An investigation of the histopathological, behavioural, and neurochemical effects of neonatal cholinergic lesions in the rat using ethylcholine mustard aziridinium (AF64A)

This study investigated the long term histopathological, behavioural and neurochemical effects of neonatal intraventricular administration of AF64A. Administration of 2.0, 0.5 and 0.1 nmol/ventricle AF64A on post natal day (PND) 2, resulted in a significant reduction of the enzyme, choline acetyltransferase (ChAT) in the hippocampus but not the cerebral cortex or the caudate nucleus on PND 16. By PND 58 however, no biochemical effects of this lesion were evident in ChAT activity. There was however, a nearly significant depletion of cortical dopamine in animals treated with 2.0 nmol/ventricle AF64A. The initial reduction of hippocampal ChAT in the 2.0 nmol group was accompanied by extensive localized tissue necrosis along the dorsal and ventral perimeters of the lateral ventricles at PND 40. This tissue damage was most evident in the forelimb and parietal areas of the left cortex, in both the right and left caudate nucleus at the decussation of the anterior commissure and finally, at the dorsal hippocampus just anterior to the decussation of the posterior commissure. Behaviourally, the 2.0 nmol-injected animals were characterized by a profound deficit in spatial learning on days 2, 3 and 4, but not on day 5 during place navigation in the Morris water maze. These animals failed to differ from controls on the cued navigation and spatial probe portions of the water maze. They were also hyperactive, entering more arms during a 5 Neonatal cholinergic lesions 3 minute exposure to the elevated-plus maze at PND 58. There were no behavioural differences between 0.5 or 0.1 nmol animals and vehicle administered controls during place navigation, cued navigation and spatial probe portions of testing in the Morris water maze and as well on the elevated-plus maze. It is concluded that the hyperactivity and the profound impairment in spatial learning observed in the 2.0 nmol animals are both the result of AF64A's nonspecific toxic effect on the dorsal hippocampus.