Pharmacological and autoradiographic studies on the pathophysiological role of GABAB receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections

The GABAB receptor (GABABR) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dtsz hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABAA receptor (GABAAR) binding in several brain regions. In order to clarify the pathophysiological role of central GABABRs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABABR agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dtsz hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 μg/0.5 μl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABABR antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 μg/0.5 μl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dtsz hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dtsz hamsters. In view of the absence of striatal changes in GABAB binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.