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Progressive myoclonus epilepsy type 1 (EPM1) is an autosomal recessively inherited childhood–adolescence onset neurodegenerative disease caused by mutations in the cystatin B (CSTB gene). The key clinical manifestation in EPM1 is progressive, stimulus-sensitive, in particular action-induced myoclonus. The cystatin B-deficient mouse model, Cstb−/−, has been described to present with myoclonic seizures and progressive ataxia. Here we describe results from in-depth behavioral phenotyping of the Cstb−/− mouse model in pure isogenic 129S2/SvHsd background covering ages from 1.5 to 6 months. We developed a method for software-assisted detection of myoclonus from video recordings of the Cstb−/− mice. Additionally, we observed that the mice were hyperactive and showed reduced startle response, problems in motor coordination and lack of inhibition. We were, however, not able to demonstrate an ataxic phenotype in them. This detailed behavioral phenotyping of the Cstb−/− mice reveals new aspects of this mouse model. The nature of the motor problems in the Cstb−/− mice seems to be more complex and more resembling the human phenotype than initially described.

Abstract α2‐Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α2‐adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail‐flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co‐administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory‐motor block and enables a reduction of the doses of both drugs. The results indicate that co‐administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia.

In order to characterize the sensitivity of an analog of levodopa and a dopamine transporter ligand to detect defects in nigrostriatal function, the uptake of [18F]FDOPA and [18F]CFT was studied ex vivo in a rat model of Parkinson's disease. The brains of these rats were unilaterally lesioned with an intranigral injection of 6-hydroxydopamine. The lesioned animals were divided into three groups subject to their behavior after pharmacological challenges. Circling behavior was recorded after amphetamine, apomorphine, and L-DOPA challenge in order to predict lesion size. The spatial distribution of radioactivity after [18F]FDOPA or [18F]CFT injection in brain sections was determined with digital autoradiography. Regions of interest were left/right striatum, left/right substantia nigra, and cerebellum. The degree of unilateral lesion for each animal was confirmed by counting of nigral tyrosine hydroxylase-positive cell bodies. With both tracers the uptake in the lesioned side was lower than in the intact side in the striatum and in the substantia nigra. In conclusion, both tracers clearly demonstrated nigrostriatal dopaminergic hypofunction and correlated with the number of nigral dopaminergic neurons. However, [18F]FDOPA showed a much higher unspecific uptake of radioactivity, due to extensive metabolism; therefore, this tracer was less sensitive than the transporter tracer [18F]CFT to detect these defects. Synapse 51:119–127, 2004. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]