Estrogen receptor immunoreactivity is present in the majority of central histaminergic neurons: Evidence for a new neuroendocrine pathway associated with luteinizing hormone-releasing hormone-synthesizing neurons in rats andhumans

The central regulation of the preovulatory LH surge requires a complex sequ ence of interactions between neuronal systems that impinge on LH-releasing hormone (LHRH)-synthesizing neurons. The reported absence of estrogen recep tors (ERs) in LHRH neurons indicates that estrogen-receptive neurons that a re afferent to LHRH neurons are involved in mediating the effects of this s teroid. We now present evidence indicating that central histaminergic neuro ns, exclusively located in the tuberomammillary complex of the caudal dienc ephalon, serve as an important relay in this system. Evaluation of this sys tem revealed that 76% of histamine-synthesising neurons display ER alpha-im munoreactivity in their nucleus; furthermore histaminergic axons exhibit ax o-dendritic and axo-somatic appositions onto LHRH neurons in both the roden t and the human brain. Our in vivo studies show that the intracerebroventri cular administration of the histamine-1 (H1) receptor antagonist, mepyramin e, but not the H2 receptor antagonist, ranitidine, can block the LH surge i n ovariectomized estrogen-treated rats. These data are consistent with the hypothesis that the positive feedback effect of estrogen in the induction o f the LH surge involves estrogen-receptive histamine-containing neurons in the tuberomammillary nucleus that relay the steroid signal to LHRH neurons via H1 receptors.