Inhibition of the substantia nigra suppresses absences and clonic seizures in audiogenic rats, but not tonic seizures: evidence for seizure specificity of the nigral control.
GABAergic inhibition of the substantia nigra pars reticulata has been shown to suppress seizures in most models of epilepsy involving forebrain networks, such as absences or clonic seizures. No such antiepileptic effects were observed, however, in genetically audiogenic rats exhibiting tonic seizures generated in the brainstem. This suggests a constitutive dysfunction of the nigral GABAergic neurotransmission in this strain of rat or a selective action of the nigral control on specific networks. In the present study, we first confirmed that bilateral injection of muscimol (700 pmol/side) in the substantia nigra had no effect in Wistar rats with audiogenic seizures (Wistar AS). [3H]Muscimol autoradiography suggested a 40% reduced density of GABA(A) receptors in the substantia nigra of Wistar AS, whereas no change was observed in the cortex and the superior colliculus (superficial and intermediate layers), as compared to control animals. In Wistar AS where 40 repetitions of audiogenic stimulations progressively induced generalised convulsive seizures with both tonic and clonic components, bilateral injection of muscimol (350 pmol/side) in the substantia nigra suppressed the clonic component but had no effect on tonic seizures. In hybrid rats issued from cross-breeding between Wistar AS and rats with spontaneous absence seizures, bilateral injection of muscimol (18 pmol/side) in the substantia nigra abolished cortical spike-and-wave discharges, but had no effect on tonic audiogenic seizures at doses up to 700 pmol/side. These results show that despite a decreased number of GABA(A) receptors in the substantia nigra, inhibition of this structure in Wistar AS still leads to inhibition of seizures involving forebrain structures. These results confirm that GABAergic inhibition of the substantia nigra has antiepileptic effects through the control of forebrain circuits. They suggest that this control mechanism has no inhibitory effect on circuits underlying audiogenic tonic seizures.
Deransart
C
C
Klinikum der Albert-ludwigs-Universität, Neurozentrum, Freiburg-im-Breisgau, Germany.
Lê-Pham
B T
BT
Hirsch
E
E
Marescaux
C
C
Depaulis
A
A
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D001306:Auditory Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000378:metabolism / Q000503:physiopathology*; D020195:Epilepsy, Reflex / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018755:GABA Agonists / Q000493:pharmacokinetics; D058785:GABA-A Receptor Agonists; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D009118:Muscimol / Q000493:pharmacokinetics; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid