Show Summary Details

Page of

PRINTED FROM the OXFORD RESEARCH ENCYCLOPEDIA, NEUROSCIENCE (neuroscience.oxfordre.com). (c) Oxford University Press USA, 2016. All Rights Reserved. Personal use only; commercial use is strictly prohibited. Please see applicable Privacy Policy and Legal Notice (for details see Privacy Policy).

date: 23 August 2017

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

Introduction

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.

Norepinephrine

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)

References

Acosta-Martinez, M., & Etgen, A. M. (2002a). Activation of mu-opioid receptors inhibits lordosis behavior in estrogen and progesterone-primed female rats. Hormones and Behavior, 41, 88–100.Find this resource:

Acosta-Martinez, M., & Etgen, A. M. (2002b). The role of delta-opioid receptors in estrogen facilitation of lordosis behavior. Behavioural Brain Research, 136(2002), 93–102.Find this resource:

Aghajanian, G. K. (1985). Modulation of a transient outward current in serotonergic neurones by alpha 1-adrenoceptors. Nature, 315, 501–503.Find this resource:

Amodei, K., Jamali, K., Malyala, A., et al. (2004). Estrogen increases calcium T-channel expression in the guinea pig hypothalamus. Washington, DC: Society for Neuroscience.Find this resource:

Ansonoff, M. A., & Etgen, A. M. (1998). Estradiol elevates protein kinase C catalytic activity in the preoptic area of female rats. Endocrinology, 139, 3050–3056.Find this resource:

Basheer, R., Strecker, R. E., Thakkar, M. M., & McCarley, R. W. (2004). Adenosine and sleep–wake regulation. Progress in Neurobiology, 73, 379–396.Find this resource:

Besse, D., Lombard, M. C., Zajac, J. M., Roques, B. P., & Besson, J. M. (1990). Pre- and postsynaptic distribution of mu, delta and kappa opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord. Brain Research, 521, 15–22.Find this resource:

Biegon, A., Fischette, C., & McEwen, B. (1982). Serotonin receptor modulation by estrogen in discrete brain nuclei. Neuroendocrinology, 35, 287–291.Find this resource:

Biegon, A., & McEwen, B. (1982). Modulation by estradiol of serotonin-1 receptors in brain. Journal of Neuroscience, 2, 199–205.Find this resource:

Bouthenet, M. L., Ruat, M., Sales, N., Garbarg, M., & Schwartz, J. C. (1988). A detailed mapping of histamine H1-receptors in guinea-pig central nervous system established by autoradiography with [125I]iodobolpyramine. Neuroscience, 26(2), 553–600.Find this resource:

Brown, R. E., Stevens, D. R., & Hass, H. L. (2001). The physiology of brain histamine. Progress in Neurobiology, 63(6), 637–672.Find this resource:

Bueno, J., & Pfaff, D. W. (1976). Single unit recording in hypothalamus and preoptic area of estrogen-treated and untreated ovariectomized female rats. Brain Research, 101, 67–78.Find this resource:

Ceccatelli, S., Grandison, L., Scott, R. E. M., Pfaff, D. W., & Kow, L.-K. (1996). Estradiol regulation of nitric oxide synthase mRNAs in rat hypothalamus. Neuroendocrinology, 64, 357–363.Find this resource:

Chamberlin, N. L., Arrigoni, E., Chou, T. C., Scammell, T. E., Greene, R. W., & Saper, C. B. (2003). Effects of adenosine on gabaergic synaptic inputs to identified ventrolateral preoptic neurons. Neuroscience, 119(4), 913–918.Find this resource:

Chemin, J., Monteil, A., Perez-Reyes, E., et al. (2002). Specific contribution of human T-type calcium channel isotypes (alpha (1G), alpha (1H) and alpha (1I)) to neuronal excitability. Journal of Physiology, 540, 3–14.Find this resource:

Chen, S., Lin, F., Iismaa, S., et al. (1996). Alpha1-adrenergic receptor signaling via Gh is subtype specific and independent of its transglutaminase activity. Journal of Biological Chemistry, 27(1), 32385–32391.Find this resource:

Chen, Z. J., & Minneman, K. P. (2005). Recent progress in alpha1-adrenergic receptor research. Acta Pharmacologica Sinica, 26, 1281–1287.Find this resource:

Chieng, B., & Williams, J. T. (1998). Increased opioid inhibition of GABA release in nucleus accumbens during morphine withdrawal. Journal of Neuroscience, 18, 7033–7039.Find this resource:

Chou, T. C., Bjorkum, A. A., Gaus, S. E., Lu, J., Scammell, T. E., & Saper, C. B. (2002). Afferents to the ventrolateral preoptic nucleus. Journal of Neuroscience, 22(3), 977–990.Find this resource:

Chu, H. P., & Etgen, A. M. (1999). Ovarian hormone dependence of alpha1-adrenoceptor activation of the nitric oxide–cGMP pathway: Relevance for hormonal facilitation of lordosis behavior. Journal of Neuroscience, 19, 7191–7197.Find this resource:

Cohen, C. J., & McCarthy, R. T. (1987). Nimodipine block of calcium channels in rat anterior pituitary cells. Journal of Physiology, 387, 195–225.Find this resource:

Cohen, G. A., Doze, V. A., & Madison, D. V. (1992). Opioid inhibition of GABA release from presynaptic terminals of rat hippocampal interneurons. Neuron, 9, 325–335.Find this resource:

Connor, J. A., & Stevens, C. F. (1971). Prediction of repetitive firing behaviour from voltage clamp data on an isolated neurone soma. Journal of Physiology, 213, 31–53.Find this resource:

Cunningham, M. J., Fang, Y., Selley, D. E., & Kelly, M. J. (1998). mu-Opioid agonist-stimulated [35S]GTPgammaS binding in guinea pig hypothalamus: Effects of estrogen. Brain Research, 791, 341–346.Find this resource:

Della Rocca, G. J., Van Biesen, T., Daaka, Y., et al. (1997). Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. Journal of Biological Chemistry, 272, 19125–19132.Find this resource:

Devidze, N., Mong, J. A., Jasnow, A. M., Kow, L. M., & Pfaff, D. W. (2005). Sex and estrogenic effects on co-expression of mRNAs in single ventromedial hypothalamic neurons. Proceedings of the National Academy of Sciences of the United States of America, 102(40), 14446–14451.Find this resource:

Devidze, N., Zhang, Q., Zhou, J., Lee, A. W., Pataki, S., Kow, L. M., & Pfaff, D. W. (2008). Presynaptic actions of opioid receptor agonists in ventromedial hypothalamic neurons in chronically estrogen- and oil-treated female mice. Neuroscience, 152, 942–949.Find this resource:

Dhawan, B. N., Cesselin, F., Raghubir, R., Reisine, T., Bradley, P. B., Portoghese, P. S., et al. (1996). International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacological Reviews, 48, 567–592.Find this resource:

Diviani, D., Anne-Laure, L., Abuin, L., et al. (2003). The adaptor complex 2 directly interacts with the alpha 1b-adrenergic receptor and plays a role in receptor endocytosis. Journal of Biological Chemistry, 278, 19331–19340.Find this resource:

Donoso, A. O., & Broitman, S. T. (1979). Effects of a histamine synthesis inhibitor and antihistamines on the sexual behavior of female rats. Psychopharmacology (Berl), 66, 251–255.Find this resource:

Dzaja, A., Arber, S., Hislop, J., et al. (2005). Women’s sleep in health and disease. Journal of Psychiatric Research, 39, 55–76.Find this resource:

Easton, A., Dwyer, E., & Pfaff, D. (2006). Estradiol and orexin-2 saporin actions on multiple forms of behavioral arousal in female mice. Behavioral Neuroscience, 120, 1–9.Find this resource:

Easton, A., Norton, J., Goodwillie, A., & Pfaff, D. (2004). Sex differences in mouse behavior following pyrilamine treatment: Role of histamine 1 receptors in arousal. Pharmacology, Biochemistry, and Behavior, 79, 563–572.Find this resource:

Eckersell, C. B., Popper, P., & Micevych, P. E. (1998). Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. Journal of Neuroscience, 18, 3967–3976.Find this resource:

Edwards, D. (2005). Regulation of signal transduction pathways by estrogen and progesterone. Annual Review of Physiology, 67, 335–376.Find this resource:

Emmerson, P. J., & Miller, R. J. (1999). Pre- and postsynaptic actions of opioid and orphan opioid agonists in the rat arcuate nucleus and ventromedial hypothalamus in vitro. Journal of Physiology, 517(pt 2), 431–445.Find this resource:

Etgen, A. M. (2002). Estrogen regulation of neurotransmitter and growth factor signaling in the brain. In D. W. Pfaff, A. Arnold, A. Etgen, A., S. Fahrbach, & R. Rubin (Eds.), Hormones, brain and behavior (pp. 381–440). San Diego, CA: Academic Press.Find this resource:

Etgen, A. M., Ungar, S., & Petitti, N. (1992). Estradiol and progesterone modulation of norepinephrine neurotransmission: Implications for the regulation of female reproductive behavior. Journal of Neuroendocrinology, 4, 255–271.Find this resource:

Exton, J. H. (1994). Phosphoinositide phospholipases and G proteins in hormone action. Annual Review of Physiology, 56, 349–369.Find this resource:

Fang, J., & Fishbein, W. (1996). Sex differences in paradoxical sleep: Influences of estrus cycle and ovariectomy. Brain Research, 73(4), 275–285.Find this resource:

Floody, O. (2002). Time course of VMN lesion effects on lordosis and proceptive behavior in female hamsters. Hormones and Behavior, 41, 366–376.Find this resource:

Forsberg, G., Eneroth, P., & Sodersten, P. (1987). Naloxone stimulates sexual behaviour in lactating rats. Journal of Endocrinology, 113, 423–427.Find this resource:

Fricke, O., Kow, L.-M., Bogun, M., & Pfaff, D. (2007). Estrogen evokes a rapid effect on intracellular calcium in neurons characterized by calcium oscillations in the arcuate nucleus. Endocrine, 31, 279–288.Find this resource:

Funabashi, T., Brooks, P., Kleopoulos, S., Grandison, L., Mobbs, C., & Pfaff, D. (1995). Changes in preproenkephalin messenger RNA levels in the rat ventromedial hypothalamus during the estrous cycle. Molecular Brain Research, 28, 129–134.Find this resource:

Gallopin, T., Fort, P., Eggerman, E., et al. (2000). Identification of sleep-promoting neurons in vitro. Nature, 404, 992–995.Find this resource:

Gallopin, T., Luppi, P.-H., Cauli, B., et al. (2005). The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus. Neuroscience, 134(4), 1377–1390.Find this resource:

Garey, J., Goodwillie, A., Frohlich, J., et al. (2003). Genetic contributions to generalized arousal of brain and behavior. Proceedings of the National Academy of Sciences of the United States of America, 100, 11019–11022.Find this resource:

Geary, N., Asarian, L., Korach, K. S., Pfaff, D. W., & Ogawa, S. (2001). Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice. Endocrinology, 142, 4751–4757.Find this resource:

Grudt, T. J., & Henderson, G. (1998). Glycine and GABAA receptor-mediated synaptic transmission in rat substantia gelatinosa: Inhibition by mu-opioid and GABAB agonists. Journal of Physiology, 507(pt 2), 473–483.Find this resource:

Grudt, T. J., & Williams, J. T. (1994). mu-Opioid agonists inhibit spinal trigeminal substantia gelatinosa neurons in guinea pig and rat. Journal of Neuroscience, 14, 1646–1654.Find this resource:

Gustafsson, B., Galvan, M., Grafe, P., & Wigström, H. (1982)A transient outward current in a mammalian central neurone blocked by 4-aminopyridine. Nature, 299, 252–254.Find this resource:

Haas, H., & Panula, P. (2003). The role of histamine and the tuberomamillary nucleus in the nervous system. Nature Reviews Neuroscience, 4(2), 121–130.Find this resource:

Hall, J., & McDonnell, D. (2005). Coregulators in nuclear estrogen receptor action: From concept to therapeutic targeting. Molecular Interventions, 5, 343–357.Find this resource:

Hammer, R. P., Jr. (1990). Mu-opiate receptor binding in the medial preoptic area is cyclical and sexually dimorphic. Brain Research, 515, 187–192.Find this resource:

Han, C., Esbenshade, T. A., & Minneman, K. P. (1992). Subtypes of alpha 1-adrenoceptors in DDT1 MF-2 and BC3H-1 clonal cell lines. European Journal of Pharmacology, 226, 141–148.Find this resource:

Hawes, B. E., Van Biesen, T., Koch, W. J., et al. (1995). Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. Journal of Biological Chemistry, 270, 17148–17153.Find this resource:

Hawkins, K. N., Knapp, R. J., Gehlert, D. R., et al. (1988). Quantitative autoradiography of [3H]CTOP binding to mu opioid receptors in rat brain. Life Sciences, 42, 2541–2551.Find this resource:

Hayaishi, O. (2002). Molecular genetic studies on sleep–wake regulation, with special emphasis on the prostaglandin D(2) system. Journal of Applied Physiology, 92, 863–868.Find this resource:

Hayaishi, O., Urade, Y., Eguchi, N., & Huang, Z.-L. (2004). Genes for prostaglandin D synthase and receptor as well as adenosine A2A receptor are involved in the homeostatic regulation of nrem sleep. Archives Italiennes de Biologie, 142, 533–539.Find this resource:

Hein, L. (2006). Adrenoceptors and signal transduction in neurons. Cell and Tissue Research, 326, 541–551.Find this resource:

Hiroi, R., McDevitt, A., & Neumaier, J. (2006). Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus. Biological Psychiatry, 60, 288–295.Find this resource:

Hiroi, R., & Neumaier, J. (2006). Differential effects of ovarian steroids on anxiety versus fear as measured by open field test and fear-potentiated startle. Behavioural Brain Research, 166, 93–100.Find this resource:

Holder, M. K., Hadjimarkou, M. M., Cornil, C. A., Ball, G. F., McCarthy, M. M., & Mong, J. A. (2007). Methamphetamine activation of the neural circuitry involved in female sexual behavior. Society for Neuroscience, Abstract # 84.5/MM6.Find this resource:

Honda, E., Ono, K., & Inenaga, K. (2004). DAMGO suppresses both excitatory and inhibitory synaptic transmission in supraoptic neurones of mouse hypothalamic slice preparations. Journal of Neuroendocrinology, 16, 198–207.Find this resource:

Horie, K., Iton, H., & Tsujimoto, G. (1995). Hamster alpha 1B-adrenergic receptor directly activates Gs in the transfected Chinese hamster ovary cells. Molecular Pharmacology, 48, 392–400.Find this resource:

Hubbard, K. B., & Hepler, J. R. (2006). Cell signalling diversity of the Gq alpha family of heterotrimeric G proteins. Cell Signalling, 18, 135–150.Find this resource:

Ishunina, T. A., van Heerikhuize, J. J., Ravid, R., & Swaab, D. F. (2003). Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: Changes in relation to sex, aging and Alzheimer’s disease. Brain Research, 988(1–2), 84–96.Find this resource:

Jackson, V., Wayman, C., & Booth, C. (2007). Electrical activity in the ventromedial nucleus in vitro predicts lordosis behaviour. Society for Neuroscience, Abstract 938.5.Find this resource:

Jasnow, A. M., Schulkin, J., & Pfaff, D. W. (2005). Estrogen facilitates fear conditioning and increases corticotropin-releasing hormone mRNA expression in the central amygdala in female mice. Hormones and Behavior, 49(2), 197–205.Find this resource:

Jorgenson, K. L., Kow, L.-M., & Pfaff, D. W. (1989). Histamine excites arcuate neurons in vitro through H1receptors. Brain Research, 502(1), 171–179.Find this resource:

Joshi, D., Billiar, R. B., & Miller, M. M. (1993). Modulation of hypothalamic mu-opioid receptor density by estrogen: A quantitative autoradiographic study of the female C57BL/6J mouse. Brain Research Bulletin, 30, 629–634.Find this resource:

Kamp, T. J., & Hell, J. W. (2000). Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circulation Research, 87, 1095–1102.Find this resource:

Kang, S. K., Kim, D. K., Damron, D. S., Baek, K. J., & Im, M. J. (2002). Modulation of intracellular Ca(2+) via alpha(1B)-adrenoceptor signaling molecules, G alpha(h) (transglutaminase II) and phospholipase C-delta 1. Biochemical and Biophysical Research Communications, 293, 383–390.Find this resource:

Karkanias, G., Ansonoff, M. A., & Etgen, A. M. (1996). Estradiol regulation of alpha 1b-adrenoceptor mRNA in female rat hypothalamus-preoptic area. Journal of Neuroendocrinology, 8, 449–455.Find this resource:

Kelly, M. J., Lagrange, A. H., Wagner, E. J., & Rønnekleiv, O. K. (1999). Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways. Steroids, 64, 64–75.Find this resource:

Kelly, M. J., Loose, M. D., & Rønnekleiv, O. K. (1992). Estrogen suppresses mu-opioid- and GABAB-mediated hyperpolarization of hypothalamic arcuate neurons. Journal of Neuroscience, 12, 2745–2750.Find this resource:

Kelly, M. J., Qiu, J., & Rønnekleiv, O. K. (2003). Estrogen modulation of G-protein-coupled receptor activation of potassium channels in the central nervous system. Annals of the New York Academy of Sciences, 1007, 6–16.Find this resource:

Kelly, M. J., Rønnekleiv, O. K., Ibrahim, N., Lagrange, A. H., & Wagner, E. J. (2002). Estrogen modulation of K(+) channel activity in hypothalamic neurons involved in the control of the reproductive axis. Steroids, 67, 447–456.Find this resource:

Kelly, M. J., & Wagner, E. J. (1999). Estrogen modulation of G-protein-coupled receptors. Trends in Endocrinology and Metabolism, 10, 369–374.Find this resource:

Kerchner, G. A., & Zhuo, M. (2002). Presynaptic suppression of dorsal horn inhibitory transmission by mu-opioid receptors. Journal of Neurophysiology, 88, 520–522.Find this resource:

Kitchen, I., Slowe, S. J., Matthes, H. W., & Kieffer, B. (1997). Quantitative autoradiographic mapping of mu-, delta- and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene. Brain Research, 778, 73–88.Find this resource:

Kleinlogel, H. (1983). The female rat’s sleep during oestrous cycle. Neuropsychobiology, 10, 228–237.Find this resource:

Kolaj, M., & Renaud, L. P. (2001). Norepinephrine acts via alpha2 adrenergic receptors to suppress N-type calcium channels in dissociated rat median preoptic nucleus neurons. Neurophamacology, 41, 472–479.Find this resource:

Komisaruk, B., Adler, N., & Hutchison, J. (1972). Genital sensory field: Enlargement by estrogen treatment in female rats. Science, 178, 1295–1298.Find this resource:

Koshimizu, T., Tanoue, A., Hirasawa, A., et al. (2003). Recent advances in alpha1-adrenoceptor pharmacology. Pharmacology and Therapeutics, 98, 235–244.Find this resource:

Koshimizu, T., Yamauchi, J., Hirasawa, A., et al. (2002). Recent progress in alpha1-adrenoceptor pharmacology. Biological and Pharmaceutical Bulletin, 25, 401–408.Find this resource:

Kow, L., Devidze, N., Pataky, S., Shibuya, I., & Pfaff, D. W. (2006). Acute estradiol application increases inward and decreases outward whole-cell currents of neurons in rat hypothalamic ventromedial nucleus. Brain Research, 1116(1), 1–11.Find this resource:

Kow, L., & Pfaff, D. (1973). Effects of estrogen treatment on the size of receptive field and response threshold of pudendal nerve in the female rat. Neuroendocrinology, 13, 299–313.Find this resource:

Kow, L., Weesner, G. D., & Pfaff, D. W. (1992). Alpha 1-adrenergic agonists act on the ventromedial hypothalamus to cause neuronal excitation and lordosis facilitation: Electrophysiological and behavioral evidence. Brain Research, 588, 237–245.Find this resource:

Kow, L. M., Brown, H. E., & Pfaff, D. W. (1994a). Activation of protein kinase C in the hypothalamic ventromedial nucleus or the midbrain central gray facilitates lordosis. Brain Research, 660, 241–248.Find this resource:

Kow, L.-M., Easton, A., & Pfaff, D. W. (2005). Acute estrogen potentiates excitatory responses of neurons in rat hypothalamic ventromedial nucleus. Brain Research, 1043(1–2), 124–131.Find this resource:

Kow, L. M., Mobbs, C. V., & Pfaff, D. W. (1994b). Roles of second-messenger systems and neuronal activity in the regulation of lordosis by neurotransmitters, neuropeptides, and estrogen: A review. Neuroscience and Biobehavioral Reviews, 18, 251–268.Find this resource:

Kow, L.-M., Pataky, S., & Pfaff, D. W. (2007). Acute estrogen potentiation of histamine (HA)-induced depolarization in rat ventromedial hypothalamic nucleus (VMN) neurons may involve attenuation of BK channels. Society for Neuroscience, Abstract 245.9.Find this resource:

Kow, L. M., & Pfaff, D. W. (1998). Mapping of neural and signal transduction pathways for lordosis in the search for estrogen actions on the central nervous system. Behavioural Brain Research, 92, 169–180.Find this resource:

Kreda, S. M., Sumner, M., Fillo, S., et al. (2001). Alpha(1)-adrenergic receptors mediate LH-releasing hormone secretion through phopholipases C and A(2) in immortalized hypothalamic neurons. Endocrinology, 142, 4839–4851.Find this resource:

Kumar, M., Chen, C., & Muther, T. (1979). Changes in the pituitary and hypothalamic content of methionine-enkephalin during the estrus cycle of rats. Life Sciences, 25, 1687–1696.Find this resource:

Kumar, R., & Thompson, E. (2003). Transactivation functions of the N-terminal domains of nuclear hormone receptors. Molecular Endocrinology, 17, 1–10.Find this resource:

Laflamme, N., Nappi, R. E., Dorlet, G., et al. (1998). Expression and neuropeptidergic characterization of estrogen receptors (ERa and ERb) throughout the rat brain: Anatomical evidence of distinct roles of each subtype. Journal of Neurobiology, 36(3), 357–378.Find this resource:

Lauber, A. H., Mobbs, C. V., Muramatsu, M., & Pfaff, D. W. (1991). Estrogen receptor mRNA expression in rat hypothalamus as a function of genetic sex and estrogen dose. Endocrinology, 129(6), 3180–3186.Find this resource:

Lauber, A. H., Romano, G. J., Mobbs, C. V., & Pfaff, D. W. (1990). Estradiol regulation of estrogen receptor messenger ribonucleic acid in rat mediobasal hypothalamus: An in situ hybridization study. Journal of Neuroendocrinology, 2(5), 605–611.Find this resource:

Lauber, A. H., Romano, G. J., & Pfaff, D. W. (1991). Sex difference in estradiol regulation of progestin receptor mRNA in rat mediobasal hypothalamus as demonstrated by in situ hybridization. Neuroendocrinology, 53, 608–613.Find this resource:

Lee, A. W., Devidze, N., Pfaff, D. W., & Zhou, J. (2006). Functional genomics of sex hormone dependent neuroendocrine systems: Specific and generalized actions in the CNS. Progress in Brain Research. Functional Genomics and Proteomics in the Clinical Neurosciences, 158, 243–272.Find this resource:

Lee, A. W., Kyrozis, A., & Chevaleyre, V. (2008a). Estradiol modulation of phenylephrine-induced excitatory responses in ventromedial hypothalamic neurons of female rats. Proceedings of the National Academy of Sciences of the United States of America, 105, 7333–7338.Find this resource:

Lee, A. W., Kyrozis, A., Chevaleyne, V., et al. (2008b). Voltage-dependent calcium channels in ventromedial hypothalamic neurones of postnatal rats: Modulation by oestradiol and phenylephrine. Journal of Neuroendocrinology, 20, 188–198.Find this resource:

Lee, A. W., et al. (2009). Genetic and epigenetic mechanisms of neural and hormonal controls over female reproductive behaviors. In D. Pfaff et al. (Eds.), Hormones, brain and behavior (2d ed.) (pp. 1141–1191). San Diego, CA: Academic Press.Find this resource:

Lefkowitz, R. J., & Shenoy, S. K. (2005). Transduction of receptor signals by beta-arrestins. Science, 308, 512–517.Find this resource:

Lepretre, N., Mironneau, J., & Morel, J. L. (1994). Both alpha1A- and alpha2A-adrenoreceptor subtypes stimulate voltage-operated L-type calcium channels in rat portal vein myocytes. Journal of Biological Chemistry, 269, 29546–29552.Find this resource:

Li, C., Brake, W. G., Romeo, R. D., et al. (2004). Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice. Proceedings of the National Academy of Sciences of the United States of America, 101, 2185–2190.Find this resource:

Li, H., & Satinoff, E. (1996). Body temperature and sleep in intact and ovariectomized female rats. American Journal of Physiology, 271, R1753–R1758.Find this resource:

Liou, S. Y., Shibata, S., Yamakawa, K., & Ueki, S. (1983). Inhibitory and excitatory effects of histamine on suprachiasmatic neurons in rat hypothalamic slice preparation. Neuroscience Letters, 41(1–2), 109–113.Find this resource:

Lu, J., Greco, M. A., Shiromani, P., & Saper, C. B. (2000). Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. Journal of Neuroscience, 20(10), 3830–3842.Find this resource:

Luine, V., Khylchevskaya, R., & McEwen, B. (1975). Effect of gonadal hormones on enzyme activities in brain and pituitary of male and female rats. Brain Research, 86, 283–292.Find this resource:

Luine, V., & McEwen, B. (1977). Effect of oestradiol on turnover of Type A monoamine oxidase in brain. Journal of Neurochemistry, 28, 1221–1227.Find this resource:

Luine, V., Park, D., Joh, T., Reis, D., & McEwen, B. (1980). Immunochemical demonstration of increased choline acetyltransferase concentration in rat preoptic area after estradiol administration. Brain Research, 191, 273–277.Find this resource:

Lupica, C. R. (1995). Delta and mu enkephalins inhibit spontaneous GABA-mediated IPSCs via a cyclic AMP-independent mechanism in the rat hippocampus. Journal of Neuroscience, 15, 737–749.Find this resource:

Maayan, R., Fisch, B., Galdor, M., et al. (2004). Influence of 17 beta-estradiol on the synthesis of reduced neurosteroids in the brain (in vivo) and in glioma cells (in vitro): Possible relevance to mental disorders in women. Brain Research, 1020, 167–172.Find this resource:

Maharjan, S., Serova, L., & Sabban, E. (2005). Transcriptional regulation of tyrosine hydroxylase by estrogen: Opposite effects with estrogen receptors alpha and beta. Journal of Neurochemistry, 93, 1502–1514.Find this resource:

Mani, S., Allen, J. M., Rettori, V., et al. (1994). Nitric oxide mediates sexual behavior in female rats. Proceedings of the National Academy of Sciences of the United States of America, 91, 6468–6472.Find this resource:

Mansour, A., Khachaturian, H., Lewis, M. E., Akil, H., & Watson, S. J. (1987). Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. Journal of Neuroscience, 7, 2445–2464.Find this resource:

Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E., & Gilbert, P. E. (1976). The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. Journal of Pharmacology and Experimental Therapeutics, 197, 517–532.Find this resource:

Martin-Alguacil, N., Pfaff, D. W., Kow, L. M., & Schober, J. M. (2008). Oestrogen receptors and their relation to neural receptive tissue of the labia minora. BJU International, 101(11), 1401–1406.Find this resource:

Martin-Alguacil, N., Pfaff, D. W., Shelley, D. N., & Schober, J. M. (2008). Clitoral sexual arousal: An immunocytochemical and innervation study of the clitoris. BJU International101(11), 1407–1413.Find this resource:

Martin-Alguacil, N., Schober, J. M., Kow, L. M., & Pfaff, D. W. (2008). Oestrogen receptor expression and neuronal nitric oxide synthase in the clitoris and prepucial gland structures of mice. BJU International, 102, 1719–1723.Find this resource:

Martin-Alguacil, N., Schober, J. M., Sengelaub, D. R., Pfaff, D. W., & Shelley, D. N. (2008). Clitoral sexual arousal: Neuronal tracing study from the clitoris through the spinal tracts. Journal of Urology, 180(4), 1241–1248.Find this resource:

Martini, L., Dondi, D., Limonta, P., Maggi, R., & Piva, F. (1989). Modulation by sex steroids of brain opioid receptors: Implications for the control of gonadotropins and prolactin secretion. Journal of Steroid Biochemistry, 33, 673–681.Find this resource:

Matteson, D. R., & Armstrong, C. M. (1986). Properties of two types of calcium channels in clonal pituitary cells. Journal of General Physiology, 87, 161–182.Find this resource:

McDonnell, D., Connor, C. E., Wijayaratne, A., et al. (2002). Definition of the molecular and cellular mechanisms underlying the tissue-selective activities of selective estrogen receptor modulators. Recent Progress in Hormone Research, 57, 295–316.Find this resource:

McEwen, B., Biegon, A., Fischette, C., Luine, V., Parsons, B., & Rainbow, T. (1984). Toward a neurochemical basis of steroid hormone action. Frontiers in Neuroendocrinology, 8, 153–176.Find this resource:

Methippara, M. M., Kumar, S., Alam, M. N., Szymusiak, R., & McGinty, D. (2005). Effects on sleep of microdialysis of adenosine A1 and A2A receptor analogs into the lateral preoptic area of rats. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 289, R1715–R1723.Find this resource:

Micevych, P. E., Rissman, E. F., Gustafsson, J. A., & Sinchak, K. (2003). Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor internalization. Journal of Neuroscience Research, 71, 802–810.Find this resource:

Michelotti, G. A., Price, D. T., & Schwinn, D. A. (2000). Alpha1-adrenergic receptor regulation: Basic science and clinical implications. Pharmacology and Therapeutics, 88, 281–309.Find this resource:

Milligan, G. (1993). Regional distribution and quantitative measurement of the phosphoinositidase C-linked guanine nucleotide binding proteins G11 alpha and Gq alpha in rat brain. Journal of Neurochemistry, 61, 845–851.Find this resource:

Mizoguchi, A., Eguchi, N., Kimura, K., et al. (2001). Dominant localization of prostaglandin receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep. Proceedings of the National Academy of Sciences of the United States of America, 98, 11674–11679.Find this resource:

Mong, J. A., Devidze, N., Frail, D. E., et al. (2003). Estradiol differentially regulates lipocalin-type prostaglandin D synthase transcript levels in the rodent brain: Evidence from high-density oligonucleotide arrays and in situ hybridization. Proceedings of the National Academy of Sciences of the United States of America, 100, 318–323.Find this resource:

Mong, J. A., Devidze, N., Goodwillie, A., & Pfaff, D. W. (2003). Reduction of lipocalin-type prostaglandin D synthase in the preoptic area of female mice mimics estradiol effects on arousal and sex behavior. Proceedings of the National Academy of Sciences of the United States of America, 100, 15206–15211.Find this resource:

Mong, J. A., & Pfaff, D. W. (2004). Hormonal symphony: Steroid orchestration of gene modules of sociosexual behaviors. Molecular Psychiatry, 9, 550–556.Find this resource:

Morairty, S., Rainnie, D., McCarley, R., & Greene, R. (2004). Disinhibition of ventrolateral preoptic area sleep–active neurons by adenosine: A new mechanism for sleep promotion. Neuroscience, 123, 451–457.Find this resource:

Moran, T. D., & Smith, P. A. (2002). Morphine-3beta-D-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa. Journal of Pharmacology and Experimental Therapeutics, 302, 568–576.Find this resource:

Morgan, M. A., & Pfaff, D. W. (2002). Estrogen’s effects on activity, anxiety, and fear in two mouse strains. Behavioural Brain Research, 132, 85–93.Find this resource:

Morgan, M. A., Schulkin, J., & Pfaff, D. W. (2003). Estrogens and non-reproductive behaviors related to activity and fear. Neuroscience and Biobehavioral Reviews, 28(1), 55–63.Find this resource:

Mote, P., Arnett-Mansfield, R. L., Gava, N., et al. (2006). Overlapping and distinct expression of progesterone receptors A and B in mouse uterus and mammary gland during the estrous cycle. Endocrinology, 147, 5503–5512.Find this resource:

Musatov, S., Chen, W., Pfaff, D. W., Kaplitt, M. G., & Ogawa, S. (2006). RNAi-mediated silencing of estrogen receptor (alpha) in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors. Proceedings of the National Academy of Sciences of the United States of America, 103(27), 10456–10460.Find this resource:

Nguyen, Q. H., & Wagner, E. J. (2006). Estrogen differentially modulates the cannabinoid-induced presynaptic inhibition of amino acid neurotransmission in proopiomelanocortin neurons of the arcuate nucleus. Neuroendocrinology, 84, 123–137.Find this resource:

Normandin J. J., & Murphy, A. Z. (2011). Somatic genital reflexes in rats with a nod to humans: Anatomy, physiology, and the role of the social neuropeptides. Hormones and Behavior, 59(5), 656–665.Find this resource:

Normandin, J., Pfaff, D., & and Murphy, A. (2012). In Neuroscience in the 21st century (vol. 4, pp. 2101–2133). Heidelberg: Springer.Find this resource:

North, R. A. (1992). Cellular actions of opiates and cocaine. Annals of the New York Academy of Sciences, 654, 1–6.Find this resource:

North, R. A., & Williams, J. T. (1985). On the potassium conductance increased by opioids in rat locus coeruleus neurons. Journal of Physiology, 364, 265–280.Find this resource:

Novak, C. M., & Nunez, A. A. (1998). Daily rhythms in Fos activity in the rat ventrolateral preoptic area and midline thalamic nuclei. American Journal of Physiology, 275(5 pt 2), R1620–R1626.Find this resource:

Ogawa, S., Chan, J., Gustafsson, J. A., Korach, K.S., & Pfaff, D. W. (2003). Estrogen increases locomotor activity in mice through estrogen receptor alpha: Specificity for the type of activity. Endocrinology, 144(1), 230–239.Find this resource:

Ogawa, S., Eng, V., Taylor, J., Lubahn, D., Korach, K., & Pfaff, D. (1998). Roles of estrogen receptor-alpha gene expression in reproduction-related behaviors in female mice. Endocrinology, 139, 5070–5081.Find this resource:

Ogawa, S., Nomura, M., Choleris, E., & Pfaff, D. W. (2005). The role of estrogen receptors in the regulation of aggressive behaviors. In R. Nelson (Ed.), Biology of aggression (pp. 231–249). New York: Oxford University Press.Find this resource:

Ogawa, S., Taylor, J., Lubahn, D. B., Korach, K. S., & Pfaff, D. W. (1996). Reversal of sex roles in genetic female mice by disruption of estrogen receptor gene. Neuroendocrinology, 64, 467–470.Find this resource:

Ogawa, S., Washburn, T., Taylor, J., Lubahn, D., Korach, K., & Pfaff, D. (1998). Modifications of testosterone-dependent behaviors by estrogen receptor-alpha gene disruption in male mice. Endocrinology, 139, 5058–5069.Find this resource:

O-Uchi, J., Komukai, K., Kusakari, Y., et al. (2005). Alpha1-adrenoceptor stimulation potentiates L-type Ca2+ current through Ca2+/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes. Proceedings of the National Academy of Sciences of the United States of America, 102, 9400–9405.Find this resource:

Pataky, S., Kow, L.-M., Martin-Alguacil, N., & Pfaff, D. W. (2005). Effects of acute estradiol (E) on histamine (HA) and NMDA induced membrane actions in the ventrolateral portion of hypothalamic ventromedial nucleus (vlVMN) neurons. Society for Neuroscience, Abstract 404.3.Find this resource:

Pawlak, J., Brito, V., Küppers, E., & Beyer, C. (2005). Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen. Molecular Brain Research, 138, 1–7.Find this resource:

Perez, D. M., De Young, M. B., & Graham, R. M. (1993). Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptors to multiple signaling pathways is both G protein and cell type specific. Molecular Pharmacology, 44, 784–795.Find this resource:

Petitti, N., & Etgen, A. M. (1991). Protein kinase C and phospholipase C mediate alpha1- and beta-adrenoceptor intercommunication in rat hypothalamic slices. Journal of Neurochemistry, 56, 628–635.Find this resource:

Pfaff, D. W. (1968). Autoradiographic localization of radioactivity in rat brain after injection of tritiated sex hormones. Science, 161, 1355–1356.Find this resource:

Pfaff, D. W. (1980). Estrogens and brain function: Neural analysis of a hormone-controlled mammalian reproductive behavior. New York: Springer.Find this resource:

Pfaff, D. W. (1982). The physiological mechanisms of motivation. New York: Springer.Find this resource:

Pfaff, D. W. (1999). Drive. Cambridge, MA: MIT Press.Find this resource:

Pfaff, D. W. (2005). Brain arousal and information theory: Neural, hormonal and genetic analyses. Cambridge, MA: Harvard University Press.Find this resource:

Pfaff, D. W. (2006). Brain arousal and information theory: Neural and genetic mechanisms. Cambridge, MA: Harvard University Press.Find this resource:

Pfaff, D., & Keiner, M. (1973). Atlas of estradiol-concentrating cells in the central nervous system of the female rat. Journal of Comparative Neurology, 151(2), 121–158.Find this resource:

Pfaff, D. W., & Sakuma, Y. (1979). Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. Journal of Physiology, 288, 203–210.Find this resource:

Pfaff, D. W., & Schwartz-Giblin, S. (1988). Cellular mechanisms of female reproductive behaviors. In E. Knobil & J. Neill (Eds.), The physiology of reproduction (pp. 1487–1568). New York: Raven Press.Find this resource:

Pfaff, D. W., Schwartz-Giblin, S., McCarthy, M. M., & Kow, L.-M. (1994). Cellular and molecular mechanisms of female reproductive behaviors. In E. Knobil & J. Neill (Eds.), The physiology of reproduction (2d ed.) (pp. 107–220). New York: Raven.Find this resource:

Pfaus, J., & Gorzalka, B. (1987). Opioid and sexual behavior. Neuroscience and Biobehavioral Reviews, 11, 1–34.Find this resource:

Pfaus, J., & Gorzalka, B. B. (1987). Selective activation of opioid receptors differentially affects lordosis behavior in female rats. Peptides, 8, 309–317.Find this resource:

Pfaus, J. G., Pendleton, N., & Gorzalka, B. B. (1986). Dual effect of morphiceptin on lordosis behavior: Possible mediation by different opioid receptor subtypes. Pharmacology, Biochemistry, and Behavior, 24, 1461–1464.Find this resource:

Pfaus, J. G., & Pfaff, D. W. (1992). Mu-, delta-, and kappa-opioid receptor agonists selectively modulate sexual behaviors in the female rat: Differential dependence on progesterone. Hormones and Behavior, 26, 457–473.Find this resource:

Piascik, M. T., & Perez, D. M. (2001). Alpha1-adrenergic receptors: New insights and directions. Journal of Pharmacology and Experimental Therapeutics, 298, 403–410.Find this resource:

Pinzar, E., Kanaoka, Y., Inui, T., Eguchi, N., Urade, Y., & Hayaishi, O. (2000). Prostaglandin D synthase gene is involved in the regulation of non-rapid eye movement sleep. Proceedings of the National Academy of Sciences of the United States of America, 97, 4903–4907.Find this resource:

Piva, F., Limonta, P., Dondi, D., Pimpinelli, F., Martini, L., & Maggi, R. (1995). Effects of steroids on the brain opioid system. Journal of Steroid Biochemistry and Molecular Biology, 53, 343–348.Find this resource:

Priest, C., Borsook, D., & Pfaff, D. (1997). Estrogen and stress interact to regulate the hypothalamic expression of a human proenkephalin promoter-beta-galactosidase fusion gene in a site-specific and sex-specific manner. Journal of Neuroendocrinology, 9, 317–326.Find this resource:

Priest, C., Eckersell, C., & Micevych, P. (1995). Estrogen regulates preproenkephalin_A mRNA levels in the rat ventromedial nucleus. Molecular Brain Research, 28, 251–262.Find this resource:

Pupo, A. S., & Minneman, K. P. (2002). Interaction of neuronal nitric oxide synthase with alpha1-adrenergic receptor subtypes in transfected HEK-293 cells. BMC Pharmacology, 2, 17.Find this resource:

Qiu, J., Bosch, M. A., Jamali, K., et al. (2006). Estrogen upregulates T-type calcium channels in the hypothalamus and pituitary. Journal of Neuroscience, 26, 11072–11082.Find this resource:

Quinones-Jenab, V., Jenab, S., Ogawa, S., Inturrisi, C., & Pfaff, D. W. (1997). Estrogen regulation of mu-opioid receptor mRNA in the forebrain of female rats. Brain Research—Molecular Brain Research, 47, 134–138.Find this resource:

Rachman, I. M., Pfaff, D. W., & Cohen, R. S. (1997). NADPH diaphorase activity and nitric oxide synthase immunoreactivity in lordosis-relevant neurons of the ventromedial hypothalamus. Brain Research, 740, 291–306.Find this resource:

Ram, A., Pandey, H. P., Matsumura, H., et al. (1997). CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats. Brain Research, 751, 81–89.Find this resource:

Rhim, H., & Miller, R. J. (1994). Opioid receptors modulate diverse types of calcium channels in the nucleus tractus solitarius of the rat. Journal of Neuroscience, 14, 7608–7615.Find this resource:

Rissman, E. F., Heck, A. L., Leonard, J. E., Shupnik, M. A., & Gustafsson, J. A. (2002). Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Proceedings of the National Academy of Sciences of the United States of America, 99, 3996–4001.Find this resource:

Romano, G., Harlan, R., Shivers, B., Howells, R., & Pfaff, D. (1988). Estrogen increases proenkephalin mRNA in the ventromedial hypothalamus of the rat. Molecular Endocrinology, 2, 1320–1328.Find this resource:

Romano, G., Mobbs, C., Lauber, A., Howells, R., & Pfaff, D. (1990). Differential regulation of proenkephalin gene expression by estrogen in the ventromedial hypothalamus of male and female rats. Brain Research, 56(3), 63–68.Find this resource:

Romano, G. J., Krust, A., & Pfaff, D. W. (1989). Expression and estrogen regulation of progesterone receptor mRNA in neurons of the mediobasal hypothalamus: An in situ hybridization study. Molecular Endocrinology, 3, 1295–1300.Find this resource:

Rønnekleiv, O., & Kelly, M. (2005). Diversity of ovarian steroid signaling in the hypothalamus. Frontiers in Neuroendology, 26, 65–84.Find this resource:

Ruan, Y., Kan, H., Jean-Hugues, P., et al. (1998). Alpha-1A adrenergic receptor stimulation with phenylephrine promotes arachidonic acid release by activation of phospholipase D in Rat-1 fibroblasts: Inhibition by protein kinase. Journal of Pharmacology and Experimental Therapeutics, 284, 576–585.Find this resource:

Sah, P., French, C. R., & Gage, P. W. (1985). Effects of noradrenaline on some potassium currents in CA1 neurones in rat hippocampal slices. Neuroscience Letters, 60, 295–300.Find this resource:

Satoh, S., Matsumura, H., Suzuki, F., & Hayaishi, O. P. (1996). Promotion of sleep mediated by the A2A-adenosine receptor and possible involvment of this receptor in the sleep induced by prostaglandin D2 in rats. Proceedings of the National Academy of Sciences of the United States of America, 93, 5980–5984.Find this resource:

Scammell, T., Geraschenko, D., Urade, Y., Onoe, H., Saper, C., & Hayaishi, O. (1998). Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2. Proceedings of the National Academy of Sciences of the United States of America, 95, 7754–7759.Find this resource:

Scammell, T. E., Gerashchenko, D. Y., Mochizuki, T., et al. (2001). An adenosine A2A agonist increases sleep and induces fos in ventrolateral preoptic neurons. Neuroscience, 107, 653–663.Find this resource:

Schober, J., & Pfaff, D. (2007). The neurophysiology of sexual arousal. Best Practice and Research Clinical Endocrinology and Metabolism, 21, 445–461.Find this resource:

Schwierin, B., Borbely, A. A., & Tobler, I. (1998). Sleep homeostasis in the female rat during the estrous cycle. Brain Research, 811, 96–104.Find this resource:

Scott, R., Wu-Peng, X., Kaplitt, F., & Pfaff, D. (2003). Gene transfer and in vivo promoter analysis of the rat progesterone receptor using a herpes simplex viral vector. Molecular Brain Research, 114, 91–100.Find this resource:

Scott, R., Wu-Peng, X., & Pfaff, D. (2002). Regulation and expression of progesterone receptor mRNA isoforms A and B in the male and female rat hypothalamus and pituitary following oestrogen treatment. Journal of Neuroendocrinology, 14, 175–183.Find this resource:

Scott, R., Wu-Peng, X., Yen, P., Chin, W., & Pfaff, D. (1997). Interactions of estrogen- and thyroid hormone receptors on a progesterone receptor estrogen response element (ERE). sequence: A comparison with the vitellogenin A2 consensus ERE. Molecular Endocrinology, 11, 1581–1592.Find this resource:

Serova, L., Rivkin, M., Nakashima, A., & Sabban, E. (2002). Estradiol stimulates gene expression of norepinephrine biosynthetic enzymes in rat locus coeruleus. Neuroendocrinology, 75, 193–200.Find this resource:

Shen, K. Z., & Johnson, S. W. (2002). Presynaptic modulation of synaptic transmission by opioid receptor in rat subthalamic nucleus in vitro. Journal of Physiology, 541, 219–230.Find this resource:

Shughrue, P., Lane, M., & Merchenthaler, I. (1997). Comparative distribution of estrogen receptor alpha and beta in the rat central nervous system. Journal of Comparative Neurology, 388, 507–525.Find this resource:

Simon, M. I., Strathmann, M. P., & Gautam, N. (1991). Diversity of G proteins in signal transduction. Science, 252, 802–808.Find this resource:

Sinchak, K., & Micevych, P. E. (2001). Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior. Journal of Neuroscience, 21, 5723–5729.Find this resource:

Sirinathsinghji, D. J. (1986). Regulation of lordosis behaviour in the female rat by corticotropin-releasing factor, beta-endorphin/corticotropin and luteinizing hormone-releasing hormone neuronal systems in the medial preoptic area. Brain Research, 375, 49–56.Find this resource:

Smith, J., Theodoris, C., & Davidson, E. (2007). A gene regulatory network subcircuit drives a dynamic pattern of gene expression. Science, 318, 794–797.Find this resource:

Song, W. J. (2002). Genes responsible for native depolarization-activated K+ currents in neurons. Neuroscience Research, 42, 7–14.Find this resource:

Szymusiak, R., Alam, N., Steininger, T. L., & McGinty, D. (1998). Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Research, 803(1–2), 178–188.Find this resource:

Taylor, S. J., & Exton, J. H. (1991). Two alpha subunits of the Gq class of G proteins stimulate phosphoinositide phospholipase C-beta 1 activity. FEBS Letters, 286, 214–216.Find this resource:

Terman, G. W., Eastman, C. L., & Chavkin, C. (2001). Mu opiates inhibit long-term potentiation induction in the spinal cord slice. Journal of Neurophysiology, 85, 485–494.Find this resource:

Thakkar, M. M., Delgiacco, R. A., Strecker, R. E., & McCarley, R. W. (2003). Adenosinergic inhibition of basal forebrain wakefulness-active neurons: A simultaneous unit recording and microdialysis study in freely behaving cats. Neuroscience, 122, 1107–1113.Find this resource:

Urade, Y., Kitahama, K., Ohishi, H., Kaneko, T., Mizuno, N., & Hayaishi, O. (1993). Dominant expression of mRNA for prostaglandin D synthase in the leptomeninges, choroid plexus, and oligodendrocytes of the adult brain. Proceedings of the National Academy of Sciences of the United States of America, 90, 9070–9074.Find this resource:

Vasudevan, N., & Pfaff, D. W. (2007). Membrane-initiated actions of estrogens in neuroendocrinology: Emerging principles. Endocrine Reviews, 28, 1–19.Find this resource:

Vathy, I., van der Plas, J., Vincent, P. A., & Etgen, A. M. (1991). Intracranial dialysis and microinfusion studies suggest that morphine may act in the ventromedial hypothalamus to inhibit female rat sexual behavior. Hormones and Behavior, 25, 354–366.Find this resource:

Vaughan, C. W., & Christie, M. J. (1997). Presynaptic inhibitory action of opioids on synaptic transmission in the rat periaqueductal grey in vitro. Journal of Physiology, 498(pt 2), 463–472.Find this resource:

Wagner, E. J., Rønnekleiv, O. K., & Kelley, M. (2001). The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: Pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis. Journal of Pharmacology and Experimental Therapeutics, 299, 21–30.Find this resource:

Wang, D., Sumners, C., Posner, P., & Gelband, C. H. (1997). A-type K+ current in neurons cultured from neonatal rat hypothalamus and brain stem: Modulation by angiotensin II. Journal of Neurophysiology, 78, 1021–1029.Find this resource:

Wang, X., Zeng, W., Soyombo, A. A., et al. (2005). Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nature Cell Biology, 7, 405–411.Find this resource:

Wang, X. L., Wettwer, E., Gross, G., & Ravens, U. (1991). Reduction of cardiac outward currents by alpha-1 adrenoceptor stimulation: A subtype-specific effect? Journal of Pharmacology and Experimental Therapeutics, 259, 783–788.Find this resource:

Weiland, N. G., & Wise, P. M. (1990). Estrogen and progesterone regulate opiate receptor densities in multiple brain regions. Endocrinology, 126, 804–808.Find this resource:

White, J. M., & Rumbold, G. R. (1988). Behavioural effects of histamine and its antagonists: A review. Psychopharmacology, 95, 1–14.Find this resource:

Wiesner, J. B., & Moss, R. L. (1984). Beta-endorphin suppression of lordosis behavior in female rats; lack of effect of peripherally-administered naloxone. Life Sciences, 34, 1455–1462.Find this resource:

Wiesner, J. B., & Moss, R. L. S. (1986). uppression of receptive and proceptive behavior in ovariectomized, estrogen-progesterone-primed rats by intraventricular beta-endorphin: Studies of behavioral specificity. Neuroendocrinology, 43, 57–62.Find this resource:

Williams, J. T., Christie, M. J., & Manzoni, O. (2001). Cellular and synaptic adaptations mediating opioid dependence. Physiological Reviews, 81, 299–343.Find this resource:

Xu, Z., Hirasawa, A., Shinoura, H., & Tsujimoto, G. (1999). Interaction of the alpha(1B)-adrenergic receptor with gC1q-R, a multifunctional protein. Journal of Biological Chemistry, 274, 21149–21154.Find this resource:

Yang, Q. Z., & Hatton, G. I. (1994). Histamine mediates fast synaptic inhibition of rat supraoptic oxytocin neurons via chloride conductance activation. Neuroscience, 6(4), 955–964.Find this resource:

Yoshinaga, T., Zhang, S., Niidome, T., Hiraoka, M., & Hirano, Y. (1999). Potentiation of recombinant L-type calcium channel currents by alpha1-adrenoceptors coexpressed in baby hamster kidney (BHK) cells. Life Sciences, 64, 1643–1651.Find this resource:

Zhang, S.-Q., Kimura, M., & Inoue, S. (1995). Sleep patterns in cyclic and pseudopregnant rats. Neuroscience Letters, 193, 125–128.Find this resource:

Zhang, T., Xu, Q., Chen, F. R., et al. (2004). Yeast two-hybrid screening for proteins that interact with alpha1-adrenergic receptors. Acta Pharmacologica Sinica, 25, 1471–1478.Find this resource:

Zhong, H., & Minneman, K. P. (1999). Differential activation of mitogen-activated protein kinase pathways in PC12 cells by closely related alpha1-adrenergic receptor subtypes. Journal of Neurochemistry, 72, 2388–2396.Find this resource:

Zhou, J., Devidze, N., Zhang, Q., & Pfaff, D. W. E. (2006). Estrogenic regulation on gene expression of histamine receptors and histidine decarboxylase in ventromedial nucleus of hypothalamus. Society for Neuroscience, Abstract 659.9.Find this resource:

Zhou, J., Devidze, N., Zhang, Q., & Pfaff, D. W. (2007a). Estrogenic regulation of behavioral arousal and its interaction with histamine 1 receptor antagonist. Society for Neuroscience, Abstract 84.2.Find this resource:

Zhou, J., Lee, A. W., Devidze, N., Zhang, Q., Kow, L.-M., & Pfaff, D. W. (2007b). Histamine-induced excitatory responses in mouse ventromedial hypothalamic neurons: Ionic mechanisms and estrogenic regulation. Journal of Neurophysiology, 98(6), 3143–3152.Find this resource:

Zhou, J., Pfaff, D. W., & Chen, G. (2005). Sex differences in estrogenic regulation of neuronal activity in neonatal cultures of ventromedial nucleus of the hypothalamus. Proceedings of the National Academy of Sciences of the United States of America, 102, 14907–14912.Find this resource: