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

Seasonal or circannual rhythms have been reported in various physiologic, b iochemical, pharmacological, and toxicological studies in mice and rats des pite laboratory conditions with standardized and controlled light cycle, te mperature, humidity, and food. This may either be explained by the existenc e of innate, free-running circannual rhythms or by the existence of seasona lly varying environmental factors ('zeitgeber') which are detected by the a nimals despite controlled laboratory conditions. In the present study, it w as evaluated whether circannual rhythms affect the anticonvulsant activity of phenobarbital, carbamazepine, or valproate in two mouse models of genera lized seizures, i.e. the threshold for generalized tonic seizures in the ma ximal electroshock seizure (MES) test and the threshold for different types of generalized seizures induced by the chemical convulsant pentylenetetraz ol (PTZ). A study protocol was used with data sampling in separate groups o f mice per month (using each group only once) over a period of 13 months be ginning and ending in late summer (September), so that data collected in th e 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 Marc h 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 valpro ate. Analysis of drug levels in plasma and brain indicated that the seasona l variation in phenobarbital's and carbamazepine's anticonvulsant effect wa s predominantly due to alterations in drug metabolism leading to reduced br ain levels in March and April, while the seasonal rhythm in valproate's act ivity appeared to be mainly related to altered pharmacodynamic activity. Th ese findings indicate that the time of the year is an important variable in the experimental evaluation of anticonvulsant drugs. Furthermore, the pres ent data add to the accumulating evidence that endogenous circannual rhythm s should be considered during animal experiments under controlled laborator y conditions. (C) 2000 Elsevier Science B.V. All rights reserved.