title: Antimyoclonic effect of MK-801: a possible role for NMDA receptors in developmental myoclonus of the neonatal rat.
abstract: 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.
authors: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors: M R
authors: MR
authors: Pranzatelli
mesh_terms: 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
chemical_list: 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