Administration of dizocilpine (MK-801, noncompetitive antagonist of NMDA glutamate receptors) into the neostriatum decreased the reproducibility and duration of hyperkinesis in rats induced by repeated microinjections of GABA(A) receptor antagonist picrotoxin. By contrast, glutamate potentiated the hyperkinetic and convulsive effect of picrotoxin and promoted the inhibition of conditioned avoidance response. Our results indicate that the striatal glutamatergic system is involved in the development of locomotor and cognitive disorders associated with deficiency of the neostriatal GABAergic system and playing a role in the pathogenesis of Huntington's chorea.
Chronic experiments were performed on rats to study the main inhibitory transmitter system of the neostriatum--the GABAergic system--in the regulation of normal and pathological motor behavior. Studies addressed the effects of separate and combined administration of GABA (45 microg) and A-type receptor antagonists, i.e., picrotoxin (1 microg) and bicuculline (5 microg), into the neostriatum on the performance by rats of spontaneous (including pathological) and conditioned reflex motor behavior (active avoidance reflex in a shuttle box). Agents were injected in a volume of 1 microl daily for three weeks; control animals received physiological saline. Activation of the GABAergic system of the neostriatum had no significant effect on behavior. Conditioned reflex avoidance behavior was impaired throughout the period of bicuculline administration (there was no significant change in spontaneous behavior); this recovered after the course of microinjections finished. Picrotoxin produced smaller negative effects on performance of the reflex, though rats showed clear imperative movements in the form of choreomyoclonic hyperkinesia. Simultaneous administration of picrotoxin and GABA into the neostriatum produced less hyperkinesia; administration of picrotoxin and bicuculline altered the nature of hyperkinesia. The importance of the GABAergic system for the antihyperkinetic activity of the basal ganglia is discussed, and it is suggested that the GABA-A subsystem is of critical importance in these functions.
The effects of slow Ca2+ channel blocker verapamil and Ca2(+)-binding agent EDTA were studied on the model of choreic hyperkinesia induced by chronic intrastriatal microinjections GABAA receptor antagonist picrotoxin. Normal and pathological movements were recorded. The test preparations facilitated the effect of picrotoxin on spontaneous and learned behavior. They exerted a permissive effect on picrotoxin-induced hyperkinesia: increase reproducibility and duration of hyperkinesia and decrease the latency of this reaction. Our results indicate that Ca2+ channels are involved into the development and progression of hyperkinesia.
Chronic experiments on rats were performed to study the effects of daily administration of the GABA(A) receptor antagonist picrotoxin (2 microg) into the rostral neostriatum in rats. Picrotoxin was injected in 1 microl of sterile apyrogenic physiological saline or in 1 microl of 1.0 M or 1.5 M MgCl(2); control animals received physiological saline or 1.0 M MgCl(2). Picrotoxin given in physiological saline induced impairments in conditioned reflex (avoidance) and free motor behavior and produced clear stereotypical imperative movements in the form of choreomyoclonic hyperkinesia of the paws, head, and trunk. These motor impairments resembled the manifestaitons of basal ganglia dysfunction typical of Huntingdon's chorea in humans. Magnesium ions prevented both the development of hyperkinesia and impairments of learned behavior. Given that magnesium is a nonspecific calcium channel antagonist, it can be suggested that one of the leading mechanisms of development of hyperkinesias is impairment of calcium homeostasis in striatal neurons.
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