The pathogenesis of Huntington's disease is still not completely understood. Several lines of evidence from toxic/non-transgenic animal models of Huntington's disease suggest that excitotoxic mechanisms may contribute to the pathological phenotype. Evidence from transgenic animal models of Huntington's disease, however, is sparse. To explore potential alterations in brain glutamate handling we studied transgenic mice expressing an N-terminal fragment of mutant huntingtin (R6/2). Intracerebral microdialysis in freely moving mice showed similar extracellular glutamate levels in R6/2 and littermate controls. However, partial inhibition of glutamate transport by L-trans-pyrrolidine-2,4-dicarboxylate (4 mM) disclosed an age-dependent increase in extracellular glutamate levels in R6/2 mice compared with controls, consistent with a reduction of functional glutamate transport capacity. Biochemical studies demonstrated an age-dependent downregulation of the glial glutamate transporter GLT-1 mRNA and protein, resulting in a progressive reduction of transporter function. Glutamate transporters other than GLT-1 were unchanged. In addition, increased extracellular glutamine levels and alterations to glutamine synthetase immunoreactivity suggested a perturbation of the glutamate-glutamine cycle. These findings demonstrate that the Huntington's disease mutation results in a progressively deranged glutamate handling in the brain, beginning before the onset of symptoms in mice. They also provide evidence for a contribution of excitotoxicity to the pathophysiology of Huntington's disease, and thus Huntington's disease may be added to the growing list of neurodegenerative disorders associated with compromised glutamate transport capacity.

The current study determined the extracellular content of glutamate, 10 additional amino acids, lactate, glucose and some antioxidants in a rodent model of malignant glioma, its peritumoral space and the adjacent cortex. RG2 tumors were induced in the right frontal cortex of Fischer-344 rats (n = 10) by a standardized procedure to obtain a maximum sagittal tumor width of 3-4 mm diameter. After confirmation of tumor growth and localization by contrast enhanced MRI three microdialysis probes were implanted simultaneously in the cortex: at the tumor implantation site (tumor), 2 mm caudally, brain around tumor (BAT) and 4 mm caudally (cortex) to the site of implantation. Dialysate concentrations of glutamate were increased 3.9-fold in tumor and 2-fold in BAT compared with cortex. Glycine was elevated 11.4-fold in tumor and 2.6-fold in BAT. Lactate was increased 1.7-fold in tumor, 1.2-fold in BAT. Levels of glucose, ascorbic acid and uric acid were not significantly different in tumor, BAT and cortex. The increased dialysate levels of glutamate and glycine in the peritumoral space may contribute to impaired neuronal function and epileptiform activity associated with this tumor type in humans.

In Huntington's disease (HD), neuronal loss is most prominent in the striatum leading to emotional, cognitive and progressive motor dysfunction. The R6/2 mice, transgenic for exon 1 of the HD gene, develop a neurological phenotype with similarities to these features of HD. In striatal tissue, electrically evoked release of tritiated acetylcholine (ACh) and dopamine (DA) were compared in wild-type (WT) and R6/2 mice. In R6/2 mice, the evoked release of ACh, its M2 autoreceptor-mediated maximum inhibition and its dopamine D2 heteroreceptormediated maximum inhibition was diminished to 51%, 74% and 87% of controls, respectively. Also, the activities of choline acetyltransferase and of synaptosomal high-affinity choline uptake decreased progressively with age in these mice. In the DA release model, however, electrical stimulation elicited equal amounts of [ 3 H]-DA both in WT and R6/2 mice. Moreover, high-affinity DA uptake into striatal slices was similar in WT and R6/2 mice. In order to confirm these findings in vivo, intrastriatal levels of extracellular DA were measured by intracerebral microdialysis in freely moving mice: striatal DA levels were found to be equal in WT and R6/2 mice. In conclusion, in the transgenic R6/2 mice changes occur mainly in striatal cholinergic neurones and their pre-synaptic modulation, but not in the dopaminergic afferent terminals. Whether similar events also contribute to the pathogenesis of HD in humans has to be established. Keywords: acetylcholine, dopamine, Huntington's disease, microdialysis, striatum, transgenic mice. Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder. It is caused by an unstable expanded CAG nucleotide repeat greater than 37 in the 5¢-coding region within the huntingtin gene on chromosome 4 (Huntington's Disease Collaborative Research Group 1993). The primary brain region affected in HD is the striatum, where selective degeneration of GABAergic projection neurones takes place. HD begins at about the age of 40 and is characterized by depression, dementia and progressive motor dysfunction, such as hyperkinesia. Currently, HD patients can only be treated symptomatically, as there is no causal therapy. Medication mainly consists of the dopamine (DA) antagonists haloperidole and tiapride to alleviate hyperkinesis, and of sulpiride to treat depression .The first transgenic HD mouse model, developed by G. Bates, is expressing exon 1 of the mutated human HD gene with a CAG repeat length of 141-157. These mice (line R6/2) display a progressive neuronal disorder (Mangiarini et al. 1996;Carter et al. 1999). At the age of 9-11 weeks they develop stereotypic and epileptic movements, irregular gait and resting tremor. Their mean lifetime is about 100 days. Histologically, no selective neurodegeneration Received October 1, 2002; revised manuscript received December 17, 2002; accepted January 16, 2003. Address correspondence and reprint requests to Jan M. Vetter, Sektion Klinische Neuropharmakologie der Neurologischen Univers...

Results from this new procedure showed a significant reduction (p = 0.009) in the average distance from the SPG microstimulator to the desired target point. Therefore, a distinct improvement could be achieved in positioning of the SPG microstimulator through the use of intraoperative navigation during the initial dissection and by post-operative matching of pre- and post-operatively performed CBCT scans.

Background Based on promising effects seen in a pilot study evaluating a generic mindfulness-based program for migraine, we developed a migraine-specific adaptation of the Mindfulness-Based Cognitive Therapy (MBCT) program. The aim of this study was to evaluate this program for feasibility and effectiveness in a randomized controlled trial. Method Fifty-four patients suffering from migraine were randomly allocated to either waitlist or the adapted MBCT. Outcomes were migraine-related parameters as well as variables of psychological functioning and coping. Assessment took place at baseline and post-intervention, for the intervention group also at follow-up (7 months). The effects of the intervention were analyzed by the use of ANCOVAs and linear mixed models. Results With respect to migraine parameters we did not find a significant group difference in the primary outcome (headache-related impairment), but the intervention resulted in a significant reduction of headache frequency (p = .04). In the analysis of secondary outcomes, MBCT showed superiority in four out of eight psychological parameters (perceived stress, anxiety, rumination, catastrophizing) with small to medium effect sizes. The intervention proved to be feasible and participants reported high degrees of contentment and achievement of personal goals. Conclusions The migraine-specific MBCT program did not result in improvements with regard to headache-related impairment but showed a reduction in headache frequency as well as improved psychological functioning in secondary outcomes. Trial Registration This trial was registered in the German Trial Registry “Deutsches Register Klinischer Studien” (ID: DRKS00007477), which is a WHO-listed primary trial register.

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