AF64A-induced working memory impairment: behavioral, neurochemical and histological correlates

The present studies examined the behavioral, neurochemical and histological consequences of intraventricular administration of ethylcholine aziridinium ion (AF64A). Male Long-Evans rats were trained to perform a radial arm maze task in which a one hour delay was imposed between the fourth and fifth arm selections. Following acquisition, animals were bilaterally injected with AF64A (3 nmol/side) or CSF into the lateral ventricles and allowed 14 days to recover before behavioral testing resumed. AF64A-treated animals were markedly impaired in their ability to perform this working/episodic memory task at a variety of delay intervals. In contrast to a long-lasting impairment on the radial maze task, these animals showed no impairment in their ability to acquire a simple discrimination task (reference/skill memory). Neurochemical analysis revealed a significant (50%) decrease in choline acetyltransferase (ChAT) activity in the hippocampus (HPC) 90 days following surgery. ChAT activity was not affected in the striatum, frontal and parietal cortices, cingulate or amygdala. Regional concentrations of catecholamines and indoleamines were not affected in any of these brain regions. Histological analysis of animals receiving unilateral injections of AF64A (3 nmol) into the right lateral ventricle revealed decreases in ChAT-immunoreactive (ChAT-IR) cells within the medial septum/vertical limb diagonal band (MS/VLDB), but not in nucleus accumbens, striatum or basal nucleus regions. These data suggest that: (1) intraventricular administration of AF64A can markedly impair working/episodic, as opposed to reference/skill memory, processes; (2) AF64A can be used to selectively alter presynaptic cholinergic indices within the hippocampus; and (3) the behavioral deficits resulting from AF64A administration are most likely a consequence of altered septohippocampal cholinergic function.