Antimyoclonic effect of MK-801: a possible role for NMDA receptors in developmental myoclonus of the neonatal rat.
Rat pups exhibit transient "developmental dyskinesias," such as tremor and myoclonus, that are analogous to motor immaturities of the human neonate. Myoclonic jerks in the neonatal rat may reflect a developmental imbalance of excitatory and inhibitory neurotransmission. To test this hypothesis, spontaneous myoclonic jerks of naive rat pups (n = 200) were characterized behaviorally and pharmacologically. The frequency of myoclonus was high (154 +/- 14 jerks/30 min) in the first week. The distribution of jerks included limbs (47%) (27% in forelimbs and 20% in hindlimbs), tail (30%), trunk (12%), and head (11%). Myoclonus constituted the predominant neonatal adventitious movement (81%). Myoclonic jerks were variable in intensity, focal and multi-focal more often than generalized, and occurred when nonrespiratory movements were infrequent or absent, suggesting sleep. Myoclonic frequency significantly diminished after the second week; therefore, drug effects were studied in the first 7 days. Systemic injection of the novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocked neonatal myoclonus in a dose-dependent manner (ID50 = 0.67 mg/kg; r = 0.93). The nonselective excitatory amino acid (EAA) receptor antagonist kynurenic acid was ineffective. The EAA antagonist AP4 (1 and 10 mg/kg) also reduced myoclonic jerks, but other drugs, such as the selective glycine antagonist Iso-THAO (1 and 10 mg/kg), strychnine (0.5 mg/kg), clonazepam, and diazepam (1 mg/kg), were ineffective blockers. The putative agonists quisqualic acid (1-50 mg/kg) and NMDA (1-10 mg/kg) altered myoclonus only at behaviorally toxic doses. These data suggest that EAA receptors participate in developmental myoclonus of the neonatal rat and that development myoclonus may be a useful quantitative model of functional maturity of excitatory/inhibitory synapses. The efficacy of MK-801 also should be evaluated in drug- and lesion-induced myoclonus. Recognition of the high frequency and state dependence of spontaneous myoclonic jerks in neonatal rats may be important to neonatal antiepileptic drug studies.
Pranzatelli
M R
MR
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
D000613:Aminobutyrates / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D009207:Myoclonus / Q000503:physiopathology*; D016202:N-Methylaspartate / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology
D000613:Aminobutyrates; D000927:Anticonvulsants; D007555:Isoxazoles; D016194:Receptors, N-Methyl-D-Aspartate; D002998:Clonazepam; D016202:N-Methylaspartate; C026803:5,6,7,8-tetrahydro-4H-isoxazolo(4,5-c)azepin-3-ol; D016291:Dizocilpine Maleate; D016318:Quisqualic Acid; D007736:Kynurenic Acid; C012729:2-amino-4-phosphonobutyric acid; D013331:Strychnine; D003975:Diazepam