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

Abstract

The GABA B receptor (GABA BR) 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 dt sz hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA A receptor (GABA AR) binding in several brain regions. In order to clarify the pathophysiological role of central GABA BRs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA BR agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt sz 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 GABA BR 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 dt sz hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt sz hamsters. In view of the absence of striatal changes in GABA B binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.