Age-dependent effect of AF64A on cholinergic activity in the septo-hippocampal pathway of the rat brain: decreased responsiveness in aged rats

Abstract

Our previous studies have demonstrated that intracerebroventricular (icv) administration of low doses of ethylcholine mustard aziridinium (AF64A), up to 1.0 nmol/side, induces a reversible cholinergic deficit in the hippocampus, paralleled by a compensatory transient increase in choline acetyltransferase (ChAT) activity in the septum [El Tamer, A., Corey, J., Wülfert, E. and Hanin, I., Neuropharmacology, 31 (1992) 397–402]. In the present study we have addressed the question as to whether this effect might differ in old rats. AF64A (0.5 nmol/side) icv administered to three groups of rats aged 4, 12 and 22 months, respectively, induced a reduction of ChAT activity in the hippocampus to the same extent (−26%, −30% and −29.6%; P < 0.01) by 7 days post-icv injection. Acetylcholinesterase (AChE) was decreased to a similar extent in the 4 and 12 month old rats (−22% and −29%; P < 0.01), respectively, but remained unchanged in the 22 month old group. Whereas AChE activity remained unchanged in the septum in all three groups of rats, ChAT activity was increased significantly (+20% and +20.8%; P < 0.05 versus corresponding control group) in the 4 and 12 month old groups, respectively. No change in ChAT activity was measured in the septum of the 22 months old group. By 14 days post-icv injection of AF64A, ChAT and AChE activities were back to normal in all three groups and in both brain regions studied. These results demonstrate that a difference in AF64A's effect does exist between the 22 month old group and the youngest group. This might reflect a possible age-dependent change in the ability of the cholinergic system to respond to the cholinotoxicity of AF64A, as well as in the potential of the cell bodies, at the septal level, to respond to such an insult by a compensatory mechanism such as increasing ChAT activity.