OVARIAN-STEROID DEPRIVATION RESULTS IN A REVERSIBLE LEARNING IMPAIRMENT AND COMPROMISED CHOLINERGIC FUNCTION IN FEMALE SPRAGUE-DAWLEY RATS

We hypothesized that estradiol (E2) serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involv ed in learning and memory. Learning/memory was assessed using the two- way active avoidance paradigm and the Morris water task. Female Spragu e-Dawley rats were either ovariectomized (OVX) or OVX for 3 weeks, fol lowed by s.c. implantation of a Silastic pellet containing 17-beta E2 (E2 pellet), resulting in a replacement of E2 to physiological levels. Ovary-intact (INTACT) animals served as our positive control. Active avoidance behavior and choline acetyltransferase (ChAT) activity in th e frontal cortex and hippocampus were assessed at 5 and 28 weeks posto variectomy while performance on the Morris water task and high-affinit y choline uptake (HACU) were measured only at the 5-week time point. A t the 5-week time point, E2 replacement caused a significant elevation in the level of active avoidance performance relative to OVX animals. At the 28-week time point, OVX animals demonstrated a significantly l ower number of avoidances relative to controls (61%) whereas E2-pellet animals not only demonstrated superior performance relative to OVX an imals but also showed an accelerated rate of learning. Morris water ta sk performance, on the other hand, was not significantly affected by e strogenic milieu despite a trend towards better performance in the E2- pellet group. Neurochemical analyses revealed that 5 weeks of ovariect omy was sufficient to reduce HACU in both the frontal cortex and hippo campus by 24 and 34%, respectively, while E2 replacement was successfu l in elevating HACU relative to OVX animals in both regions. ChAT acti vity was decreased in the hippocampus but not the frontal cortex of 5- week OVX animals. E2 replacement resulted in a reversal of this effect . At the 28-week time period, an unexpected decrease in ChAT activity was observed across all treatment groups. Interestingly, E2-pellet ani mals demonstrated the least severe decline in ChAT. This phenomenon wa s most evident in the frontal cortex where ChAT decreased by 61 and 56 % in INTACT and OVX animals, respectively, whereas the decline in E2-p ellet animals was only 16% over the same time period, suggesting a pre viously unreported cytoprotective effect of E2. Taken together, these findings demonstrate important effects of estrogens on cholinergic neu rons and support the potential use of estrogen therapy in treatment of dementias in postmenopausal women.