ROLE OF GLUCOCORTICOIDS IN THE CHOLINERGIC DEGENERATION IN RAT HIPPOCAMPUS INDUCED BY ETHYLCHOLINE AZIRIDINIUM (AF64A)

Glucocorticoids potentiate hippocampal damage induced by various noxio us insults in vivo and in vitro and are implicated in age-related loss of neurons in the hippocampus of various species. The cholinergic inn ervation of the hippocampus appears to be especially prone to the enda ngering effect of glucocorticoids, since corticosterone, like acute st ress or ACTH, induces a rapid activation of the cholinergic septohippo campal pathway. We now report the influence of glucocorticoids on the degeneration of this pathway induced by the cholinergic neurotoxin eth ylcholine aziridinium (AF64A). The toxic effect of a submaximal dose o f AF64A on cholinergic neurons was evaluated in rats during exposure t o glucocorticoids or vehicle as well as in adrenalectomized or sham-op erated rats. Daily treatment with either corticosterone or dexamethaso ne, starting 7 d before the bilateral intracerebroventricular injectio n of AF64A (1 nmol/ventricle), significantly increased the AF64A-induc ed loss of ChAT activity in the whole hippocampus, whereas bilateral a drenalectomy 7 d prior to AF64A-injection attenuated the effect of AF6 4A. Short-term exposure to corticosterone starting 24 hr before AF64A was as effective as the 7 d pretreatment. Dexamethasone exacerbated th e AF64A-induced cholinergic lesion in the hippocampal subregions CA1, CA3, and dentate gyrus, and adrenalectomy protected all subregions aga inst the action of AF64A. Along the longitudinal axis of the hippocamp us a comparable influence was seen in the dorsal and ventral parts. Th e subregional pattern in the response to glucocorticoid suggests the i nvolvement of mineralocorticoid type I receptors. In conclusion, gluco corticoids enhance the susceptibility of the septohippocampal choliner gic neurons to AF64A and probably do this by increasing the velocity o f the high-affinity choline transport and stimulating the noradrenergi c function. The present data suggest a pathophysiological link between glucocorticoids and the age-dependent decline in basal forebrain chol inergic function, with possible implications for the process of cholin ergic degeneration occurring in Alzheimer's disease.