The role of technical, biological, and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. VII. Seasonal influences on anticonvulsant drug actions in mouse models of generalized seizures

Abstract

Seasonal or circannual rhythms have been reported in various physiologic, biochemical, pharmacological, and toxicological studies in mice and rats despite laboratory conditions with standardized and controlled light cycle, temperature, humidity, and food. This may either be explained by the existence of innate, free-running circannual rhythms or by the existence of seasonally varying environmental factors (‘zeitgeber’) which are detected by the animals despite controlled laboratory conditions. In the present study, it was evaluated whether circannual rhythms affect the anticonvulsant activity of phenobarbital, carbamazepine, or valproate in two mouse models of generalized seizures, i.e. the threshold for generalized tonic seizures in the maximal electroshock seizure (MES) test and the threshold for different types of generalized seizures induced by the chemical convulsant pentylenetetrazol (PTZ). A study protocol was used with data sampling in separate groups of mice per month (using each group only once) over a period of 13 months beginning and ending in late summer (September), so that data collected in the other seasons could be compared with summer values of 2 subsequent years. With all three anticonvulsants, marked seasonal variation was observed in both seizure models with lowest anticonvulsant efficacy and potency in March and April, i.e. in late winter and early spring. The most marked loss of anticonvulsant activity in this period of the year was observed with valproate. Analysis of drug levels in plasma and brain indicated that the seasonal variation in phenobarbital’s and carbamazepine’s anticonvulsant effect was predominantly due to alterations in drug metabolism leading to reduced brain levels in March and April, while the seasonal rhythm in valproate’s activity appeared to be mainly related to altered pharmacodynamic activity. These findings indicate that the time of the year is an important variable in the experimental evaluation of anticonvulsant drugs. Furthermore, the present data add to the accumulating evidence that endogenous circannual rhythms should be considered during animal experiments under controlled laboratory conditions.