Characterization of Susceptibility to Audiogenic Seizures in Ethanol-Dependent Rats after Microinjection of γ-Aminobutyric Acid (GABA) Agonists into the Inferior Colliculus Substantia Nigra or Medial Septum

摘要

The relative anticonvulsant potential of the γ-aminobutyric acid (GABA) agonist, muscimol, was compared after microinjection into either the inferior colliculus, substantia nigra or medial septum of ethanol-dependent rats. Bilateral microinjection of muscimol (10–30 ng) into the inferior colliculus 15 to 60 min before testing suppressed all sound-induced seizure components (wild running, clonus and tonus) in rats withdrawn from ethanol for 6.5 to 8.5 hr. However, forelimb tremors were not altered. Audiogenic seizures were suppressed for at least 3 hr after muscimol (30 ng). In the medial septum and substantia nigra, microinjection of muscimol (30–100 ng) only partially reduced the tonic component of audiogenic seizures and exerted no effect on the frequency of wild running or clonus. GABA (10 μg) and two other GABA agonists [4,5,6,7-tetrahydroisoxa-zolo[5,40c]pyridin-3-ol (THIP), 300 ng and chlordiazepoxide, 10–30 μg], microinjected into the inferior colliculus, also reduced audiogenic seizure susceptibility. However, 1,3-butanediol, which suppresses ethanol withdrawal seizures after peripheral administration in rats, was inactive. The relative proconvulsant potential of the GABA antagonist, bicuculline methiodide, also was compared after microinjection into either the inferior colliculus, substantia nigra or medial septum of ethanol naive rats. In each animal, audiogenic seizure-like wild running, clonus and tonus were evoked by microinjecting bicuculline methiodide into the inferior colliculus at the rate of 6.0 ng/6 min. However, these reactions did not occur when bicuculline methiodide was applied at a slower rate (1.8 ng/6 min). Similar injections of bicuculline methiodide (600 ng/6 min) into the substantia nigra caused only clonus and tonus without wild running. A smaller dose (180 ng/6 min) had no effect. In the medial septum, microinjection of this GABA antagonist (1800 ng/6 min) did not exert any obvious seizure-like activity. These results suggest that the inferior colliculus is important in GABAmimetic suppression of audiogenic seizures and that reduced GABAergic activity in this nucleus may be responsible for the increased susceptibility to audiogenic seizures in rats during ethanol withdrawal.