Is the anticonvulsant effect of substantia nigra infusion of gamma-vinyl-GABA (GVG) mediated by the GABA_A receptor in rat pups?

The substantia nigra GABAergic system is considered important for the modification of seizures. Our previous studies have shown that, in rat pups, nigral infusions of baclofen suppressed flurothyl-induced seizures. In the present study, we determined, in rat pups, the effect of nigral infusions of γ-vinyl-GABA (GVG) on clonic-tonic seizures induced by flurothyl, generated a dose-response curve of the GVG effect and investigated the possible role of the nigral GABA_A receptor in mediating the GVG effect. Bilateral nigral infusions of GVG profoundly suppressed flurothyl-induced tonic seizures in a dose-dependent fashion. Flurothyl-induced clonic seizures were not modified. The lowest effective dose of nigral GVG administration was 5 μg/0.25 μl per site. Nigral infusions of GVG at doses greater than 10 μg/0.25 μl induced sedation as well. Infusions of GVG, 2 mm dorsal to the substantia nigra, did not alter seizure latencies. Bilateral nigral infusions of bicuculline, a specific GABA_A receptor antagonist, reduced the protective potency of GVG against flurothyl-induced seizures. Nigrally administered muscimol, a GABA_A receptor agonist, also attenuated the anticonvulsant effect of GVG. These findings suggest that the optimal dose of nigrally infused GVG against flurothyl-induced seizures is in the range of 5-10 μg/0.25 μl and that GVG may be more efficient as an anticonvulsant for the treatment of tonic seizures in developing animals. The anticonvulsant effect of GVG may, in part, involve the nigral GABA_A receptor. The data, together with the previous experiments, indicate that both nigral GABA_A and GABA_B receptors may play a role in the regulation of seizures in rat pups. The possible mechanisms through which nigrally infused muscimol reduced the action of GVG are discussed.