine alone compared with the normal saline group. CONCLUSIONS: The levels of DA and HVA are reduced in mice with DOI-induced HTR. DOI-induced mouse mode of HTR can mimic the neurochemical and behavioral changes of TS paritially. Haloperidol can inhibit DOI-induced HTR in mice, but fluoxetine can not.