EFFECTS OF ESTROGEN ON BASAL FOREBRAIN CHOLINERGIC NEURONS VARY AS A FUNCTION OF DOSE AND DURATION OF TREATMENT

Studies suggest that estrogen replacement can influence learning and m emory processes via effects on cholinergic neurons located in specific regions of the basal forebrain. In the present study, immunocytochemi cal techniques were used to examine the effects of estrogen on basal f orebrain cholinergic neurons asa function of the dose and duration of estrogen treatment. Ovariectomized rats received 2, 10, 25, or 100 mu g estradiol every other day for a period of 1.2, or 4 weeks. Sections through the basal forebrain were then processed for the detection of c holine acetyltransferase (ChAT) or the low-affinity nerve growth facto r receptor (p75NGFR), and the number of immunoreactive cells in the me dial septum (MS), the horizontal limb of the diagonal band of Broca (H DB) and the nucleus basalis magnocellularis (NBM) were counted. The ef fects of dose and duration of estrogen treatment were evaluated by ana lysis of variance and individual group means were compared with ovarie ctomized controls using a two-tailed Dunnets test. Administration of 2 , 10, or 25 mu g estradiol for 1 week produced a dose-related increase in the number of ChAT-like immunoreactive (IR) cells detected in the MS. Likewise treatment with 10 mu g estradiol for 1 week or with 2 mu g estradiol for 2 weeks resulted in a significant increase in the numb er of ChAT-IR cells detected In the NBM. These effects were not observ ed following treatment with higher doses of estradiol. Nor were they m aintained following repeated administration of estradiol for longer pe riods of time. in contrast, repeated administration of estradiol for 2 or 4 weeks resulted in significant decreases in the number of p75NGFR -IR cells detected in the MS, with the greatest effects observed follo wing treatment with the higher doses of estradiol for longer periods o f time. These findings demonstrate that (1) estrogen replacement produ ces regionally selective effects on basal forebrain cholinergic neuron s which vary as a function of both the dose and duration of estrogen t reatment, and (2) estrogen has both short-term and longer-term effects on basal forebrain cholinergic neurons, each of which may contribute to the effects of estrogen on learning and memory process and the deve lopment of age- and disease-related cognitive decline.