Effect of cholinergic deficit induced by ethylcholine aziridinium on serotonergic parameters in rat brain.

The consequence of loss of cholinergic input on the function of serotonergic neurons has been studied in rat brain after bilateral intracerebroventricular injections of various doses of the cholinotoxin ethylcholine aziridinium ion (1 to 5 nmoles/ventricle). This treatment resulted in a dose-dependent decrease in acetylcholine content in hippocampus, which occurred 2 days after injection and persisted during the 28 day observation period. The reduction in acetylcholine content ranged from 50.3 +/- 6.0% to 76.9 +/- 3.8% when compared to vehicle-injected rats. Other brain areas, including cortex, striatum and hypothalamus, showed only minor and transient changes in acetylcholine levels. Treatment with ethylcholine aziridinium was accompanied by a dose-dependent response of serotonergic neurons. The predominant reaction, which we observed in all areas studied, was an initial increase in 5-hydroxyindoleacetic acid content, a decrease in serotonin content, and consequently an increase in the molar ratio of metabolite/amine, indicating an increase in serotonin turnover. As with acetylcholine, the decrease in serotonin content was most pronounced in the hippocampus, ranged from 19.4 +/- 2.9% to 53.4 +/- 4.1%, and even persisted at 28 days after injection of 3 and 5 nmoles of the toxin/ventricle, although serotonin levels returned towards normal at that time point after injection of 1 or 2 nmoles of the toxin/ventricle. These data suggest that, in the rat, withdrawal of cholinergic input to the hippocampus might have a considerable impact on serotonergic function. This includes an initial increase in activity and, as cholinergic degeneration progresses, a decrease in serotonergic function. The most likely explanation for the serotonergic deficit is that it may reflect adaptation of these neurons to the withdrawal of cholinergic input. Such a phenomenon might help to increase our understanding of the events taking place in the brains of patients with Alzheimer's disease as the cholinergic system starts to degenerate.