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GABAB receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of disorders such as epilepsy and spasticity. In dystonia, a movement disorder in which muscle co-contractions cause repetitive twisting movements or abnormal postures, their pathophysiological role is still unknown, although the GABAB receptor agonist baclofen has been reported to be beneficial in dystonic patients and the dtsz hamster. Furthermore, studies in this animal model of primary paroxysmal dystonia demonstrated alterations of the GABAergic system, e.g., a decreased density of striatal GABAergic interneurons and changes in GABAA receptor binding. In order to clarify the role of central GABAB receptors in the pathophysiology of dystonia in the dtsz mutant, we examined the effect of intrastriatal applications of the GABAB receptor agonist baclofen and performed quantitative autoradiographic analysis of ligand binding to the selective GABAB receptor antagonist [3H]-CGP54626.
In the dtsz hamster, dystonia is stress-inducible and occurs between 16 and 70 d of life. For pharmacological studies, groups of 5-8 dtsz hamsters received intrastriatal injections of (R)-baclofen (0.125 µg, 0.25 and 0.5 µg/0.5 µl per hemisphere) at the age of maximum expression of dystonic attacks (30-44 d). For autoradiographic analysis, 10 dtsz hamsters were decapitated (age: 34-36 d) together with an age- and gender-matched control group without preceding induction of dystonia. The brain slices were incubated with 2 nM [3H]-CGP54626 and in order to define non-specific binding 10 µM CGP55845 was used. Densitometric analysis was performed with the MCID system.
All intrastriatal injections of baclofen reduced the severity of dystonic attacks in the dtsz hamster significantly, but in none of the examined 32 brain regions significant differences in [3H]-CGP54626 binding were found between dtsz hamsters and control animals (Bonferroni-corrected: p<0.0016).
The present pharmacological data suggest that a decreased activation of striatal GABAB receptors plays a critical role in the manifestation of dystonic attacks in the dtsz mutant hamster. The [3H]-CGP54626 results suggest that this is not related to altered baseline binding to the GABAB receptor. Autoradiographic studies of dtsz hamsters which were decapitated during dystonic attacks are currently underway.