Hemicholinium-3 prevents the working memory impairments and the cholinergic hypofunction induced by ethylcholine aziridinium ion (AF64A)

The present study examined whether intraventricular administration of the potent high affinity choline transport (HAChT) inhibitor hemicholinium-3 (HC-3) would attenuate the memory impairments and the neurochemical deficits induced by i.c.v. ethylcholine aziridinium ion (AF64A). Male Sprague-Dawley rats were trained to perform a delayed-non-match to sample radial arm maze (RAM) task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following 30 acquisition trials, animals were bilaterally injected with AF64A (3 nmol/side) or AF64A preceded by HC-3 (20 micrograms/side) into the lateral ventricles and allowed 7 days to recover before behavioral testing resumed. Control animals received either artificial cerebrospinal fluid or HC-3. AF64A-treated rats were significantly impaired in their performance of the RAM task as evidenced by fewer correct choices following the delay and more total errors to complete the task. This behavioral deficit was associated with a significant (32%) decrease in HAChT in the hippocampus. In contrast, animals pretreated with HC-3 exhibited no significant decreases in HAChT or decrements in RAM performance. These findings indicate that the memory deficits resulting from intraventricular administration of AF64A are a consequence of the compound's cholinotoxic properties and in particular its interaction with the HAChT carrier. Furthermore they demonstrate that a select alteration of septohippocampal cholinergic activity is sufficient to disrupt working memory processes.