Estradiol and Progesterone Modulation of Norepinephrine Neurotransmission: Implications for the Regulation of Female Reproductive Behavior

A long range objective of research in behavioral neuroendocrinology is to elucidate the mechanisms by which hormones modify behavior. Significant progress in understanding hormone-brainbehavior relationships is most likely to be achieved if one studies a behavior: 1) which can be measured with a high degree of validity and reliability, 2) whose occurrence can be manipulated in a predictable fashion by hormone administration, and 3) whose neural circuitry, including the necessary and sufficient sensory inputs and motor outputs and the sites of hormone action, has been established. One of the few mammalian behaviors which fits these criteria is the lordosis response of female rodents (for detailed descriptions of the lordosis posture and underlying neural circuitry, see 1). In rodents, the expression of this component of female reproductive (sexual, estrous, mating) behavior is strictly dependent on sequential exposure of neurons in specific hypothalamic sites to the ovarian steroids, estradiol (E,) and progesterone (P) (1-3). It should be emphasized that hormones do not ‘elicit’ or ‘activate’ lordosis; rather, the hormonal milieu determines the probability that animals display the behavior in response to appropriate sensory stimulation (in this case, flank and perineal stimulation). The lordosis response is also of great physiological importance; unless female rodents assume the lordosis posture when mounted by males, penile insertion and hence fertilization cannot take place. In addition, the hormonal control of reproduction in female vertebrates is an elegant example of neuroendocrine integration. Ovarian E2 and P act in extensively interconnected neuronal populations (4) to ensure that the release of pituitary gonadotropins which trigger ovulation (especially luteinizing hormone; LH) coincides with the expression of behavioral receptivity (5) . This neuroendocrine coordination of physiology and behavior maximizes the probability that a female will contact and be inseminated by a conspecific male at the optimal time for achieving fertilization. If one accepts the view that behavior is the product of neuronal activity, then it is reasonable to examine the influence of hormones on brain cells in the neural circuits that mediate hormoneregulated behaviors. Indeed, there is compelling evidence that E2 facilitation of lordosis behavior in rats requires increased excitability of neurons in the ventromedial hypothalamus (VMH) which project to the midbrain central gray, a critical site of sensory and motor integration of lordosis (1, 4, 6, 7). Similarly, it is rational to propose that hormone-dependent changes in chemical neurotransmission in specific neural circuits are likely to produce behavioral changes. In keeping with this perspective, numerous reports of alterations in neurotransmitter metabolism, release, and receptor binding as a function of estrous cycle stage and/or experimental manipulation of circulating E, and P have appeared (5, 8). Likewise, pharmacological manipulation of a variety of neurotransmitter systems can either facilitate or inhibit hormonedependent lordosis (810). Nevertheless, we still have only a rudimentary knowledge of which molecular components of specific neurotransmitter systems are regulated by E, and/or P in brain regions that control reproductive behavior, and of how the regulated molecules alter neuronal function such that stimuli which have a low probability of eliciting lordosis responses in hormone-deprived rodents have a high probability of doing so in hormone-exposed animals. Moreover, the development over the past decade of sensitive new methods for monitoring transmitter release in vivo and for mapping the qualitative and quantitative distribution of putative neurotransmitters, neuromodulators and their receptors in discrete neuronal populations, has produced an explosive increase in the number of potential molecular targets for hormonal regulation. In an attempt to begin developing a coherent picture of the neural mechanisms that mediate ovarian steroid regulation of lordosis, we have elected to focus on the monoamine neurotransmitter norepinephrine (NE). As summarized below, consideration of a variety of neuroendocrine, behavioral, neuroanatomical and neurophysiological observations which had accumulated by the mid 1980s led us to this choice.