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 magnocellularis has been shown to prevent the loss of cortically-projecting neurons in that basal forebrain region. The present study tested whether this neuroprotective activity would lead to chronic sparing of a behaviour known to be impaired by that lesion, as well as to chronic maintenance of cholinergic activity in cortical target regions of the nucleus basalis. CEP-1347/KT-7515 was injected into adult rats that had sustained bilateral ibotenic acid lesions of the nucleus basalis magnocellularis; the first injection occurred 18-24 h after lesioning, with subsequent injections of CEP-1347/KT-7515 occurring every other day over 12 days. One day following the last injection the animals were tested for retention of a previously-learned delayed alternation task. Animals that received CEP-1347/KT-7515 committed significantly fewer errors than lesioned animals receiving vehicle. These same animals were tested again eight to 10 weeks later (which was 10-12 weeks post-dosing), without receiving further drug or behaviour training during the test-retest interval. The animals that had received CEP-1347/KT-7515 continued to commit significantly fewer errors than vehicle animals. Furthermore their performance at this time point was indistinguishable from normal controls. Analysis of errors showed that CEP-1347/KT-7515 prevented a lesion-induced increase in perseverative errors, suggesting the drug improved attention in the lesioned animals. Choline acetyltransferase activity in the frontal cortex of the behaviourally tested animals that received CEP-1347/KT-7515 three months previously showed a significant 40% recovery of the lesion-induced loss seen in the vehicle 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 behaviour.
DiCamillo
A M
AM
Cephalon, Inc., West Chester, PA 19380, USA.
Neff
N T
NT
Carswell
S
S
Haun
F A
FA
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D007839:Functional Laterality; D007051:Ibotenic Acid / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D013377:Substantia Innominata / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D013997:Time Factors
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C106592:3,9-bis((ethylthio)methyl)-K-252a; D007051:Ibotenic Acid; D002795:Choline O-Acetyltransferase