Repeated acute testing of anticonvulsant drugs in amygdala kindled rats: increase in anticonvulsant but decrease in adverse effect potential.
OBJECTIVE
Because preparation of kindled rats is laborious, time-consuming, and expensive, such animals are often used for several experiments in the evaluation of anticonvulsant drugs (AEDs). Furthermore, for comparison with data on new drugs, often "historical" data on standard drugs obtained in previous experiments in other groups of kindled rats are used. Without knowing how factors such as repeated drug testing or seasonal variation in drug responses affect drug potencies in the kindling model, false conclusions and predictions might be drawn from such comparisons. In this study, we examined the anticonvulsant and adverse effects of the three clinically established AEDs carbamazepine (CBZ), phenobarbital (PB), and valproate (VPA) once per month in the same two groups of amygdala-kindled rats over a period of 9 (group 1) or 6 (group 2) consecutive months. To evaluate the possible effect of the season, experiments in group 1 were started in autumn, and experiments in group 2 in spring.


METHODS
For quantification of anticonvulsant activity, the focal seizure threshold (threshold for afterdischarges; ADT) was determined after each acute drug treatment and compared with a control ADT determined 2-3 days before.


RESULTS
The repeated acute (single-dose) drug testing in the same groups of amygdala-kindled rats led to three pronounced alterations in the animals: (a) a significant decrease in ADT, (b) a marked potentiation of AED effects on ADT, and (c) a striking reduction in ataxia produced by drug treatments. Drug levels in plasma, which were determined in each drug trial, showed only moderate variation over the period of the experiments, so that the observed alterations in drug responses were certainly not due to pharmacokinetic factors. PB and VPA, but not CBZ, showed a more potent anticonvulsant effect when experiments were started in October (group 1) compared with April (group 2), but this difference was rapidly overridden by the marked and progressive potentiation of anticonvulsant activity on repeated drug testing.


CONCLUSIONS
These data demonstrate that repeated use of the same kindled rats for acute drug testing significantly alters the sensitivity of the animals to the anticonvulsant and adverse effects of drugs. Because the anticonvulsant potency increases, whereas the adverse effect potential decreases during repeated acute drug testing, this may lead to false-positive data on a test compound. The mechanisms involved in these observations deserve further studies.
Löscher
W
W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany. wloscher@pharma.tiho-hannover.de
Fiedler
M
M
D000679:Amygdala / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D001259:Ataxia / Q000209:etiology / Q000517:prevention & control; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002220:Carbamazepine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004558:Electric Stimulation; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D010507:Periodicity; D010634:Phenobarbital / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012621:Seasons; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D010634:Phenobarbital