Chemically induced choreiform activity: Antagonism by GABA and EEG patterns

Relative potencies were determined for several agents capable of inducing choreiform activity when applied unilaterally to the striatum of unanesthetized rats. Picrotoxinin, 2.59 × 10^-10 moles 10 μl, was followed in order of decreasing potency by d-tubocurarine, alcuronium, carbachol, bicuculline, and thiosemicarbazide. The involuntary movements induced by d-tubocurarine were blocked by intrastriatal infusions of either γ-aminobutyric acid or glutamic acid but not by glycine, aspartic, acid or homocysteic acid. The blocking actions of glutamic acid were attenuated by the presence of allylglycine, a glutamic acid decarboxylase inhibitor. Similarly, striatal infusions of glutamic acid reduced or blocked the choreiform activity induced by picrotoxinin, carbachol, alcuronium, or thiosemicarbazide.. The EEG patterns following intrastriatal d-tubocurarine in unanesthetized, immobilized rats were characterized by large cortical potentials, 0.5-1.5 mv, with a frequency of 0.5/sec. This activity was interrupted every 30-90 sec by episodes of seizurelike activity, lasting 5-10 sec. Unilateral perfusion of the cat caudate nucleus, using a push-pull cannula and Locke's solution containing d-tubocurarine, 1-2 mg/ml, produced large rhythmic discharges in both cerebral cortices and the caudate nucleus. In most animals, this discharge pattern was interrupted periodically by seizure-like activity. Gamma-aminobutyric acid (GABA), added to the perfusion fluid, did not antagonize the effects of d-tubocurarine on the EEG. These results suggest that the involuntary movements induced by d-tubocurarine in the rat may be due to GABA-receptor blockade in the striatum or an increased dopamine release resulting from GABA-receptor blockade. These conclusions are consistent not only with the long-held theory that human hyperkinetic disorders are the result of an increased dopaminergic activity in the basal ganglia, but also with the more recent finding of an abnormally low GABA content in the basal ganglia of patients with Huntington's chorea. Although the EEG changes induced in rats and cats by d-tubocurarine are not consistent with clinical EEG data in Huntington's chorea, the apparent biochemical, behavioral, and pharmacological correlates between this model and hyperkinetic syndromes in man may suggest some common neurochemical denominator.