Effects of bilateral cholinotoxin infusions on the behavior and brain biochemistry of the rats

We examined behavioral and biochemical specificity and the general usefulness of the proposed rat model of Alzheimer's disease. Bilateral infusions of ethylcholine aziridinium (AF64A) into the basal magnocellular nuclei caused a deterioration of learning in passive and active avoidance tests, increased emotional reactivity, and decreased motoric activity. Choline acetyltransferase activity was decreased by 22% in the frontal cortex but increased by 8-10% in the hippocampus and hypothalamus. Noradrenaline and dopamine levels in the frontal cortex were decreased by 20%. In striatum, dopamine and its metabolites were strongly suppressed (by 50-60%). Also striatal noradrenaline (-48%) and 5-hydroxytryptamine (-34%) were significantly decreased. Hypothalamic 5-hydroxytryptamine was increased (+25%). Bilateral AF64A lesions decreased significantly (by 14-20%) activities of prolyl endopeptidase, dipeptidyl peptidase II and IV in hippocampal and frontal cortical brain homogenates. These results show that AF64A can be used to induce long-term learning deficits in the rat. However, striatal amine levels are also strongly suppressed, and are reflected as hypomotility and increased emotional reactivity. These changes may limit the usefulness of the rat model. Universally decreased peptidase activities offer interesting views regarding the role of peptidase inhibitors in amnestic disorders.