Administration of tamoxifen but not flutamide to hormonally intact, adult male rats mimics the effects of short-term gonadectomy on the catecholamine innervation of the cerebral cortex

Gonadectomy in adult male rats induces a series of changes in cortical catecholamine innervation that begins with a large, but transient decrease in the density of tyrosine hydroxylase- but not dopamine-beta-hydroxylase-immunoreactive axons in sensory, motor, and association cortices. More recent studies have shown that estradiol maintains these presumed dopamine afferents but that supplementing acutely gonadectomized rats with dihydrotestosterone provides no protective effects for innervation. These findings suggest that the depression of mesocortical dopamine axons that follows gonadectomy is stimulated by changes in estrogen signaling. The studies presented here examined tyrosine hydroxylase and dopamine-beta-hydroxylase innervation in hormonally intact adult male rats treated for 4 days with the nonsteroidal antiestrogen tamoxifen or with the nonsteroidal antiandrogen flutamide to probe for additional evidence for this selective hormone sensitivity and for insights into the intracellular mechanisms that may govern it. Qualitative and quantitative comparisons of innervation with corresponding data from control and acutely gonadectomized rats revealed that administration of the antiestrogen tamoxifen in hormonally intact rats produced deficits in catecholamine innervation that mirrored those induced by short-term gonadectomy. The antiandrogen flutamide, however, had no discernible impact on cortical afferents. When considered within the context of the known pharmacology and sites of action of tamoxifen, these findings not only provide additional support for an initial phase of selective estrogen sensitivity among the cortical catecholamines but also suggest that it is stimulation of intracellular estrogen receptors that confers this sensitivity in the adult rat cerebrum.