Hemicholinium-3 (HC3) blocks the effects of ethylcholine mustard aziridinium (AF64A) in the developing rat

Two- to 3-day-old rat pups received bilateral intracerebroventricular (i.c.v.) injections of 2.0 nmol/microliters AF64A or vehicle. Half of the pups had been preinjected i.c.v. with hemicholinium-3 (HC3) and the other half with saline. The administration of AF64A impaired spatial learning/memory and caused brain damage characterized by marked loss of forebrain cortical/subcortical tissue and ventricular hypertrophy when these were assessed in adulthood. Neither the behavioral nor the histopathological effects of AF64A were observed in rats that had been pretreated with HC3. Since HC3 is a potent and relatively selective inhibitor of high affinity choline uptake (HACU), the results indicate that the toxic effects of AF64A in the neonatal rat are dependent upon its uptake via the HACU site. If as other research suggests, this site is primarily on Ach neurons in the neonatal rat, then the consequences of neonatal damage to cholinergic neurons are severe for forebrain development.