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Sexual Behavior in Females from a Neuroendocrine Perspective

Summary and Keywords

Understanding of the brain mechanisms regulating reproductive behaviors in female laboratory animals has been aided greatly by our knowledge of estrogen receptors in the brain. Hypothalamic neurons that express the gene for estrogen receptor-alpha regulate activity in the neural circuit for the simplest female reproductive response, lordosis behavior. In turn, many of the neurotransmitter inputs to the critical hypothalamic neurons have been studied using electrophysiological and neurochemical techniques. The upshot of all of these studies is that lordosis behavior presents the best understood set of mechanisms for any mammalian behavior.

Keywords: arousal, estrogen, gene, histamine, hormone receptor, hypothalamus, lordosis, norepinephrine, progesterone, transcription


In the recent history of neuroscience, many biologists have strategized by saying that mammalian behaviors are too complex for detailed neuroanatomical, electrophysiological, and genomic analysis. Those biologists, therefore, might study the worms, E. coli, or fruit flies (drosophila). However, the choice of hormone-regulated behaviors coupled with the choice of a behavior that features a very simple motor pattern has enabled an entire behavioral circuit to be worked out. Lordosis behavior in female laboratory animals is triggered by somatosensory stimuli (from the male mounting) on the flanks and rump. Spinal circuitry is not sufficient for lordosis behavior. Instead, ascending signals carrying the sensory information reach the brainstem reticular formation and the midbrain central grey. There, the hormone-dependent signal from the hypothalamus can activate the lordosis behavior circuit. That is, neurons in the midbrain central grey project to vestibulospinal and reticulospinal neurons, which, in turn, govern the motor neurons that execute the vertebral dorsiflexion of lordosis behavior. Thus, the entire circuit for producing the behavior has worked out (Pfaff & Schwartz-Giblin, 1988; Pfaff, Schwartz-Giblin, McCarthy, & Kow, 1994). The key to the solution of these mechanisms lay in the strong dependence of the behavior on estrogen and progesterone.

Sex hormone effects on female sexual behavior demonstrate two principles: (1) the ability of combinations of hormones to influence behavior, and (2) the importance of timing. Long periods of estrogen exposure followed by a brief progesterone exposure will powerfully facilitate female reproductive behavior in laboratory animals. However, the reverse sequence, progesterone followed by estrogen, does not work. Receptivity in vertebrate animals typically involves a postural stance called lordosis behavior, which consists of dorsiflexion of the vertebral column and deviation of the tail. This posture facilitates vaginal penetration by the male.

The influence of sex hormones on sexual behaviors is dependent on where the sex hormones are acting (i.e., which circuit—central or peripheral—is being acted upon). Thus, a major amount of work has been conducted on the characterization of hormone receptors in the brain.

Neurons expressing estrogen receptors are widespread in the brain but are particularly concentrated in the hypothalamus, the preoptic area, and in the ancient forebrain; a limbic/hypothalamic system that is universal among vertebrates. In molecular evolution, there is thought to have been a single primitive estrogen receptor protein. Then, it is generally accepted, there was a “gene duplication” event that produced two genes, estrogen receptor alpha (ERα‎) and estrogen receptor beta (ERβ‎), The greatest number of ERα‎-containing neurons are found in brain regions primarily associated with the control of reproductive functions, whereas neurons expressing ERβ‎ are more widespread, for example, in areas such as the cerebral cortex.

Several behaviors are dependent on estradiol binding to ERα‎ within the hypothalamus, including the medial preoptic nucleus and the ventromedial nucleus. The simplest behavior, lordosis, was the first to be explained. Estrogen-regulated cells in the ventromedial nucleus of the hypothalamus send outputs to the midbrain central grey. Neurons there allow the activation of a spinal-brainstem-spinal loop, the motor neurons of which cause deep back muscles to contract, thus initiating the lordosis behavior.

Coordination Between Females and Males

Sequences of reproductive behaviors by males and females can be thought of as “hormone-dependent behavioral funnels.” These behaviors serve to bring reproductively competent conspecific, and only then, into the same place at the same time, so that productive mating can occur. Among humans, how are gender roles sorted out?

The attraction of individuals to members of the opposite (heterosexual), same (homosexual), or both (bisexual) sexes is the most basic definition of sexual orientation as pointed out in Normandin, Pfaff, and Murphy (2012). Little is known how the developmental process of sexual orientation takes place, but a few important clues have been found. Most people are heterosexual, but approximately 5% of people are homosexual or bisexual, which appears to be a stable cross-cultural and history-spanning phenomenon. A number of animals including, but not limited to, bonobo chimpanzees, Japanese macaques, sheep, and penguins exhibit same-sex sexual behavior. In some of these animals, such as sheep, the behavior is exclusive, as in people, and in others, such as the bonobo and macaque, the nonexclusive same-sex sexual behavior appears to serve for both sexual gratification and other social functions such as conflict resolution. A number of studies have found small but significant differences in a few brain regions depending on the sexual orientation of the individual. The first such study found that the suprachiasmatic nucleus of the hypothalamus is smaller in homosexual men compared to heterosexual men. This is also true of the third interstitial nuclei of the anterior hypothalamus, whereas the anterior commissure appears to be larger in homosexual men in comparison to heterosexual men. The functional significance of these brain differences is not understood. Similar brain sexual orientation differences have been described in sheep and Japanese macaques. In addition, recent findings from fMRI work point to a network of activity associated with sexual orientation. The brain activity of homosexuals is similar to that of heterosexuals of the opposite sex in response to visual sexual stimuli or exposure to a putative human pheromone. A number of studies have found a genetic link to sexual orientation. Identical twins raised apart are more likely to have the same sexual orientation than chance would allow. In addition, a particular marker on the X chromosome (Xq28) appears more often in homosexual than in heterosexual men, though this study has failed at least once to be replicated. The mothers of homosexual men also have “skewed X-inactivation” in which one X-chromosome is preferentially inactivated, whereas this process is usually random. The maternal relatives of homosexual men also have high fecundity rates, implying that genes related to homosexuality incur a selective benefit in related individuals, providing an explanation for how genes related to homosexuality could survive in a population if homosexuals are less likely to reproduce. The development of sexual orientation is still quite a mystery for neuroscience, but the evidence suggests that some combination of gene/environment interaction, most likely involving a sex hormone pathway in some fashion, produces different sexual orientations.

Insights from Molecular Biology

A multitude of genes related to the sexual differentiation of the brain, the development of sexual behavior systems, and the expression of sexual behavior have been identified. For example, in female laboratory animals, many years of research have revealed genes that have two properties: (1) mRNA levels are heightened by treatment with estradiol, and (2) their gene products facilitate female reproductive behavior. Binding of each respective ligand to the appropriate sex hormone receptor initiates a cascade of events resulting in the ligand/receptor complex acting as a transcription factor, initiating a slow process of gene transcription that can modify neuronal properties such as the proliferation of dendritic arborization and changes in neurotransmitter receptor density. ERα‎ and ERβ‎ ligand/receptor complexes both bind to the estrogen response element on DNA but differ in their ability to bind to other response elements. Transcriptional events associated with estrogenic effects on lordosis behavior have been reviewed (Mong & Pfaff, 2004).

Neurotransmitter Inputs to Hormone-Dependent Hypothalamic Neurons Important for Lordosis Behavior

Multiple transmitters and subsequent signal transduction pathways were tied into the regulation of lordosis behavior by classical studies (reviewed in Kow, Mobbs, & Pfaff, 1994b). As updated by Lee et al. (2009), we now cover recent work on several systems.

Histamine: Histamine Actions and Influences by Estrogens

Histamine is well known to play an important role in arousal. It has also long been known to be involved in a wide variety of behaviors, including sexual behavior, drinking, and eating (White & Rumbold, 1988). Female mice are more sensitive to the arousal-reducing effects of an H1 receptor blocker than male mice (Easton, Norton, Goodwillie, & Pfaff, 2004). In the brain, histamine (HA) actions are mediated through three subtypes of G-protein–coupled receptors (GPCRs): H1, H2, and H3. The functions and the distributions in the brain of these receptors have been reviewed in Brown, Stevens, and Hass (2001), Haas and Panula (2003) and Lee, Devidze, Pfaff, and Zhou (2006). Briefly, H1 receptors have a widespread distribution in the brain, especially regions involved in arousal. In brain regions rich in ERα‎, such as the amygdala (medial), preoptic area, and ventromedial hypothalamus, the densities of H1 receptors are also high, suggesting an interaction of ERα‎-mediated estrogen actions and H1-mediated HA actions (see below). H1 receptors are coupled primarily to the Gq/11–PLC–PKC system (PLC = prelimbic cortex), which appears to be responsible for the electrophysiological actions of HA mediated by H1 that are predominantly excitatory but occasionally inhibitory. The mechanisms of the actions varied in neurons from different brain regions. H2 receptors distribute differently from those of H1 though with some overlap in regions such as cerebral cortex (but at different layers). It appears, therefore, that H1 and H2 function mostly independently, although collaboratory or synergistic actions are possible in overlapped areas. H2 is coupled to the Gs–cAMP–PKA system (PKA = protein kinase A). Like H1, H2 also mediates neuronal excitations, but unlike H1, the excitations are due mainly to the reduction of afterhyperpolarization resulting from the inhibition of Ca-dependent K currents consequent to phosphorylation by PKA. Shifting of a cation channel (Ih) by cAMP can also contribute to H2 excitation. H2 actions may also be inhibitory. Pharmacological evidence has indicated that H2 can mediate inhibitory actions in arcuate (Jorgenson, Kow, & Pfaff, 1989), supraoptic (Yang & Hatton 1994), and suprachiasmatic nuclei (Liou, Shibata, Yamakawa, & Ueki, 1983). H3 is distributed widely in the brain with high density in many brain regions but only moderate in the hypothalamus. H3 is an autoreceptor for a negative-feedback regulation of the release and synthesis of HA. It can also regulate the release of many other neurotransmitters. Its inhibitory action is due mainly to the inhibition of high voltage–activated Ca2+ currents as a result of the coupling and activation of Gi/o.

Both estrogens (Pfaff, 1999, 2005) and HA are known to increase arousal. The latter’s involvement in arousal (and even hibernation) is well known and is indicated by several lines of evidence (Brown et al., 2001; Haas & Panula, 2003). These two arousal modulators may interact with each other, as suggested by the overlaps of the distribution of their receptors mentioned above. First, the sole source of brain HA—the histaminergic neurons in the tuberomammilary nucleus—is known to contain both ERα‎ and ERβ‎ (Ishunina, van Heerikhuize, Ravid, & Swaab, 2003; Laflamme et al., 1998; Shughrue, Lane, & Merchenthaler, 1997). Estrogens may thus be acting through these receptors to increase general arousal. Indeed, our behavioral studies have shown that estrogen treatment–induced increase in arousal, indicated by increase in motor activities, could be attenuated by an H1 antagonist, pyrilamine (Zhou, Devidze, Zhang, & Pfaff, 2007a).

Another brain region where estrogens and HA can interact is the hypothalamic VMN, which is rich in both ER (Pfaff & Keiner, 1973) and H1 receptors (Bouthenet, Ruat, Sales, Garbarg, & Schwartz, 1988). In rodents at least, VMN is essential for estrogen induction of female sexual behaviors and, hence, sexual arousal. That this estrogen action is enhanced by HA is indicated by findings from behavioral studies: intraventricular administration of an HA synthesis inhibitor or HA receptor antagonists attenuated lordosis and soliciting behaviors induced by estrogen (Donoso & Broitman, 1979). Similarly, but in the opposite direction, estrogens can also potentiate HA-evoked neuronal excitation. Using whole-cell patch clamp recording, we have found that the depolarization and the inward currents induced in mouse VMN neurons by HA are enhanced by estrogen priming that would induce lordosis. This enhancement could be due to an increase in the expression of HA receptors in VMN neurons, as suggested by an increase in HA receptor mRNA in VMN by estrogen priming (Zhou, Devidze, Zhang, & Pfaff, 2006).

Estrogens can enhance HA excitation/depolarization not only through their genomic actions (by estrogen priming) but also through nongenomic, membrane-initiated actions by acute application. Using extracellular single-unit recording, we found that the excitation (increase in firing rate) of VMN neurons in hypothalamic slices evoked by bath application of HA was reversibly potentiated by brief (10–15 min) application of E2 (estradiol) (Kow, Easton, & Pfaff, 2005). Interestingly, the excitation by N-methyl-d-aspartate (NMDA) was also potentiated, and the inhibition by HA that was observed occasionally was abbreviated by acute E2 application. Since the excitations by HA (apparently through H1/Gq/11/PLC/PKC system) and by NMDA (through NMDA receptor, a ligand-gated ion channel that does not require the activation of a G-protein) and the inhibition by HA (probably mediated by H2 and a G-protein other than Gq/11) are evoked by different receptor/signaling systems, it is very likely that they are modulated by nongenomic estrogen actions through different mechanisms. To look further into the mechanism(s) of the nongenomic actions, whole-cell patch clamp recording was employed. Corresponding to increasing firing rate in extracellular recording, HA and NMDA evoked depolarization and increase in firing under current clamp or inward currents under voltage clamp. As in the case of extracellular recording, these excitatory membrane events were also reversibly potentiated by acute application of E2. That is, during the brief exposure to E2, HA and NMDA evoked greater depolarization and inward currents and more action potentials than before or after the exposure (Pataky, Kow, Martin-Alguacil, & Pfaff, 2005). To locate the targets of the estrogen actions, attempts were made to determine the ion channels responsible for HA excitation. In mouse VMN, HA-induced depolarization was mediated by H1, and not by H2, receptors and was not affected by the blockade of Na or Ca channels, but was abolished by K channel blockade (Zhou et al., 2007b). Further analyses indicated that HA depolarization was due to an inhibition of a leak K current (Zhou et al., 2007b). For reasons unknown other than the simplest explanation of species difference, the makeup of HA depolarization in rat VMN was somewhat different from that of mice. The depolarization in rats was still not affected by the blockade of Na channels, but unlike that in mice, it was attenuated by the blockade of either K or Ca channels and there was evidence that the depolarization might involve the inhibition of Ca-activated K channels (Kow, Pataky, & Pfaff, 2007). Thus, in rats, acute estrogen application can potentiate HA depolarization by modulating certain K and Ca channels. Also, we knew that E2 can increase neuronal excitability by potentiating inward Na currents in VMN neurons (Kow, Devidze, Pataky, Shibuya, & Pfaff, 2006). This provides an alternative that estrogens can enhance HA depolarization by simply potentiating the inward currents. Whether the modulation of these ion channels was achieved by estrogens acting directly on the channels or indirectly through signaling systems remains to be investigated.

In summary, estrogens and HA can enhance each other’s actions in at least two estrogen functions: raising arousal and induction of female sexual behaviors. Estrogens can enhance HA actions through both chronic genomic and acute nongenomic actions.


α‎1B-Noradrenergic transmission can facilitate estrogen-dependent lordosis behavior (Etgen, Ungar, & Petitti, 1992; Kow, Weesner, & Pfaff, 1992). Estradiol treatment in vivo increases levels of mRNA encoding the α‎1B receptor in the hypothalamus (Etgen, 2002; Karkanias, 1996). In the VMN, estradiol treatment potentiates α‎1B-adrenergic signaling by increasing the proportion of neurons that respond to stimulation of α‎1B-adrenergic receptors. Thus, estradiol may modulate α‎1B-adrenergic receptors in the VMN to promote neuronal excitability and ultimately lordosis.

α‎1B-ARs, members of the GPCR superfamily of membrane proteins, are located on the cell surface. Although α‎1B-ARs are abundant in the brain, much of our knowledge about their function and signaling is based on studies of the sympathetic nervous system, particularly on cardiovascular regulatory activities. α‎1B-ARs can couple to a variety of G-proteins and second-messenger systems, but it is generally agreed that the primary pathway involves activation Gq/11, eliciting second messenger signals, including Ca2+, diacylglycerol (DAG), and inositol triphosphate (IP3). However, α‎1B-ARs may also couple to other G-proteins, including Gh (Kang, Kim, Damron, Baik, & Im, 2002), Gs (Horie, Iton, & Tsujimoto, 1995; Ruan et al., 1998), and Gi/Go (Perez, De Young, & Graham, 1993). There is compelling evidence that α‎1B-ARs can activate other effectors, including the mitogen-activated protein kinase (MAPK) pathway (Della Rocca et al., 1997; Piascik & Perez, 2001), cAMP (Horie et al., 1995; Petitti & Etgen, 1991), phospholipase D (PLD) (Ruan et al., 1998), and PLA2 (Kreda et al., 2001; Perez et al., 1993). Phosphorylation of activated adrenoceptors by G-protein–activated receptor kinases (GRKs) is followed by the binding of arrestin, which may prevent further G-protein activation and downstream signaling (Hein, 2006). GRK-mediated phosphorylation of adrenoceptors may also generate a protein scaffold for further signaling processes, activating MAPK pathways, Akt, and phosphoinositide-3 (PI3) kinases (Lefkowitz & Shenoy, 2005). Other α‎1B-adrenoceptor–associated proteins such as spinophilin and transglutaminase may fine-tune intracellular signaling (Chen et al., 1996; Wang et al., 2005).

Gq/11-Coupled Primary Signaling Pathway

G-proteins, consisting of several subfamilies, are heterotrimers consisting of α‎-, β‎-, and γ‎-subunits. Gs, Go, and Gi are sensitive to toxins and couple primarily to the adenylate cyclase second-messenger system. The toxin-insensitive Gq-protein couples to the PI pathway (Simon, Strathman, & Gautam, 1991). In the Gq subfamily, there are several G‎α‎ isoforms (α‎q, α‎11, α‎14–16), but α‎q and α‎11 are known to be present in the hypothalamus and are probably most relevant for mediating lordosis facilitation (Hubbard & Hepler, 2006; Milligan, 1993). It is generally agreed that the α‎-subunits of the Gq family regulate β‎-isozymes of PLC (Exton, 1994). Of the PLC-β‎ isozymes, PLC-β‎1 is the most sensitive to stimulation by G‎α‎q and G‎α‎11 (Taylor & Exton, 1991). In the VMN, activation of PKC, a key component of the PI pathway, has been shown to facilitate lordosis (Kow et al., 1994a). Thus, the most likely intracellular signal transduction pathway for mediating the facilitation of lordosis can be outlined as follows: NE binds to α‎1B-adrenoceptor causing conformational change → activates α‎-subunit of G‎α‎q/11 → stimulates phophatidyl-inositol–specific PLC-β‎1 in the plasma membrane → hydrolyzes membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) → generates second messengers IP3 and DAG → mobilizes intracellular Ca2+ and activates PKC, respectively → phosphorylates a variety of cellular substrates to achieve the final functional results (Kamp & Hell, 2000; Koshimizu et al., 2002; Kow & Pfaff, 1998; Michelotti, Price, & Schwinn, 2000; Piascik & Perez, 2001).

Other Signaling Pathways

In addition to coupling to PTx-insensitive G-proteins of the Gq/11 family, α‎1B-ARs can also couple to PTx-sensitive G-proteins (Gi or Go), activating PLA2 and increasing arachidonic acid (AA) release in COS-1 and Chinese hamster ovary (CHO) cells (Perez et al., 1993). In Rat-1 fibroblasts, the increase in AA is mediated by the activation of PLD (Ruan et al., 1998). α‎1B-ARs can also activate another class of PTx-insensitive G-proteins, termed Gh, also known as transglutaminase type II (TGII) (Kang et al., 2002). α‎1B-AR/TGII coupling leads to stimulation of PLC-δ‎1, producing second messengers IP3 and DAG, and increased intracellular Ca2+ (Kang et al., 2002). α‎1B-ARs can also couple to Gs, elevating intracellular cAMP and PKA (Horie et al., 1995; Ruan et al., 1998). However, the increase in cAMP is probably via a PKC-dependent potentiation of adenylyl cyclase activity (Perez et al., 1993; Petitti & Etgen, 1991).

Although the precise signaling cascade is unknown, α‎1B-ARs can activate all three major subfamilies of MAPK: the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and the p38 kinases, depending on the cell type (Piascik & Perez, 2001). α‎1B-ARs mediate ERK1 and ERK2 activation via a Ras-dependent mechanism in HEK-293 cells, and Ras-independent mechanism in COS-7 cells (Della Rocca et al., 1997; Hawes et al., 1995). The α‎1B-AR-mediated signal is dependent on stimulation of PLC-β‎, leading to PKC activation, increased intracellular Ca2+, and activation of calmodulin (CaM) and proline-rich tyrosine kinase 2 (Pyk2) (Della Rocca et al., 1997; Koshimizu et al., 2003). Pky2 stimulates Src, resulting in phosphorylation of the Shc adaptor protein, recruitment of the Grb2-Sos complex to the membrane, and activation of Ras (Della Rocca et al., 1997). Ras then activates Raf kinases, which activate MEK1 and MEK2. MEK1 and MEK2 phosphorylate ERK1 and ERK2 (Della Rocca et al., 1997). ERK then translocates to the cell nucleus, where it phosphorylates and activates other kinases and nuclear transcription factors, such as pCREB (CREB—cAMP response element binding), and plays a role in gene expression and protein synthesis (Koshimizu et al., 2003).

Activation of α‎1B-AR/G‎α‎q can activate the JNK pathway, which involves PLC-β‎, Src family tyrosine kinases, Rho family small GTPases, and MKK4 (Koshimizu et al., 2002). JNK phosphorylates transcription factors—c-Jun and activating transcription factor 2 (ATF2)—and is involved in a variety of biological functions, such as cell movement, development, and cell cycle arrest (Koshimizu et al., 2003). In PC12 cells, α‎1B-ARs activate ERKs and p38 kinases, but not JNKs (Zhong & Minneman, 1999), suggesting that activation of specific MAPK pathways may depend on the cell line or tissue where it is expressed (Piascik & Perez, 2001).

A handful of other receptor-associated proteins have been identified for α‎1B-ARs (Chen & Minneman, 2005). The scaffold protein spinophilin, as well as tissue transglutaminase, both of which bind to the third intracellular loop, are involved in α‎1B-AR intracellular signaling (Chen et al., 1996; Wang et al., 2005). The multifunctional protein gC1qR binds with the carboxyl-terminal cytoplasmic domain of the α‎1B-AR and is involved in cell localization and expression of α‎1B-ARs (Xu, Hirasawa, Shinoura, & Tsujimoto, 1999). The μ‎2 subunit of the clathrin adapter complex 2 interacts with the carboxyl-terminal tail of the α‎1B-AR and is involved in α‎1B-AR internalization (Diviani et al., 2003). Neuronal nitric oxide synthase (nNOS) and filamin C also interact with α‎1B-ARs, but their roles are not known (Pupo & Minneman, 2002; Zhang et al., 2004).

Roles of Ion Channels

Calcium channels, especially the L-type channels, are targets of modulation by norepinephrine and α‎1-adrenergic agonists (Kolaj & Renaud, 2001; Lepretre, Mironneau, & Morel, 1994; O-Uchi et al., 2005; Yoshinaga, Zhang, Niidome, Hiraoka, & Hirano, 1999), but the majority of these studies has been carried out in cardiac myocytes. In cardiac myocytes, activated PKC is proposed to bind to anchoring proteins referred to as receptor for activated C kinases (RACKs) located near the high-voltage–activated (HVA) L-type Ca2+ channel, which is then phosphorylated (Kamp & Hell, 2000). α‎1B-ARs are also linked to Ca2+ influx through voltage-independent channels in DDT1 MF-2 and BC3H-1 cells (Han, Esbenshade, & Minneman, 1992). Thus, activation of α‎1B-ARs can increase Ca2+ by mobilizing intracellular stores of Ca2+, as well as via voltage-dependent and -independent Ca2+ channels. In immortalized hypothalamic neurons, an increase in Ca2+ can stimulate cytosolic PLA2 and release AA (Kreda et al., 2001). Activation of PLA2 occurs downstream from PLC stimulation, triggered initially by an increase in cytoplasmic Ca2+ and further augmented by the influx of extracellular Ca2+ (Kreda et al., 2001). However, Ca2+ influx is not necessary for α‎1B-AR-mediated PLC activation, since it is resistant to chelation of extracellular Ca2+ with EGTA and to the L-type Ca2+ channel blocker nifedipine (Perez et al., 1993). Increased Ca2+ has also been suggested to activate nitric oxide synthase, producing nitric oxide, which in turn stimulates cyclic guanosine monophosphate production by activating soluble guanylyl cyclase (Chu & Etgen, 1999).

In VMN neurons, phenylephrine (PHE) enhances HVA barium currents in some neurons, and estradiol increases the proportion of neurons that respond to PHE (Lee et al., 2008a, b). Both L- and N-type calcium channels contribute to the PHE response, although N-type calcium channels predominate. PHE also increases low-voltage–activated (LVA) currents in the majority of VMN neurons. These results are important, as an increase in calcium entry can be expected to modulate second-messenger systems and increase the release of neurotransmitters as well as modulate spike frequency by facilitating action potential firing. Although these effects may be important, in the VMN, PHE-mediated membrane excitability is not coupled to an increase in intracellular calcium (Lee et al., 2008a, b). The effect of adrenergic stimulation on VMN neurons is probably due to effects on K+ conductances.

The classical K+ channel blocker tetraethylammonium (TEA), which blocks the delayed rectifier channel and Ca2+-activated K+ channel, does not block the excitatory action of PHE (Lee et al., 2008a, b). However, the convulsant agent 40-aminopyridine (4-AP) significantly attenuates the excitatory response, indicating that PHE could be depressing a 4-AP–sensitive K+ channel following interaction with α‎1-adrenoceptors (Lee et al., 2008a, b). 4-AP has been shown to block, in a voltage-dependent manner, a transient outward K+ current, likely the A type (Gustafsson, 1982; Sah, French, & Gage, 1985; Song, 2002). A-type K+ current plays an important role in the control of neuronal excitability, repetitive firing, and neurotransmitter release (Connor & Stevens, 1971; Gustafsson, 1982; Wang, Sumners, Posner, & Gelband, 1997). The A-type channel can be identified by its unique voltage-dependent activation, fast kinetics of inactivation, and steady-state inactivation (Wang et al., 1997). NE or α‎1-adrenoceptor agonists have been shown to reduce the amplitude of an early transient outward current presumed to be an A current in neurons from CA1 hippocampus (Sah et al., 1985) and dorsal raphe nucleus (Aghajanian, 1985), as well as in ventricular myocytes (Wang, Wettwer, Gross, & Ravens, 1991). A significant role of other potassium currents in hypothalamic regions includes an inwardly rectifying K+ current (Kelly, Qiu, & Rønnekleiv, 2003), a Ca2+-activated K+ current (Kelly, Rønnekleiv, Ibrahim, Lagrange, & Wagner, 2002), and SK current (Wagner, Rønnekleiv, & Kelley, 2001).

PHE depolarizes VMN neurons by reducing membrane conductance for K+ via an A-type K+ channel (Lee et al., 2008a, b). Thus, PHE may increase the excitability of VMN neurons by diminishing A-type K+ currents, and perhaps potentiating Ca2+ currents. It is possible that α‎1-adrenergic receptors couple to Gq/11, activating PKC to phosphorylate the A-type K+ channel and inhibit its activity. This pathway is potentiated by estradiol in two ways: by increasing levels of mRNA encoding the α‎1B adrenergic receptor and by increasing PKC (Etgen, 2002; Karkanias, 1996; Kelly, Lagrange, Wagner, & Rønnekleiv, 1999). These results show a role for the noradrenergic system in modulating potassium channels, and this may provide a powerful way to increase the excitability of hormone-dependent VMN neurons that govern female sexual behavior.

Mechanisms of Estrogenic Actions

Estrogens can facilitate transcription of several genes, including certain norepinephrine receptors to promote lordosis behavior (Etgen, 2002; Mong & Pfaff, 2004). Estradiol treatment in vivo induces α‎1B-adrenergic receptor mRNA and increases the density of α‎1B-adrenoceptor binding in the hypothalamus (Etgen, 2002; Karkanias, 1996). Since α‎1B-adrenergic receptors can facilitate lordosis (Kow et al., 1992), this estrogen action may amplify α‎1-adrenoceptor–mediated facilitation of lordosis. Noradrenergic agonists and their receptors are not the only targets of estrogen actions. Estrogen can also modulate components of the intracellular signaling pathway involved in lordosis, including G-proteins, PLC, and PKC (Kow et al., 1994b). Estrogen potentiates G-protein activity in the ventrolateral VMN (Kow & Pfaff, 1998), which may be a mechanism whereby estrogen can enhance the excitatory action of noradrenergic agonists to facilitate lordosis. Estrogen has been shown to potentiate PCK activity in rat brain (Ansonoff & Etgen, 1998), and PKC-dependent facilitation of lordosis is estrogen dependent (Kow et al., 1994a). Thus, estrogen may potentiate certain PKC isozymes in the VMN to facilitate lordosis.

Estradiol Effects on Calcium Channels

In VMN neurons, the α‎1-adrenergic agonist PHE enhances HVA calcium channel activity in some neurons, and estradiol treatment amplifies this effect by increasing the proportion of neurons that respond to PHE (Lee et al., 2008a, b). Estradiol increases LVA calcium channel activity in VMN (Lee et al., 2008a, b) and arcuate neurons (Qiu et al., 2006). Estradiol has also been shown to upregulate mRNA expression of Cav3.1 (a T-type calcium channel) in the hypothalamus (Amodei et al., 2004; Qiu et al., 2006). The specific linkage between estradiol effects on calcium channels and excitability, and ultimately lordosis behavior, remains to be established. T-type LVA channels, due to their low activation threshold, can open near resting membrane potential, and can generate neuronal firing and pacemaker activities (Chemin et al., 2002; Cohen & McCarthy, 1987; Matteson & Armstrong, 1986). Estradiol effects on LVA channels may be a mechanism by which estradiol increases excitability of VMN neurons, which are critical in the hypothalamic circuits controlling lordosis behavior.

μ‎-Receptor Opioid Agonists

Among three major opioid receptors identified (μ‎-, δ‎-, and κ‎-receptors), the μ‎-receptor is the principal receptor responsible for narcotics addiction and reward-seeking behaviors. Gene for μ‎-opioid receptor was identified and pharmacologically characterized in the 1970s on the basis of its high affinity for morphine (mu for morphine) (Martin, Eades, Thompson, Huppler, & Gilbert, 1976). A typical GPCR, μ‎-receptor is highly expressed in several brain regions: thalamus, hypothalamus, caudate putamen, neocortex, nucleus accumbens, amygdala, interpeduncular complex, and inferior and superior colliculi (Mansour, Khachaturian, Lewis, Akil, & Watson, 1987), periaqueductal gray(PAG) and raphe nuclei (Hawkins et al., 1988), as well as in the superficial layers of the dorsal horn of the spinal cord (Besse, Lombard, Zajac, Roques, & Besson, 1990). μ‎-Receptor distribution varies by species; for example, in the hypothalamus, there is a higher density of μ‎-receptor in mouse than in rat, while the opposite is true in the hippocampus (Kitchen, Slowe, Matthes, & Kieffer, 1997). Their pattern of distribution may differ by species, but their physiological function remains the same: analgesia, respiratory and cardiovascular functions, regulation of intestinal transit, feeding, mood, thermoregulation, hormone secretions, and immune functions (Dhawan et al., 1996). In addition, μ‎-receptors are known to be involved in steroid hormone–regulated sexual behaviors (Forsberg, Eneroth, & Sodersten, 1987; Pfaus & Gorzalka, 1987a, 1987b; Pfaus & Pfaff, 1992; Vathy, Vincent, & Etgen, 1991).

The most intensively studied sex behavior, displayed by female rodents in a laboratory setting, is estrogen-dependent lordosis (Pfaff et al., 1994), which has served as a very useful model to examine the mechanisms of opioid actions during female reproduction. For instance, exogenous opiates such as morphine and morphiceptin inhibit lordosis, depending on method of administration as well as on concentration used (Pfaus, Pendleton, & Gorzalka, 1986; Vathy et al., 1991). Infusion of low doses of endogenous opioid peptide β‎-endorphin into a steroid-primed female OVX rat’s third ventricle (Wiesner & Moss, 1984, 1986), lateral ventricles (Pfaus & Gorzalka, 1987b; Pfaus et al., 1986), or medial preoptic area (mPOA) (Sirinathsinghji, 1986) inhibits lordosis behavior. The opposite effect is achieved, that is, lordosis behavior is facilitated, when naloxone is administered centrally and this effect displayed dose and site specificity (Pfaus & Gorzalka, 1987a). Many of the brain regions involved in the hormonal regulation of lordosis behavior contain opioid peptides as well as opioid receptors. Infusion of a potent μ‎-receptor agonist into VMH and mPOA inhibits lordosis (Acosta-Martinez & Etgen, 2002a).

While a primary function of opioids is related to pain regulation, they also reduce generalized central nervous system (CNS) arousal (Pfaff, 2005). In this regard, it is important to examine the potential impact of a generalized arousal (Garey et al., 2003) neurochemical system (μ‎-receptor signaling) on neurons concerned with specifically sexual arousal.

In one of our latest studies, we hypothesized that μ‎-receptor signaling would oppose estrogenic actions on hypothalamic neurons (Devidze et al., 2008). Indeed, in female rats, estrogens also oppose inhibitory effects of μ‎-receptors on neurons regulating sex behavior (Eckersell, Popper, & Micevych, 1998; Micevych, Rissman, Gusrafsson, & Sinchak, 2003; Sinchak & Micevych, 2001). However, relations between estrogens and opioid systems are complex. Estrogen treatment of OVX animals can increase μ‎-receptor levels (Hammer, 1990; Joshi, Billiar, & Miller, 1993; Martini, Dondi, Limonta, Maggi, & Piva, 1989; Piva et al., 1995; Quinones-Jenab, Jenab, Ogawa, Inturrisi, & Pfaff, 1997; Weiland & Wise, 1990). It is important to consider the electrophysiological properties of opioid receptors: first, they hyperpolarize cells by increasing membrane K+ conductance, and second, they inhibit synaptic transmission by reducing voltage-dependent Ca2+ currents. Estrogens have been reported to modulate the coupling of μ‎-receptor to a K+ channel (Cunningham, Fang, Selley, & Kelly, 1998). Twenty-four-hour pretreatment of OVX guinea pigs with estrogen decreases the potency of the μ‎-receptor agonist DAMGO to hyperpolarize hypothalamic arcuate neurons (Kelly, Loose, & Rønnekleiv, 1992). Since lordosis is fostered by increased electrical activity in VMH (Pfaff, 1999), we tested the hypothesis that a general and a μ‎-receptor–selective agonist would decrease synaptic transmission to VMH neurons (Devidze et al., 2008), where a high percentage of these neurons express estrogen receptors (Pfaff & Keiner, 1973), and destruction of these neurons abolishes lordosis behavior (Pfaff & Sakuma, 1979). Novel findings showed that estrogen pretreatment increased synaptic transmission in VMH neurons; MERF and DAMGO presynaptically inhibited sEPSCs, as well as mEPSCs, via presynaptic μ‎-receptors, wiping out the estrogen effect (Devidze et al., 2008). Activating μ‎-receptors specifically and powerfully mimicked the MERF effect but did not quite achieve the same magnitude of effect numerically, allowing for small potential roles by δ‎- and κ‎-opioid agonists (Devidze et al., 2008), which very well could have been due to the possibility that the nature of opioid peptide effects in our biophysical recording studies could similarly depend upon the concentrations of these peptides in the recording chamber—e.g., a low dose of a selective δ‎-receptor agonist infused intraventricularly facilitates lordosis behavior (Acosta-Martinez & Etgen, 2002b), whereas a high dose of the same δ‎-receptor agonist directly into the ventromedial hypothalamus inhibits lordosis (Acosta-Martinez & Etgen, 2002a).

Knowing that activation of μ‎-receptors in the hypothalamus can decrease lordosis (Pfaus & Gorzalka, 1987b; Pfaus et al., 1986) and that lordosis requires increased VMH electrical activity (Pfaff, 1999), μ‎-receptor inhibition of sEPSCs and mEPSCs in ventrolateral VMH neurons offers a possible mechanism for the effect of μ‎-receptor active opioid peptides on lordosis (Devidze et al., 2008). Second, because opioid peptides affect generalized CNS arousal (Pfaff, 2006), the effects of MERF and DAMGO on VMH illustrate how a generalized CNS arousal neurochemical can affect a specific manifestation of arousal: female sex behavior.

Mechanisms of Estrogen and μ‎-Opioid Receptor Effects

A study by Nguyen and Wagner (2006) (in which glutamatergic and GABAergic synaptic inputs in arcuate neurons were presynaptically inhibited by cannabinoids and differentially modulated by estrogen) showed that estrogen-mediated remodeling of excitatory synaptic transmission in vivo appears to be a widespread phenomenon. Further, estrogenic actions on VMH neuronal sEPSCs have been studied by Zhou, Pfaff, & Chen (2005), who showed that estrogen treatment increased spontaneous synaptic events in cultured female VMH neurons. With respect to mechanisms underlying this estrogenic effect, there is mounting evidence describing at least two causal routes for estrogens to affect synaptic transmission in the CNS. For a long time, most of estrogenic effects were attributed to classical nuclear estrogen receptors (genomic actions of estrogens). However, studies from the past two decades show that estrogens could rapidly alter neuronal firing within seconds; this action of estrogens was described as nongenomic, meaning that estrogenic actions could be exerted via other cellular mechanisms. One class of hormone receptors that could be involved are GPCRs (Kelly & Wagner, 1999); an integral part of this class would be opioid receptors. However, it should be noted that results by Devidze et al. could be explained either by genomic or by nongenomic hormone actions, and, in fact, those two have been shown to act in concert (Vasudevan & Pfaff, 2007).

Opioid actions on central neurons are primarily inhibitory in nature: presynaptically by inhibiting transmitter release and postsynaptically by opening several types of K+ channels or inhibiting Ca2+ conductance (North, 1992; Williams, Christie, & Manzoni, 2001). Findings by Devidze et al. indicated that the majority of inhibitory effects of MERF takes place through the μ‎-receptor. This view is supported by other studies. μ‎-Receptor–mediated presynaptic inhibition of GABA release in central inhibitory synapses is present in many brain regions and in the spinal cord (Chieng & Williams, 1998; Cohen, Doze, & Madison, 1992; Grudt & Henderson, 1998; Kerchner & Zhuo, 2002; Lupica, 1995; Vaughan & Christie, 1997). μ‎-Receptor–mediated presynaptic inhibition of glutamatergic EPSCs in central excitatory synapses by μ‎-receptor agonists has been reported in neurons of the arcuate nucleus, ventromedial hypothalamus, subthalamic and supraoptic nuclei, PAG, and spinal dorsal horn (Emmerson & Miller, 1999; Grudt & Williams, 1994; Honda, Ono, & Inenaga, 2004; Moran & Smith, 2002; Shen & Johnson, 2002; Terman, Eastman, & Chavkin, 2001; Vaughan & Christie, 1997).

In the hypothalamus, opioid actions are involved in the control of the neuroendocrine, reproductive, thermoregulatory, and orexigenic systems. However, the specific mechanisms by which opioids act are often not completely clear. The present studies using selective opioid agonists (and antagonists) suggest that opioids inhibited the release of excitatory transmitters onto VMH neurons. μ‎-Receptors appeared primarily to mediate this inhibition. This conclusion is based on (1) mimicry of the action of MERF by DAMGO, (2) lack of effect of U69593 and DPDPE, and (3) blockade of the effect of MERF by a μ‎-receptorselective antagonist. Furthermore, opioids decreased the frequency of spontaneous miniature EPSCs without altering their amplitude. These observations indicate a presynaptic action of μ‎-receptors to reduce the release of glutamate onto VMH neurons (Devidze et al., 2008). From the present results, it might be noted that presynaptic glutamate-containing fibers have predominantly μ‎-type receptors (Shen & Johnson, 2002). Studies have shown that opioids modulate the entry of Ca2+ into neurons of the nucleus tractus solitarius (Rhim & Miller, 1994) and increase a Ba2+-sensitive K+ conductance (North & Williams, 1985)


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