Pharmacological and autoradiographic studies on the pathophysiological role of GABA(B) receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections.
The GABA(B) receptor (GABA(B)R) 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(A)R) binding in several brain regions. In order to clarify the pathophysiological role of central GABA(B)Rs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA(B)R 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 microg/0.5 microl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA(B)R antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 microg/0.5 microl] 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.
Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Freie Universität Berlin, Koserstr. 20, 14195 Berlin, Germany. sander.svenja@vetmed.fu-berlin.de
S E
SE
Sander
F
F
Richter
R
R
Raymond
M
M
Diwan
N
N
Lange
J N
JN
Nobrega
A
A
Richter
D000818:Animals; D030801:Animals, Genetically Modified; D001345:Autoradiography; D001418:Baclofen / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D006224:Cricetinae; D004421:Dystonia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D008845:Microinjections; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000502:physiology*
D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C066430:CGP 35348; D001418:Baclofen