Brain Research, 557 (1991) 57-63 Elsevier Science Publishers B.V. ADONIS 000689939116886T BRES 16886 57 Effects of tetrahydroaminoacridine (THA) on functional recovery after sequential lesion of the entorhinal cortex J.P. Kesslak, A. Korotzer, A. Song, K. Kamali and C.W. Cotman Department of Psychobiology, University of California, lrvine, lrvine, CA 92717 (U.S.A.) (Accepted 26 March 1991) Key words: Tetrahydroaminoacridine; Functional recovery; Entorhinal cortex; Serial lesion Unilateral lesions of rat entorhinai cortex produce a transitory performance deficit on spatial learning tasks, such as reinforced alternation in a T-maze. Tetrahydroaminoacridine (THA), a cholinesterase inhibitor, was administered to determine its effects on behavioral recovery using a reinforced alternation task in a T-maze. Rate of recovery after unilateral entorhinal lesion was not affected by a low dose of THA (0.05 mg/kg), while a higher dose (5.0 mg/kg) impaired recovery. Behavioral recovery was subsequently evaluated in the same rats following lesions to the contralateral entorhinal cortex. Serial bilateral lesions of the entorhinal cortex are known to produce a prolonged performance deficit on the alternation task. The 0.05 mg/kg THA group exhibited an intermediate rate of recovery, between the undamaged control group and bilateral lesion-saline injected groups. The group receiving 5.0 mg/kg of THA after bilateral lesion did not differ from the bilateral lesiun-saline group. The failure of THA to significantly improve functional recovery in rats with lesions of the entorhinal cortex indicates that the compound may have limited applicability in treating human neurodegenerative disorders such as Alzheimer's disease. INTRODUCTION Damage to rat entorhinal cortex results in learning and memory impairments on a variety of tasks 16'23'25. The deficits observed vary according to the extent of hippo- campal denervation and the type of behavioral task. Transient deficits on spatial alternation performance in response to unilateral entorhinal cortex lesions have been reported for the T-maze 15'21'23, Y-maze 2° and Hebb- Williams maze ~6. More persistent deficits occur on spatial alternation tasks after bilateral entorhinal cortex dam- age5A2,15,20,22,23,26. The rate of behavioral recovery after lesions of the entorhinal cortex can be accelerated by various treat- ments. Administration of gangliosides n'18"19 or nerve growth factor (NGF 24) increases the rate of recovery on spatial alternation tasks after entorhinal lesions. There is also evidence that administration of the anticholinester- ase tetrahydroaminoacridine (THA) may improve per- formance after neural loss, particulary after lesion of the nucleus basalis in rats 4A4. Chronic administration of THA can improve memory in normal 7 and age-related memory impaired mice 6. Preliminary clinical results have noted behavioral improvement after administration of THA to patients with Alzheimer's Disease (AD) 12'27'28, but not in all cases 9. The entorhinal cortex experiences severe neural loss in AD s'l°. This finding is particularly noteworthy since septal cholinergic fibers sprout into the outer molecular layer of the hippocampus after entorhi- nal lesions in rats 25 and in A D 2'9'10. In the present set of experiments, we have examined the effect of THA on recovery of performance on a spatial alternation task after unilateral and serial bilateral lesions of the entorhinal cortex in rats. The serial lesion model was selected to evaluate the effects of progressive neural loss, which also occurs in the course of AD. In the rat, transitory behavioral deficits are seen after minor damage to the entorhinal cortex (i.e. unilateral lesion), whereas more prolonged and severe deficits are produced by increased cell loss (i.e. bilateral lesion) 25. THA affected recovery after unilateral lesions in a dose- dependent manner, with the smaller dose having no effect and the larger dose having detrimental effects. Administration of THA after serial bilateral entorhinal lesions did not significantly improve performance on the alternation task. MATERIALS AND METHODS Subjects Male Sprague-Dawley rats (200-225 g), obtained from Charles River, were housed two per cage in a 12/12 h light/dark vivarium. Rats were given ad lib access to Purina Lab Chow. During maze Correspondence: P. Kesslak, Department of Psychobiology, University of California, Irvine, Irvine, CA 92717, U.S.A.