Effects of the anticholinesterase drug tacrine on the development of PTZ kindling and on learning and memory processes in mice.
BACKGROUND
The anticholinesterase drug tacrine (Tac) is known to have a beneficial effect on memory deficit in mice involving in the process the cholinergic system in the brain. Chemically induced kindling is a well-known model of petit mal epilepsy. Kindling develops after repeated administration of subconvulsant doses of pentylenetetrazole (PTZ). This model is suitable for studying the two CNS disturbances associated with epilepsy, i.e. seizure attacks and memory impairment. OBJECTIVE. The aim of the present study was to examine the effect of the anticholinesterase drug Tac on the model of PTZ kindling and on active avoidance in mice. METHODS. Kindling was induced by repeated administration of PTZ (40 mg/kg) s.c. at 48-hour intervals. Tac (at doses of 0.1, 0.5 and 1 mg/kg) was injected 40 minutes before PTZ over an 8 - week period in 4 experimental groups of mice. Seizure intensity was scored using a 5-grade scale. Kindling was defined as 3, 4 or 5 grade seizures evoked by 3 consecutive doses of PTZ and treatment was discontinued. The active avoidance method (training session consisting of 50 trials) was used to test learning and memory functions. On day 7 following the learning session a memory retention test was performed. The challenge dose of PTZ was given after a 15-day discontinuation of treatment.


RESULTS
In control mice, kindling was developed over a 7-week period of treatment. Mice injected with Tac (in 3 consecutive doses) showed increased seizure intensity from week 1 through week 7 of the study. On learning and memory retention tests kindled mice showed a reduced learning capabilities whereas a statistically significant upward tendency in the number of conditioned responses (avoidances) was recorded in mice treated with Tac (1 mg/kg), when compared with the controls. Mice treated with Tac (in doses of 0.1 and 0.5 mg/kg) also exhibited an increased number of avoidances on learning and memory retention tests.


CONCLUSIONS
1. The anticholinesterase drug Tac increased the seizure intensity and facilitated the development of PTZ kindling in mice. 2. On the basis of well-developed kindling Tac did not impair the memory of the experimental animals, which is possibly due to its CNS stimulating effect.
Getova
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Correspondence and reprint reqHigher Medical Institute, Department of Pharmacology Plovdiv, Bulgaria.
Dimitrova
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DS
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole; D011336:Probability; D012016:Reference Values; D012680:Sensitivity and Specificity; D013619:Tacrine / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D013619:Tacrine; D010433:Pentylenetetrazole