Pharmacogenetic studies of the serotonergic system in association with convulsive seizures in mice

Tryptophan hydroxylase (TPH) activity was determined in whole brain from male C57BL/10/Bg and DBA/1Bg mice at 14 different ages between postnatal days 4 and 33. Brain TPH activity was higher at every age in C57BL/10/Bg than in DBA/1/Bg mice, the difference being 30-50% after day 20. The apparent Km of the enzyme for substrate was identical (1.4 X 10(-5) M) in both strains. The reciprocal F1's between DBA/1/Bg and C57BL/10/Bg strains were similar in TPH activity, being slighlty lower than the predicted midparental value. At 30 days of age, C57BL/6/Bg males also had high TPH activity, indistinguishable from the C57BL/10/Bg strain. Audiogenic seizure susceptibility in these strains and their hybrid F1's was inversely correlated with their brain TPH activities. These results indicate that seizure susceptibility and aggression in mice may be related to the serotonergic activity in the brain. In the case of seizures, ethanol-induced susceptibility to audiogenic seizures in mice was enhanced by reserpine, and the effect of reserpine could be reversed by 5-HTP but not by DOPA. Furthermore, p-chlorophenylalanine also enhanced such susceptibility, whereas alpha-methyltyrosine had no effect. In the withdrawal audiogenic seizures in mice during chronic ethanol treatment, adrenalectomy blocked the ethanol-induced increase of brain TPH activity and also prevented the withdrawal seizures. Our results are consistent with the hypothesis that the serotonergic system is among the components regulating excitability in the brain.