Attacks of sustained dystonic postures of limbs and trunk can be initiated by mild environmental stimuli in an inbred line of Syrian hamsters. The trait is determined by an autosomal simple recessive genetic mutation, originally designated by the gene symbol sz, because the abnormal movements were thought to represent epileptic seizures. The attacks, which can be reproducibly initiated by placing the sz mutant hamsters in a new environment, begin with rapid twitches of the vibrissae, flattened ears, and flattened posture of the trunk while walking, followed by facial contortions, rearing, and sustained posturing of trunk and limbs, often resulting in falling over to the side or backwards. In the final stage, the hamsters became immobile, which can last for hours. An increased tone of limbs and trunk muscles can be palpated during the attack. Electromyographical recordings in awake, unrestrained mutant hamsters showed that the onset of the attack coincided with continuous tonic muscle activity and phasic bursts, which were present even when the animals did not move. During the attack, the animals continue to react to external stimuli. Bilateral electroencephalographic (EEG) recordings before and during motor disturbances in sz mutant hamsters showed no abnormalities. The severity of the dystonic syndrome in hamsters is age dependent with a peak at about 30-40 days of age. A score system for grading type and severity of dystonic attack was developed for use in drug activity studies. The severity of the attack was reduced or attacks were completely prevented by diazepam (1-2.5 mg/kg i.p.) and valproic acid (100-400 mg/kg i.p.) in a dose-dependent fashion. The latency to dystonic movements was significantly increased by diazepam but markedly reduced by subconvulsive doses of pentylenetetrazol (40 mg/kg s.c.). Diazepam antagonized the latency-reducing action of pentylenetetrazol in the hamsters. The pathophysiology and pharmacological sensitivity of the dystonic attacks in these animals remain to be further clarified, but the data indicate that the sz mutant hamsters might represent an interesting genetic model for paroxysmal dystonia. In view of these data, we propose that the hamster mutation should be re-named dystonic and that the new gene symbol should be designated dtsz.
T h e initial exposure to sound provokes seizures in genetically audio-sensitive mice. I n a stock (e.g., CF# 1) generally considered audio-resistant, repeated sound exposure will under certain conditions induce seizure susceptibility. Susceptibilty is dramatically influenced by age and interval (days) between initial and subsequent exposure to sound. Previous auditory stimulation is absolutely essential for the genesis of convulsions. Selection of age and condition-test interval produced seizures of predictable incidence and severity. Incidence in 12-or 45-day-old mice was about 5% at any interval. However, 18-day-old mice subjected to brief auditory stimulation (60 sec at 95 db) and tested at intervals of 1, 2, 3, 4, or 5 days resulted in a high incidence of convulsions. Clonic-tonic convulsions characterized the seizures at the 2-or 3-day interval; but at 5 days only clonus was seen. Without further sound stimulation mice show a transitory audio-sensitivity lasting about 5 days. Sound-induced convulsions or repeated auditory stimulation prolong sensitivity. Important characteristics of the genetically controlled audiogenic crisis in contrast with other sound-induced convulsions include: the essential prior auditory stimulation, the brief duration of susceptibility, and the adaptation to chronic noise. age-dependent seizure susceptibility sound induced convulsions audiogenic seizures neuro-ontogenic critical period neuro-behavioral development
In mice, an initial audiosensitizing sound (30 sec of a 95 db bell) induces seizure susceptibility to subsequent sound stimuli. Unilateral blockade of opposite ears during sensitization and testing reduced seizure incidence and severity in CF-1 mice, and prolonged latencies. Reduced total seizure incidence was best evidence of the unilateral component of the phenomenon since reduced severity was largely due to blockade of one ear during testing. The unilateral component increased with age and was striking only in animals audiosensitized at 21 days of age. Prolonged latencies were restored to control range by anesthesia during audiosensitization, but were unaffected by electroshock. Since the unilateral component of audiosensitization increases with age as susceptibility to sensitization is declining, both changes may be related to the development of inhibitory mechanisms.
Twenty-three substituted 3,4-dihydro-4-oxoquinazolines or 3,4-dihydro-4-oxoazaquinazolines have been synthesized utilizing 2-amino-3-cyano-4,5-dimethylfuran and methyl acrylate as precursors for synthesis of the required substituted anthranilates. Six additional azaquinazolones were synthesized from 2-aminonicotinic or 3-aminopicolinic acid for comparison studies. All compounds were evaluated in mice with the maximal electroshock (MES) seizure and pentylenetetrazol (sc Met) seizure threshold tests for potential anticonvulsant activity and in the rotorod test to evaluate neurotoxicity. Nine of the twenty-nine compounds in the series demonstrated anticonvulsant action. The azaquinazolones were found to possess the most significant activity.
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