Moderately aged OFA rats as a novel model for mild age-related alterations in learning and memory.

Aged rodents have been used as preclinical models of age-associated cognitive decline. Most of those models displayed substantial impairments in learning and memory. The initial, more subtle changes that precede more severe losses in cognitive abilities have not been well characterized. Here, we established a model detecting initial subtle cognitive changes by comparing the performance of moderately aged Oncins France Strain A Sprague Dawley rats with young rats in the Morris water maze (MWM) and the Open Field (OF) test. Both age groups improved their performance during the training period at a similar rate; however, the older rats performed worse in several parameters measured in the MWM. Our results suggest that already at the age of 18-20 months rats show changes in their approach to solve the spatial memory task while their ability to learn is not yet diminished. The disparate spatial information processing of the moderately aged rats provides a novel animal model for early age-related cognitive alterations that could be useful to test the effect of early intervention strategies. Moreover, our results suggest that the sensitivity of cognitive tests in the elderly could be substantially enhanced if they assess both the improvement after several trials, and the strategy used to solve a certain task.

First Sequencing of Caprine Mdr1 (Abcb1) mRNA Due to Suspected Neurological Adverse Drug Reaction in a Thuringian Goat Following Extra-Label Use of Doramectin.

The multidrug resistance gene MDR1 encodes for an efflux transporter called P-glycoprotein (P-gp). In the canine Mdr1 gene, a nonsense mutation was identified in certain dog breeds causing increased drug sensitivity to various P-gp substrates such as antiparasitic macrocyclic lactones. Symptoms of neurologic toxicity include ataxia, depression, salivation, tremor, apparent blindness, and mydriasis. In the current report, a Thuringian goat developed similar neurological signs after treatment with doramectin, a compound from the macrocyclic lactone class. Therefore, Mdr1 might be defective in this individual goat. For diagnostic purposes, sequencing of the complete mRNA transcript coding for caprine Mdr1 was performed to investigate a potential missense mutation. The Mdr1 transcripts of two related goats without drug sensitivity were also sequenced to allow differential diagnosis and were compared to the suspected drug-sensitive goat. The only position where the Mdr1 sequence from the suspected drug-sensitive goat differed was in the 3'-untranslated region, being a heterozygous single nucleotide polymorphism c.3875C>A. It can be suspected that this variant affects the expression level, stability, or translation efficiency of the Mdr1 mRNA transcript and therefore might be associated with the suspected drug sensitivity. To clarify this, further studies are needed, particularly investigating the Mdr1 mRNA and protein expression levels from brain material of affected goats. In conclusion, Mdr1 variants may exist not only in dogs, but also in individual goats. The current report provides the first Mdr1 mRNA transcript sequence of a goat and therefore represents the basis for more detailed Mdr1 sequence and expression analyses.

Detection of the ABCB11930_1931del TC Mutation in Two Suspected Ivermectin-Sensitive Cats and Their Relatives by a Novel TaqMan Allelic Discrimination Assay.

The multidrug resistance gene MDR1 (syn. ABCB1) encodes for the multidrug efflux transporter P-glycoprotein (P-gp), which is highly expressed at the blood-brain barrier and protects the brain from potentially neurotoxic compounds, such as ivermectin. MDR1 mutation in dogs is known to be linked to dramatically increased brain accumulation of ivermectin and life-threatening neurological toxicity. The present report describes two suspected ivermectin-sensitive Maine Coon cats, which exhibited neurological toxicity following subcutaneous application of therapeutic doses of ivermectin. Both cats showed a homozygous 2-bp deletion in the MDR1/ABCB1 coding sequence (ABCB11930_1931del TC, syn. MDR1 nt1930(del2)) that had previously been associated with a drug-sensitive phenotype in cats. For cat MDR1 genotyping, a novel TaqMan allelic discrimination assay was established and validated. This assay was used for ABCB11930_1931del TC genotyping of the drug-sensitive cats as well as of more than 50 relatives. About half of them had the heterozygous MDR1(+/-) genotype, while none of these related cats with former ivermectin treatment had a history of drug-sensitivity. In conclusion: The present study supports previous findings on drug-sensitivity in cats with homozygous ABCB11930_1931del TC mutation. The newly established TaqMan allelic discrimination assay provides a useful and reliable method for routine MDR1 genotyping in cats in order to identify drug-sensitive cats prior to treatment with established P-gp substrates such as ivermectin and other macrocyclic lactones and thus to improve therapeutic safety.

Severity assessment in mice subjected to carbon tetrachloride.

The Directive 2010/63 EU requires classifying burden and severity in all procedures using laboratory animals. This study evaluated the severity of liver fibrosis induction by intraperitoneal carbon tetrachloride (CCl4) injections in mice. 29 male C57BL/6N mice were treated three times per week for 4 weeks with an intraperitoneal injection (50 µl) of either 0.6 ml/kg body weight CCl4-vehicle solution, germ oil (vehicle-control) or handling only. Severity assessment was performed using serum analysis, behavioral tests (open field test, rotarod, burrowing and nesting behavior), fecal corticosterone metabolite (FCM) measurement, and survival. The most significant group differences were noticed in the second week of treatment when the highest AST (1463 ± 1404 vs. 123.8 ± 93 U/L, p < 0.0001) and nesting values were measured. In addition, respective animals showed lower moving distances (4622 ± 1577 vs. 6157 ± 2060 cm, p < 0.01) and velocity in the Open field, identified as main factors in principal component analysis (PCA). Overall, a 50% survival rate was observed within the treatment group, in which the open field performance was a good tracer parameter for survival. In summary, this study demonstrates the feasibility of assessing severity in mice using behavioral tests and highlight the open field test as a possible threshold parameter for risk assessment of mortality.

Adverse Drug Reactions After Administration of Emodepside/Praziquantel (Profender®) in an MDR1-Mutant Australian Shepherd Dog: Case Report.

A 3-year-old male Australian Shepherd was presented with signs of neurological toxicity following the administration of Profender® at the recommended dosage. Unfortunately, the owner had received the product from a veterinarian without any further instructions on fasting as recommended by the manufacturer, so the dog was fed prior to Profender® administration. Neurological toxicity included generalized tremor, agitation and panting, and required hospitalization of the dog. All neurological signs resolved after symptomatic treatment within 24 h and the dog was discharged without the need for further medication. MDR1 genotyping revealed a homozygous mutation of the MDR1 gene, which is normally important to prevent brain penetration of emodepside by an efflux-based transport mechanism at the blood brain barrier. This case indicates that Profender® can lead to serious, but transient neurological toxicity in dogs with homozygous MDR1 mutation even at therapeutic dosage, in particular when fasting recommendations are disregarded. Therefore, the case report highlights both the importance of MDR1 genotyping in predisposed dog breeds as well as strict compliance with fasting recommendations around the time of Profender® administration.

Suspected neurological toxicity after oral application of fluralaner (Bravecto®) in a Kooikerhondje dog.

BACKGROUND: Although the new isoxazoline drug fluralaner (Bravecto®) is generally well tolerated in dogs, adverse drug reactions involving neurological dysfunction occurred in individual dogs. However, most of these cases are documented inadequately and none of them is reported and discussed in the literature. As isoxazoline drugs target neuronal chloride channels with a clear preference for invertebrates, they are considered to have a good safety profile. However, pharmacodynamic effects in the nervous system of vertebrates cannot be ruled out completely. CASE PRESENTATION: A seven-month-old female Kooikerhondje dog was treated with Bravecto® at the recommended dose. About 24 h after administration, the dog exhibited signs of neurological toxicity, including generalized ataxia, myoclonic jerks, tremor of head and body, muscle twitching and oral dysphagia. All symptoms were transient and the dog fully recovered without any treatment after 10 h. CONCLUSION: This case report describes transient occurrence of neurological dysfunction after administration of Bravecto®. It may help to better classify adverse drug reactions after application of isoxazoline drugs and documents a good prognosis even after occurrence of severe neurological dysfunction in the present case.

Alterations of M1 and M4 acetylcholine receptors in the genetically dystonic (dtsz) hamster and moderate antidystonic efficacy of M1 and M4 anticholinergics.

Striatal cholinergic dysfunction has been suggested to play a critical role in the pathophysiology of dystonia. In the dtsz hamster, a phenotypic model of paroxysmal dystonia, M1 antagonists exerted moderate antidystonic efficacy after acute systemic administration. In the present study, we examined the effects of the M4 preferring antagonist tropicamid and whether long-term systemic or acute intrastriatal injections of the M1 preferring antagonist trihexyphenidyl are more effective in mutant hamsters. Furthermore, M1 and M4 receptors were analyzed by autoradiography and immunohistochemistry. Tropicamide retarded the onset of dystonic attacks, as previously observed after acute systemic administration of trihexyphenidyl. Combined systemic administration of trihexyphenidyl (30mg/kg) and tropicamide (15mg/kg) reduced the severity in acute trials and delayed the onset of dystonia during long-term treatment. In contrast, acute striatal microinjections of trihexyphenidyl, tropicamid or the positive allosteric M4 receptor modulator VU0152100 did not exert significant effects. Receptor analyses revealed changes of M1 receptors in the dorsomedial striatum, suggesting that the cholinergic system is involved in abnormal striatal plasticity in dtsz hamsters, but the pharmacological data argue against a crucial role on the phenotype in this animal model. However, antidystonic effects of tropicamide after systemic administration point to a novel therapeutic potential of M4 preferring anticholinergics for the treatment of dystonia.

Towards optimized anesthesia protocols for stereotactic surgery in rats: Analgesic, stress and general health effects of injectable anesthetics. A comparison of a recommended complete reversal anesthesia with traditional chloral hydrate monoanesthesia.

Although injectable anesthetics are still widely used in laboratory rodents, scientific data concerning pain and distress during and after stereotactic surgery are rare. However, optimal anesthesia protocols have a high impact on the quality of the derived data. We therefore investigated the suitability of recommended injectable anesthesia with a traditionally used monoanesthesia for stereotactic surgery in view of optimization and refinement in rats. The influence of the recommended complete reversal anesthesia (MMF; 0.15mg/kg medetomidine, 2mg/kg midazolam, 0.005mg/kg fentanyl; i.m.) with or without reversal and of chloral hydrate (430mg/kg, 3.6%, i.p.) on various physiological, biochemical and behavioral parameters (before, during, after surgery) was analyzed. Isoflurane was also included in stress parameter analysis. In all groups, depth of anesthesia was sufficient for stereotactic surgery with no animal losses. MMF caused transient exophthalmos, myositis at the injection site and increased early postoperative pain scores. Reversal induced agitation, restlessness and hypothermia. Even the low concentrated chloral hydrate led to peritonitis and multifocal liver necrosis, corresponding to increased stress hormone levels and loss in body weight. Increased stress response was also exerted by isoflurane anesthesia. Pronounced systemic toxicity of chloral hydrate strongly questions its further use in rodent anesthesia. In view of undesired effects of MMF and isoflurane, thorough consideration of anesthesia protocols for particular research projects is indispensable. Reversal should be restricted to emergency situations. Our data support further refinement of the current protocols and the importance of sham operated controls.

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias.

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals.

Role of striatal NMDA receptor subunits in a model of paroxysmal dystonia.

Dystonia is a movement disorder in which abnormal plasticity in the basal ganglia has been hypothesized to play a critical role. In a model of paroxysmal dystonia, the dt(sz) mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by subunit-unspecific antagonists at NMDA receptors, which blocked LTP. NR2B subtype selective antagonists aggravated dystonia after systemic treatment in dt(sz) hamsters, suggesting that beneficial effects involved the NR2A receptor subtype. In the present study, NVP-AAM077, an antagonist with preferential activity on NR2A-containing NMDA receptors, exerted significant antidystonic effects in mutant hamsters after systemic administration (20 and 30mg/kg i.p.) and delayed the onset of a dystonic episode after intrastriatal injections (0.12 and 0.24µg). As shown by present electrophysiological examinations in corticostriatal slices of dt(sz) hamsters and non-dystonic control hamsters, NVP-AAM077 (50nM) completely blocked LTP in dt(sz) slices, but did not exert significant effects on LTP in non-dystonic controls. In contrast, the NR2B antagonist Ro 25-6981 (1-10µmol) reduced LTP to a lower extent in dt(sz) mutant hamsters than in control animals. By using quantitative RT-PCR, the NR2A/NR2B ratio was found to be increased in the striatum, but not in the cortex of mutant hamsters in comparison to non-dystonic controls. These data indicate that NR2A-mediated activation may be involved in the pathophysiology of paroxysmal dystonia. Since significant antidystonic effects were observed after systemic administration of NVP-AAM077 already at well tolerated doses, antagonists with preferential activity on NR2A-containing NMDA receptors could be interesting candidates for the treatment of dystonia.

Environmental risk factors and their impact on the age of onset of schizophrenia: Comparing familial to non-familial schizophrenia.

BACKGROUND AND AIMS: Several risk factors for schizophrenia have yet been identified. The aim of our study was to investigate how certain childhood and adolescent risk factors predict the age of onset of psychosis in patients with and without a familial component (i.e. a relative with schizophrenia or schizoaffective disorder). METHODS: Aside from the age of onset of psychosis, we examined the risk factors for schizophrenia including obstetric complications, birth during winter or spring, behavioral deviances or delayed motor and speech development, exposure to adverse life events and exposure to substance use within a group of 100 patients (45 female, 55 male) with a mean age (± standard deviation) of 35.15 ± 13.21. RESULTS: Birth complications and cannabis abuse are predictors for an earlier onset of schizophrenia in patients with non-familial schizophrenia. No environmental risk factors for an earlier age of onset in familial schizophrenia have been identified. CONCLUSIONS: Certain environmental risk factors for schizophrenia seem to have an impact on the age of onset of psychosis in non-familial schizophrenia, they do not seem to have an impact on familial schizophrenia.

Changes in dynorphin immunoreactivity but unaltered density of enkephalin immunoreactive neurons in basal ganglia nuclei of genetically dystonic hamsters.

Dystonia is regarded as a basal ganglia disorder. In the dt(sz) hamster, a genetic animal model of paroxysmal dystonia, previous studies demonstrated a reduced density of striatal GABAergic interneurons which inhibit striatal GABAergic projection neurons. Although the disinhibition of striatal GABAergic projection neurons was evidenced in the dt(sz) hamster, alterations in their density have not been elucidated so far. Therefore, in the present study, the density of striatal methionin-(met-) enkephalin (ENK) immunoreactive GABAergic neurons, which project to the globus pallidus (indirect pathway), was determined in dt(sz) and control hamsters to clarify a possible role of an altered ratio between striatal interneurons and projection neurons. Furthermore, the immunoreactivity of dynorphin A (DYN), which is expressed in entopeduncular fibers of striatal neurons of the direct pathway, was verified by gray level measurements to illuminate the functional relevance of an enhanced striato-entopeduncular neuronal activity previously found in dt(sz) hamsters. While the density of striatal ENK immunoreactive (ENK(+) ) neurons did not significantly differ between mutant and control hamsters, there was a significantly enhanced ratio between the DYN immunoreactive area and the whole area of the EPN in dt(sz) hamsters compared to controls. These results support the hypothesis that a disbalance between a reduced density of striatal interneurons and an unchanged density of striatal projection neurons causes imbalances in the basal ganglia network. The consequentially enhanced striato-entopeduncular inhibition leads to an already evidenced reduced activity and an altered firing pattern of entopeduncular neurons in the dt(sz) hamster.

Behavioural and pharmacological examinations in a transgenic mouse model of early-onset torsion dystonia.

Early-onset torsion dystonia is an autosomal dominant movement disorder associated with the DYT1 gene (TOR1A) defect which results in a deletion of a glutamic acid residue in the protein torsinA. The pathophysiology of dystonia is poorly understood. Well characterized animal models can help to give insights into the underlying mechanisms and thereby to develop new therapeutics. In the present study, we further characterized transgenic DYT1 mice, which were initially described to exhibit "dystonia-like" postures. In the present study, several behavioural tests in untreated animals did not show strong differences between transgenic and control mice, but nearly all transgenic mice showed "dystonia-like" postures. However, these movements, also observed in control mice, have to be regarded as a clasping reflex. Since dystonia is thought to be related to dopaminergic dysfunctions, pharmacological investigations have been performed to clarify if dopaminergic substances alter motor behaviour in transgenic mice. Chronic treatment with L-DOPA (combined with carbidopa) enhanced the hindlimb claspings only in transgenic mice, while acute applications of drugs, which exert more selective effects on the dopaminergic system, caused similar reactions in transgenic mice and control mice. Therefore, these data do not provide clear evidence for dysfunctions of the dopaminergic system in this mouse model.

Non-invasive genotyping of transgenic mice: comparison of different commercial kits and required amounts.

The usefulness of genetically modified mice is discussed critically. Nevertheless, their number has increased dramatically over the past years. A principle for the use these mice is the isolation of DNA to determine whether an individual carries the genetic modification or not. This "genotyping" is usually done by invasive tissue sampling, e.g. tail biopsies, which likely causes discomfort and pain to the animals and is therefore discussed in animal welfare regulations. Although non-invasive tissue sampling by stool samples was already described over 10 years ago, it is not commonly used so far. In the present study we therefore tested the practicality of this method by the use of three commercial kits for genotyping and compared the results to those attained using tail biopsies. Our data shows that DNA isolation from stool samples is practical, sensitive and effective. In addition, the possibility of repeated sampling represents a clear advantage to invasive genotyping. Therefore, this method represents a useful tool in the 3R concept, since replacement of invasive tissue sampling refines the use of transgenic mice.

Effects of pharmacological entopeduncular manipulations on idiopathic dystonia in the dt(sz) mutant hamster.

The pathophysiology of idiopathic dystonias is still unknown, but it is regarded as a basal ganglia disorder. Previous experiments in the dt(sz) hamster, a model of primary paroxysmal dystonia, demonstrated reduced discharge rates and an abnormal pattern within the entopeduncular nucleus (EPN), a basal ganglia output structure. To clarify if this is based on abnormal gamma-aminobutyric acid(GABA)ergic or glutamatergic input, microinjections into the EPN were done in mutant hamsters in the present study. The GABA(A) receptor antagonists pentylenetetrazole and bicuculline exerted moderate antidystonic effects, while previous systemic administrations worsened dystonia in the dt(sz) mutant. GABA-potentiating drugs, i.e., the GABA(A) receptor agonist muscimol and the GABA transporter inhibitor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxy-lic acid (NNC-711), which are known to improve dystonia after systemic treatment in mutant hamsters, did not exert significant effects after EPN injections, but NNC-711 tended to increase the severity at the highest dose (2.5 ng bilateral). The NMDA receptor antagonist D(-)-2-amino-5-phosphopentanoic acid (AP-5) retarded the onset of a dystonic attack. However, this effect was not dose dependent and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline (NBQX) alone or in combination with AP-5 and NNC-711, also failed to show any effects on dystonia. The present data do not provide clear evidence for an enhanced striatal GABAergic input or a reduced glutamatergic activation of the EPN via the subthalamic nucleus, i.e., more pronounced antidystonic effects of GABA(A) receptor antagonists and stronger prodystonic effects of GABAmimetics and glutamate receptor antagonists were expected. Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters.

Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster.

Dystonia is a heterogeneous syndrome of movement disorders characterized by involuntary muscle contractions leading to abnormal movements and postures. While medical treatment is often ineffective, deep brain stimulation (DBS) of the internal pallidum improves dystonia. Here, we studied the impact of DBS in the entopeduncular nucleus (EP), the rodent equivalent of the human globus pallidus internus, on basal ganglia output in the dt(sz)-hamster, a well-characterized model of dystonia by extracellular recordings. Previous work has shown that EP-DBS improves dystonic symptoms in dt(sz)-hamsters. We report that EP-DBS changes firing pattern in the EP, most neurons switching to a less regular firing pattern during DBS. In contrast, EP-DBS did not change the average firing rate of EP neurons. EP neurons display multiphasic responses to each stimulation impulse, likely underlying the disruption of their firing rhythm. Finally, neurons in the substantia nigra pars reticulata display similar responses to EP-DBS, supporting the idea that EP-DBS affects basal ganglia output activity through the activation of common afferent fibers.

High frequency stimulation of the entopeduncular nucleus sets the cortico-basal ganglia network to a new functional state in the dystonic hamster.

High frequency stimulation (HFS) of the internal pallidum is effective for the treatment of dystonia. Only few studies have investigated the effects of stimulation on the activity of the cortex-basal ganglia network. We here assess within this network the effect of entopeduncular nucleus (EP) HFS on the expression of c-Fos and cytochrome oxidase subunit I (COI) in the dt(sz)-hamster, a well-characterized model of paroxysmal dystonia. In dt(sz)-hamsters, we identified abnormal activity in motor cortex, basal ganglia and thalamus. These structures have already been linked to the pathophysiology of human dystonia. EP-HFS (i) increased striatal c-Fos expression in controls and dystonic hamsters and (ii) reduced thalamic c-Fos expression in dt(sz)-hamsters. EP-HFS had no effect on COI expression. The present results suggest that EP-HFS induces a new network activity state which may improve information processing and finally reduces the severity of dystonic attacks in dt(sz)-hamsters.

Altered nicotinamide adenine dinucleotide (NADH) fluorescence in dt sz mutant hamsters reflects differences in striatal metabolism between severe and mild dystonia.

The dt(sz) mutant hamster represents a unique rodent model of idiopathic paroxysmal dystonia. Previous data, collected post-mortem or in anesthetized hamsters under basal conditions, indicated the critical involvement of enhanced striatal neuronal activity. To assess the importance of an enhanced striatal neuronal activity directly during a dystonic episode, continuous monitoring of changes in brain metabolism and therefore neuronal activity indirectly in awake, freely moving animals is necessary. Determination of CNS metabolism by NADH measurement by laser-induced fluorescence spectroscopy in conscious dt(sz) and nondystonic control hamsters revealed reversible decreased NADH fluorescence during dystonic episodes. The degree of change corresponded to the severity of dystonia. This study represents the first application of this innovative method in freely moving animals exhibiting a movement disorder. Our data clearly confirm that the expression of paroxysmal dystonia in dt(sz) mutant hamsters is associated with enhanced striatal neuronal activity and further underscore the versatile application of NADH fluorescence measurements in neuroscience.

Brivaracetam and seletracetam, two new SV2A ligands, improve paroxysmal dystonia in the dt sz mutant hamster.

Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of paroxysmal dystonia.

Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dt sz mutant.

Striatal dysfunctions seem to play a key role in the pathophysiology of dystonia in the dt(sz) mutant hamster, a model of paroxysmal non-kinesigenic dyskinesia, in which stress precipitates dystonic episodes. Previous examinations have shown changes in kynurenic acid levels and antidystonic effects of the kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfon-amide (Ro 61-8048) after systemic treatment in dt(sz) hamsters. In the present study, intrastriatal injections of Ro 61-8048 (60-80 microg/hemisphere) significantly reduced the severity of dystonia in dt(sz) hamsters, suggesting that kynurenine 3-hydroxylase inhibitors may be interesting candidates for managing dyskinesias which are related to striatal dysfunction.