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Effects of Dehydroepiandrosterone and Flutamide on Hippocampal CA1 Spine Synapse Density in Male and Female Rats: Implications for the Role of Androgens in Maintenance of Hippocampal Structure

Departments of Obstetrics, Gynecology, and Reproductive Sciences (N.J.M., T.H., C.L.) and Neurobiology (C.L.), Yale University School of Medicine, New Haven, Connecticut 06520; Laboratory of Molecular Neurobiology (T.H.), Biological Research Center, Hungarian Academy of Sciences, H-6701 Szeged, Hungary; and Center for Reproductive Sciences (N.J.M.), Columbia University Medical School, New York, New York 10032

Address all correspondence and requests for reprints to: Csaba Leranth, M.D., Ph.D., Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, FMB 313, New Haven, Connecticut 06520-8063. E-mail: csaba.leranth{at}yale.edu.

The effects of androgens and the androgen antagonist, flutamide, on the density of dendritic spine synapses in the CA1 subfield of the hippocampus were studied in gonadectomized male and female rats. Treatment of orchidectomized male rats with dehydroepiandrosterone (DHEA; 2 d, 1 mg/d sc) increased the density of CA1 spine synapses observed 2 d later, by 106%, without significantly affecting ventral prostate weight. The hippocampal response to DHEA was unaffected by blockade of intracerebral estrogen biosynthesis using the aromatase inhibitor, letrozole. By contrast, flutamide alone (2 d; 5 mg/d, sc) increased CA1 spine synapse density by 66%, whereas in combination the effects of flutamide and DHEA were additive rather than inhibitory. Additive effects on CA1 synapse density were also observed in males using combinations of flutamide with 5-dihydrotestosterone (2 d, 500 µg/d, sc). At the same doses, flutamide had no effect on prostate weight and completely blocked the effects on the prostate of treatment with 5-dihydrotestosterone. Treatment of ovariectomized females with DHEA increased CA1 spine synapse density to a level similar to that observed in the male. As in males, flutamide in females increased CA1 spine synapse formation and further augmented the response to DHEA. These results demonstrate that flutamide and DHEA have positive effects on hippocampal CA1 spine synapse density in both sexes. They also suggest that conventional measures of androgen agonist or antagonist activity, exemplified by ventral prostate growth, may not be indicative of effects on hippocampal CA1 synaptogenesis.

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