The metabotropic
glutamate 5 (mGlu5) receptor has been suggested as therapeutic target for
L-Dopa-induced
dyskinesia which is often associated with dystonic symptoms. Therefore, we investigated the acute effects of the non-competitive mGlu5 receptor antagonist
fenobam as well as the positive modulator
3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (
CDPPB) on the severity of inherited
dystonia in the mutant dtsz hamster, a phenotypic model with age-dependent episodes of
dystonia.
Fenobam did not exert significant antidystonic effects (20-50 mg/kg intraperinoneal, i.p.).
CDPPB (10, 20 mg/kg i.p.) which was expected to worsen
dystonia also failed to show any effects on the severity of
dystonia. Interestingly,
CDPPB caused axial
dyskinesia in addition to the dystonic symptoms in mutant hamsters. This adverse effect could not be observed in non-dystonic control hamsters, indicating possible changes in the expression of mGlu5 receptors in dystonic hamsters. The mGlu5 receptor
mRNA did not differ between the dtsz mutant and control hamsters, while immunohistochemical studies indicated that the mGlu5 receptor expression was about 35% higher in striatum and cortex of mutant hamsters at the age of high
dystonia severity scores, notably not after spontaneous remission of
dystonia, compared to age-matched controls. This difference in mGlu5 receptor
protein may be due to altered protein conformation instead of
protein level, as western blots revealed similar amounts of monomeric and dimeric
protein in mutant hamsters versus control. Thus, the present data do not provide clear evidence for an important role of the mGlu5 receptor in the pathophysiology and as a therapeutic target for types of inherited
dystonia.