Effect of Selective Lesions within the Substantia Nigra on the Anticonvulsant Effect of Antiepileptic Drugs in Fully-Kindled Rats

Abstract

A substantial body of evidence suggests that the substantia nigra (SN), particularly the pars reticulata region, is a critical site involved in seizure propagation (1,2). Autoradiographic studies of 2-deoxyglucose metabolism have shown that activation of the SN is a stable feature of fully generalized convulsions induced by chemoconvulsants (3) or amygdala-kindling (4). Extracellular, single-cell recording studies have shown that SN neurons exhibit a change in firing pattern, to a bursting mode, during amygdala-kindled seizures (5). Bilateral intranigral micro-injection of either muscimol, a GABA agonist, or gamma-vinyl GABA (GVG), a GABA-elevating drug, were shown to attenuate or block seizures induced by electroshock (6), amygdaloid kindling (7,8), chemoconvulsants such as pentylenetetrazol and bicuculline (6), flurothyl-induced seizures (7), ethanol withdrawal seizures (8), pilocarpine-induced seizures (9), seizures obtained in genetically epilepsy-prone rats (10) as well as spontaneous generalized non-convulsive seizures in rats (11). Furthermore, bilateral microinjection of GVG into the SN retarded kindling development (8,12). In fully kindled rats, biochemical evidence of impaired GABAergic transmission has been found in the SN (13,14). Because GABA has been shown to inhibit nigral efferents, it is likely that the anti-convulsant effect of intranigral application of muscimol or GVG relates to an inhibition of nigral projections that are permissive or facilitative to seizure propagation (1). In support of this, bilateral destruction of the SN by electrocoagulation or microinjection of the neurotoxin kainic acid attenuated bicuculline-induced clonic and tonic seizures as well as tonic electroshock seizures (15). In amygdala-kindled rats, bilateral destruction of SN by N-methyl-D,L-aspartate (NMDA) not only suppressed motor seizures but also reduced afterdischarges recorded at the amygdala, suggesting that the nigra not only transmits seizure activity from rostral to caudal sites but is actively involved in the generation of limbic seizures at the site of origin (7).