The sz mutant hamster: a genetic model of epilepsy or of paroxysmal dystonia?

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.

Synthesis of previously inaccessible quinazolines and 1,4-benzodiazepines as potential anticonvulsants.

A series of 4,6,7,8- tetrasubstituted 3,4- dihydroquinazolines , quinazolines, quinazolin -2-ones, 1,2,3,4- tetrahydroquinazolin -2-ones, and 5,7,8,9- tetrasubstituted 1,4-benzodiazepines have been synthesized by utilizing the Diels -Alder reaction between furan o-amino nitriles and various alkyl or aryl vinyl ketone dienophiles to obtain the anthranilic acid precursors. All of the newly synthesized target compounds were evaluated in mice for anticonvulsant activity. Pro- and anticonvulsant action was quantified by the timed intravenous pentylenetetrazol seizure threshold method. Selected compounds were also evaluated for benzodiazepine receptor binding properties and in vivo antagonist potential. Although the compounds lack potency, the data suggest that previously inaccessible substituted analogues may be useful to segregate the proconvulsant , anticonvulsant, and antagonist actions of benzodiazepines and quinazolines.

Synthesis of 3,4-dihydro-4-oxoquinazoline derivatives as potential anticonvulsants.

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.

Quantitative GLC determination of pentylenetetrazol in biological fluids.

A quantitative, sensitive, and specific GLC method was developed for the determination of pentylenetetrazol in water, plasma, and urine. The assay involves a single extraction of the sample into chloroform followed by centrifugation, evaporation, and chromatography. The method for pentylenetetrazol is reproducible, and the sensitivity limit of the assay is 0.5 mug of pentylenetetrazol/ml of biological fluid using a 2-ml sample. This method has a sensitivty sufficient to detect human plasma levels after therapeutic clinical doses and was successfully applied to monitor complete plasma level profiles of this drug in dogs. The data indicate that this drug is very rapidly absorbed following an oral dose, and the half-life of the drug in plasma is approximately 1 hr.

Infantile auditory exposure and unusual response to antipsychiotic drugs (38510).

Reserpine and prochlorperazine were administered in separate experiments to adult CAW:CF1 mice and to adult LVG:LAK hamsters that had recovered from audiosensitization induced by 30 sec of doorbell sound during a critical period of infantile development. In contrast to controls that showed tranquilization in response to these drugs, the previously audiosensitized animals o both species responded with a high incidence of convulsive seizures. The proconvulsant effect of reserpine and prochlorperazine in previously audiosensitized mice was present one hour after drug administration, but had subsided 20 hr post-administration. The proconvulsant effect of reserpine in previously audiosensitized mice was shown to be dose-dependent. The proconvulsant effect of reserpine in previously sensitized hamsters was present 100 days after reserpine and prochlorperazine are poorly understood, possible mechanisms are discussed. Environmental noise during early inantile development appears to have significant residual effects persisting into adult life. This study has shown that idiosyncratic responses to antipsychotic drugs in adult laboratory animals can result from infantile auditory exposure, and it is speculated that human idiosyncrasies to psychoactive drugs may be similarly based.