The pathophysiology of idiopathic dystonias is still unknown, but it is regarded as a
basal ganglia disorder. Previous experiments in the dt(sz) hamster, a model of primary
paroxysmal dystonia, demonstrated reduced discharge rates and an abnormal pattern within the entopeduncular nucleus (EPN), a basal ganglia output structure. To clarify if this is based on abnormal
gamma-aminobutyric acid(
GABA)ergic or glutamatergic input, microinjections into the EPN were done in mutant hamsters in the present study. The
GABA(A) receptor antagonists pentylenetetrazole and
bicuculline exerted moderate antidystonic effects, while previous systemic administrations worsened
dystonia in the dt(sz) mutant.
GABA-potentiating drugs, i.e., the
GABA(A) receptor agonist muscimol and the
GABA transporter inhibitor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxy-lic
acid (NNC-711), which are known to improve
dystonia after systemic treatment in mutant hamsters, did not exert significant effects after EPN
injections, but
NNC-711 tended to increase the severity at the highest dose (2.5 ng bilateral). The
NMDA receptor antagonist D(-)-2-amino-5-phosphopentanoic
acid (AP-5) retarded the onset of a dystonic attack. However, this effect was not dose dependent and the
AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline (
NBQX) alone or in combination with AP-5 and
NNC-711, also failed to show any effects on
dystonia. The present data do not provide clear evidence for an enhanced striatal GABAergic input or a reduced glutamatergic activation of the EPN via the subthalamic nucleus, i.e., more pronounced antidystonic effects of
GABA(A) receptor antagonists and stronger prodystonic effects of GABAmimetics and
glutamate receptor antagonists were expected. Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters.