CHRONIC SPARING OF DELAYED ALTERNATION PERFORMANCE AND CHOLINE-ACETYLTRANSFERASE ACTIVITY BY CEP-1347 KT-7515 IN RATS WITH LESIONS OF NUCLEUS BASALIS MAGNOCELLULARIS/

Peripheral injection of the indolocarbazole CEP-1347/KT-7515 into rats that have sustained ibotenic acid lesions of the nucleus basalis magn ocellularis has been shown to prevent the loss of cortically-projectin g neurons in that basal forebrain region. The present study tested whe ther this neuroprotective activity would lead to chronic sparing of a behaviour known to be impaired by thar lesion, as well as to chronic m aintenance of cholinergic activity in cortical target regions of the n ucleus basalis. CEP-1347/KT-7515 was injected into adult rats that had sustained bilateral ibotenic acid lesions of the nucleus basalis magn ocellularis; the first injection occurred 18-24 h after lesioning, wit h subsequent injections of CEP-1347/KT-7515 occurring every other day over 12 days. Orle day following the last injection the animals were t ested for retention of a previously-learned delayed alternation task. Animals that received CEP-1347/KT-7515 committed significantly fewer e rrors than lesioned animals receiving vehicle. These same animals were tested again eight to 10 weeks later ( which was 10-12 weeks post-dos ing), without receiving further drug or behaviour training during the test-retest interval. The animals that had received CEP-1347/KT-7515 c ontinued to commit significantly fewer errors than vehicle animals. Fu rthermore their performance at this time point was indistinguishable f rom normal controls. Analysis of errors showed that CEP-1347/KT-7515 p revented a lesion-induced increase in perseverative errors, suggesting the drug improved attention in the lesioned animals. Choline acetyltr ansferase activity in the frontal cortex of the behaviourally tested a nimals that received CEP-1347/KT-7515 three months previously showed a significant 40% recovery of the lesion-induced loss seen in the vehic le animals. These results demonstrate that treatment with CEP-1347/KT- 7515 over 12 days following excitotoxic damage to the nucleus basalis magnocellularis produces long-term sparing of an attention-demanding b ehaviour. (C) 1998 IBRO. Published by Elsevier Science Ltd.