Neostriatal glutamatergic system is involved in the pathogenesis of picrotoxin-induced choreomyoclonic hyperkinesis

Abstract

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.

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia

“…Hyperkinetic disorders (increased movement) are thought to be a selective loss of GABA/enkephalinergic intrinsic striatal neurons projecting to the lateral globus pallidus and substantia nigra. This results in decreased inhibitory stimulation to the thalamus leading to increased activity of the excitatory glutamatergic thalamocortical pathways and in turn greater neuronal activity in the premotor-motor and supplementary motor cortices [12]. The result is over-facilitation of motor programs resulting in increased motor activity.…”

Verapamil Aggravates Hyperkinesia Produced by Intrastriatal Administration of Picrotoxin in Rats

“…The results of experiments with control and PTtreated animals were described previously [5]. Microinjections of physiological saline into NS had little effect on rat behavior.…”

“…Our previous experiments showed that the glutamatergic system of NS is involved in the development of PT-induced hyperkinesia [5]. Activity of this system is realized via the increase in calcium entry through the corresponding ligand-dependent neuronal channels.…”

“…It can be hypothesized that PT blocks Cl -channels of GABA A receptors and impairs ion exchange and Ca 2+ homeostasis in the striatum via several intermediate (hypothetic) stages. Additional modulation of Ca 2+ channels more significantly changes the effect of PT than activation or blockade of major neuromediators in the nervous system [1,2,5].…”

Intrastrial injection of magnesium after picrotoxin does not reduce motor hyperactivity in rats

“…These data agree with the notions on the pathogenesis of Huntington's chorea [2,8] (picrotoxin hyperkinesia is an analog of this condition). Our studies showed high efficiency of microinjections of magnesium ions into NS simultaneously (in the same cannula) with PT [4,5].We compared the antihyperkinogenic effects of MgCl 2 injected in rat NS before or after PT microinjection. …”