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Department of Biology Boston University Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Michael J. Baum, Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215. E-mail: baum{at}bu.edu.
It is widely accepted that estradiol formed perinatally in specific subcortical regions of the male rodent nervous system via the aromatization of circulating testosterone contributes to the development of several male-typical features of brain morphology (1) and of social and reproductive behaviors in later life (2). These actions of estradiol are thought normally to depend on the binding of the steroid to intracellular estradiol receptors (ER) of either the 
or ß subtypes. These estradiol-ER complexes together with coactivator proteins bind to DNA and initiate a cascade of transcriptional events (3) leading to many, although not all, features of male-typical brain sexual differentiation. A new study (4) published in this issue of Endocrinology suggests that the activation of membrane-bound type 1 dopamine receptor (D1) in newborn female rat brain can activate ER- in the absence of its cognate ligand, estradiol, causing an immediate increase in ER-dependent expression of progesterone receptor (PR) and organizing female subjects’ capacity to show male-typical levels of play behavior during adolescence.
An initial experiment was inspired by evidence (5) showing that there are significantly more PR immunoreactive neurons in the medial preoptic area (MPOA) of perinatal male vs. female rats due to the increased activation of ER in the male’s hypothalamus. Olesen et al. (4) found that sc injection of the D1 agonist, SKF-38393, into female rats on postnatal d 1 significantly increased the number of PR-immunoreactive cells present 24 h later in one hypothalamic structure, the bed nucleus of the stria terminalis (BST), as well as in the central nucleus of the amygdala (CeA). Neonatal administration of estradiol to other females augmented PR expression in these same two regions and in two additional hypothalamic regions, the MPOA and the ventromedial nucleus of the hypothalamus. The stimulatory effect of neonatal SKF on PR immunoreactive cell number was completely blocked by pretreating female rats with the ER- antagonist, tamoxifen, suggesting that the acute action of this D1 receptor agonist on PR expression was mediated by the activation of ER. Olesen et al. then proceeded to link ligand-independent neonatal activation of ER to the sexual differentiation of social behavior in an unexpected fashion. The sexually dimorphic behavior studied was the display of rough and tumble play behavior (wrestling/boxing, pouncing, pinning, and biting behaviors) by juvenile rats living in mixed-sex groups. Previous work (6) established that male rats display significantly more of this play behavior than females at this age, and suggested (7, 8) that this sex dimorphism depends on the perinatal activation of androgen receptors in the male’s amygdala. First, Olesen et al. (4) showed that administration of a high dose of estradiol benzoate to female rats on postnatal d 0–2 increased their later display of play behavior to a level shown in control males. They also found that this effect of neonatal estrogen treatment was completely blocked by pretreating females with ER- antagonist, tamoxifen. This suggests that ER- activation normally promotes the organization of neural circuits controlling male-typical levels of play behavior, although it does not rule out a role for androgen receptor activation in this process. Administering the D1 agonist, SKF, neonatally to female rats duplicated the behavioral effects of neonatal estradiol treatment, and again, neonatal pretreatment with tamoxifen completely blocked the masculinizing effect of SKF. This result shows that ligand-independent activation of ER- by a D1 receptor agonist in neonatal rats is capable of organizing neural circuits that control male-typical levels of play behavior displayed several weeks later. At present, however, there is no reason to believe that early ER-mediated, ligand-independent activation of PR expression organizes this potential to show high levels of play behavior.
One possible trivial explanation for the observed effects of neonatal SKF on PR expression and later play behavior is that this treatment somehow augmented circulating levels of estradiol. Olesen et al. (4) present data showing that neonatal injection of SKF failed to influence serum estradiol levels measured 6 h later, a time at which the prior injection of 100 µg of estradiol benzoate caused a dramatic increase in serum levels of this hormone. Further evidence suggesting that SKF did not stimulate estradiol secretion from ovarian or adrenal sources derives from the observation (4) that neonatal SKF treatment augmented PR expression in only the BST and CeA, and not in the MPOA or ventromedial nucleus of the hypothalamus. In contrast, neonatal EB treatment augmented PR expression in all four brain regions. If SKF had acted by raising circulating levels of estradiol, it should have augmented PR expression uniformly in all brain regions studied and not solely in the BST and CeA. It was recently suggested (9) that de novo synthesis of estradiol from cholesterol precursor may occur in the female rat cerebral cortex and hippocampus, but not in hypothalamus. Although the possibility has not been definitively ruled out, it also seems unlikely that neonatal treatment with D1 receptor agonist by Olesen et al. exerted its effects on PR expression and play behavior by augmenting the de novo neural synthesis of estradiol. There is no evidence that the enzymes necessary for de novo estradiol synthesis are expressed in the hypothalamus, yet SKF treatment stimulated PR expression in the BST, a hypothalamic structure.
The Olesen et al. report (4) provides the first published example of a dopamine-receptor mediated, ligand-independent activation of ER- in the developing nervous system. Other work had shown that epidermal growth factor (10) as well as IGF-1 (11) augmented in vitro ER-dependent gene transcription and that intracerebroventricular administration of either epidermal growth factor or IGF-1 facilitated sexual behavior (lordosis) in ovariectomized female rats in the absence of estradiol or progesterone (12). The Olesen et al. work (4) also follows previous studies (13, 14) showing that intracerebroventricular administration of the D1 receptor agonist, SKF, substituted for progesterone in activating lordosis behavior in estrogen-primed female rats and mice, and that these effects of D1 agonist were blocked by pretreatment with PR antagonist drugs, antisense oligonucleotides that inhibited the synthesis of PR, or a null mutation of the PR.
A central question raised by the Olesen et al. findings (4) as well as the other published examples of ligand-independent activation of estradiol or PR-mediated neural-behavioral events is whether such effects ever occur in nature or whether instead they represent interesting pharmacological phenomena? Evidence exists (15) suggesting that ligand-independent activation of PR may in certain circumstances stimulate sexual behavior in female rats. Thus the receipt of vaginal-cervical stimulation augmented sexual receptivity in estradiol-primed female rats which lacked peripheral sources of progesterone, and pretreating such rats with a PR antagonist blocked this facilitation of lordosis. The observation by Olesen et al. (4) that neonatal treatment of female rats with a D1 receptor agonist increased juvenile play behavior via a ligand-independent activation of ER- raises the question of whether such events normally occur in the developing male nervous system? The senior author (A. P. Auger, personal communication) of the Olesen et al. paper reports that his group has recently observed that neonatal administration of either a D1 receptor antagonist or of a specific ER- antagonist to male rats reduced their display of juvenile play behavior. This result suggests that ligand-independent activation of ER- may, indeed, normally contribute to the sexual differentiation of neural circuits that control this type of sexually dimorphic behavior.
The Olesen et al. results (4) also raise the question of whether other male-typical features of behavioral sexual differentiation such as the defeminization of lordosis capacity and/or the masculinization of sexual motivation and mating behavior, both of which have been linked to the perinatal activation of estrogen receptors (16, 17, 18), may depend on ligand-independent activation of these receptors. Olesen et al. did not report data pertaining to this issue in their Endocrinology article; however, an early study (19) reported that perinatal administration of a dopamine receptor antagonist, haloperidol, reduced later ejaculatory capacity in male rats. An obvious next study (A. P. Auger, personal communication) will be to determine whether neonatal administration of a dopamine receptor agonist such as SKF to female rats duplicates the defeminizing and/or masculinizing action of neonatal estradiol on later mating performance and whether these effects can be blocked by neonatal pretreatment with a specific estrogen receptor antagonist. The antiestrogen administered by Olesen et al. (4), tamoxifen, itself exerted a small but statistically significant ER- agonist action by stimulating PR expression in the MPOA. The masculinizing actions of estradiol on males’ mating capacity are thought to occur, at least partially, in the MPOA (16). This fact implies that another, more specific, ER- antagonist drug that lacks any estrogen agonist action in the brain will best be used in any future experiment seeking to establish link between ligand-independent, dopaminergic activation of ER- and the masculinization of sexual behavior.
The suggestion (4) that a ligand-independent, dopaminergic mechanism operates neonatally in the male nervous system to produce later male-typical levels of play behavior implies that there must be a sex difference in either the dopaminergic innervation of brain regions that control this behavior (e.g. the CeA) and/or a sex difference in the neonatal activation of these dopaminergic afferents. Other than a report (20) that hypothalamic metabolism of dopamine was higher in male than in female rats over the first several postnatal hours, there is no information about possible neonatal sex dimorphisms in the dopaminergic innervation of any brain region. However, it is noteworthy that over the first 18 postpartum days male rats receive significantly more ano-genital licking than females (21). This stimulation may facilitate adult ejaculatory capacity in males (22, 23). It is not known whether the increased level of ano-genital stimulation received by males differentially activates dopamine neurons or contributes in any way to the development of male-typical levels of juvenile play behavior. The challenge for the future will be to identify circumstances when ligand-independent activation of neural ER- and/or ER-ß occurs perinatally in the male and to understand how these actions complement the well established role of the cognate ER ligand, estradiol, in promoting aspects of male-typical brain and behavioral sexual differentiation.
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Abbreviations: ER, Estradiol receptor; PR, progesterone receptor; MPOA, medial preoptic area; BST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; D1, type 1 dopamine receptor.
Received June 1, 2005.
Accepted for publication June 3, 2005.
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