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ABSTRACT: Methadone is widely used in treatment of short-acting opiate addiction. The on-off effects of opioids have been documented to have profound differences from steady-state opioids. The authors hypothesize that opioids play important roles in either generalized arousal (GA) or aversive state of arousal during opioid withdrawal. Both male and female C57BL6 mice received steady-state methadone (SSM) through osmotic pumps at 10 or 20 mg/kg/day, and GA was measured in voluntary motor activity, sensory responsivity, and contextual fear conditioning. SSM did not have any effect on those GA behaviors in either sex. Females had higher activity and less fear conditioning than males. The effects of SSM on stress-responsive orexin gene expression in the lateral hypothalamus (LH) and medial hypothalamus (MH, including perifornical and dorsomedial areas) were measured after the behavioral tests. Females showed significantly lower basal LH (but not MH) orexin mRNA levels than males. A panel of GA stressors increased LH orexin mRNA levels in females only; these increases were blunted by SSM at 20 mg/kg. In summary, SSM had no effect on GA behaviors. In females, SSM blunted the GA stress-induced LH orexin gene expression.
Behavioral Neuroscience 01/2009; 122(6):1248-56. · 2.62 Impact Factor
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ABSTRACT: The first demonstration of how biochemical changes in neurons in specific parts of the brain direct a complete mammalian behavior derived from the effects of estrogens in hypothalamic neurons that facilitate lordosis behavior, the primary reproductive behavior of female quadrupeds (Pfaff. Estrogens and Brain Function. 1980; Pfaff. Drive: Neurobiological and Molecular Mechanisms of Sexual Motivation. 1999). Sex behaviors depend on sexual arousal that in turn depends on a primitive function: generalized CNS arousal (Pfaff. Brain Arousal and Information Theory. 2006). Here we summarize one of the ways in which a generalized arousal transmitter, norepinephrine, can influence the electrical excitability of ventromedial hypothalamic cells in a way that will foster female sex behavior.
The Journal of Physiological Sciences 06/2008; 58(4):213-20. · 1.61 Impact Factor
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ABSTRACT: Estrogens act upon ventromedial hypothalamic (VMH) neurons, and their effects on female arousal and sexual behaviors mediated by VMH neurons involve several neurotransmitters and neuromodulators. Among these are opioid peptides which might be predicted to oppose estrogenic action on VMH because they tend to decrease CNS arousal. Spontaneous excitatory postsynaptic currents were recorded from VMH neurons from 17beta-estradiol- (E, 10 mug/0.1 ml) or oil-treated control ovariectomized (OVX) mice using whole-cell patch-clamp techniques. To examine the impact of opioidergic inputs, recordings of neurons from both treatment groups were obtained in the presence of the general opioid receptor agonist methionine enkephalin-Arg-Phe (MERF, 3 muM), or mu-receptor specific agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO, 1 muM). Compared with oil, E treatment for 48 h significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without affecting their amplitude. MERF and DAMGO each abolished this E effect, causing significant reductions in sEPSCs. The effect of MERF was abolished by naltrexone (general opioid receptor antagonist, 3 muM) and the effect of DAMGO by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (mu-opioid receptor selective antagonist, 1 muM); in contrast, kappa- and delta-opioid receptor agonists, U69593 (300 nM) and [d-Pen(2),d-Pen(5)]-enkephalin (DPDPE, 1 muM) respectively, had little effect on the sEPSCs compared with DAMGO. To consider presynaptic vs. postsynaptic effects of opioids, miniature excitatory postsynaptic currents (mEPSCs) were investigated in E- and oil-treated VMH neurons and opioid receptor antagonist effects on mEPSCs were observed. Both MERF and DAMGO reduced the frequency of mEPSCs, but had no effect on their amplitude. Our findings indicate that opioids suppress excitatory synaptic transmissions in VMH neurons primarily through mu-receptors and could thereby decrease sexual arousal in mice.
Neuroscience 05/2008; 152(4):942-9. · 3.38 Impact Factor
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ABSTRACT: Reverse engineering takes the facts we know about a device or a process and reasons backwards to infer the principles underlying the structure-function relations. The goal of this review is to apply this approach to a well-studied hormone-controlled behavior, namely the reproductive stance of female rodents, lordosis. We first provide a brief overview on the considerable amount of progress in the analysis of female reproductive behavior. Then, we propose an analysis of the mechanisms of this behavior from a reverse-engineering perspective with the goal of generating novel hypotheses about the properties of the circuitry elements. In particular, the previously proposed neuronal circuit modules, feedback signals, and genomic mechanisms are considered to make predictions in this manner. The lordosis behavior itself appears to proceed ballistically once initiated, but negative and positive hormonal feedback relations are evident in its endocrine controls. Both rapid membrane-initiated and slow genomic hormone effects contribute to the behavior's control. We propose that the value of the reverse-engineering approach is based on its ability to provide testable, mechanistic hypotheses that do not emerge from either traditional evolutionary or simple reductionistic perspectives, and several are proposed in this review. These novel hypotheses may generalize to brain functions beyond female reproductive behavior. In this way, the reverse-engineering perspective can further develop our conceptual frameworks for behavioral and systems neuroscience.
Hormones and Behavior 05/2008; 54(3):347-54. · 3.87 Impact Factor
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ABSTRACT: Social and sexual incentive motivation, defined as the intensity of approach to a social and a sexual incentive, respectively, were studied in female Swiss Webster mice. In the first experiment, the social incentive was a castrated mouse of the same strain as the females, whereas the sexual incentive was an intact male mouse of the same strain. Ovariectomized females were first tested after oil treatment and then after administration of estradiol benzoate + progesterone in doses sufficient to induce full receptivity. The hormones increased sexual incentive motivation while leaving social incentive motivation unaffected. This suggests that sexual incentive motivation in the female mouse is dependent on ovarian hormones. In the next experiment, ovariectomized females were tested with an intact, male estrogen receptor alpha knockout and its wild type as incentives, first without hormones and then when fully receptive. There were no differences in incentive properties between the wild type and the knockout. In a similar experiment, we used an intact male estrogen receptor beta knockout and its corresponding wild type as incentives. The wild type turned out to be a more attractive social incentive than the knockout, while they were equivalent as sexual incentives. Finally, an intact male oxytocin knockout and its wild type were used as incentives. The knockout turned out to be a superior incentive, particularly a superior sexual incentive. The fact that the estrogen receptor beta and oxytocin knockouts have incentive properties different from their wild types may be important to consider in studies of these knockouts' sociosexual behaviors.
Genes Brain and Behavior 03/2008; 7(1):70-7. · 3.48 Impact Factor
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ABSTRACT: Oestradiol actions in the hypothalamus play an important role in reproductive behaviour. Oestradiol treatment in vivo induces alpha(1b)-adrenoceptor mRNA and increases the density of alpha(1B)-adrenoceptor binding in the hypothalamus. Oestradiol is also known to modulate neuronal excitability, in some cases by modulating calcium channels. We assessed the effects of phenylephrine, an alpha(1)-adrenergic agonist, on low-voltage-activated (LVA) and high-voltage-activated (HVA) calcium channels in ventromedial hypothalamic (VMN) neurones from vehicle- and oestradiol-treated female rats. Whole-cell and gramicidin perforated-patch recordings were obtained, with barium as the charge carrier. In the absence of phenylephrine, oestradiol treatment increased the magnitude of LVA currents compared to controls, but had no effect on HVA currents. Phenylephrine enhanced HVA currents in a significantly greater proportion of neurones from oestradiol-treated rats (76%) than from vehicle-treated (41%) rats. The L-channel blocker nifedipine abolished this oestradiol effect on phenylephrine-enhanced HVA currents. Preincubating slices with the N-type channel blocker omega-conotoxin GVIA completely blocked the phenylephrine response, suggesting that the N-type channel is essential. Phenylephrine also stimulated LVA currents in approximately two-thirds of neurones in slices from both vehicle- and oestradiol-treated rats. Our data show that oestradiol increases LVA currents in the VMN. Oestradiol also amplifies alpha(1)-adrenergic signalling by increasing the proportion of neurones showing phenylephrine-stimulated HVA currents mediated by N- and L-type calcium channels. In this way, oestradiol may increase excitatory responses to arousing adrenergic inputs to VMN neurones governing oestradiol-dependent reproductive behaviour.
Journal of Neuroendocrinology 03/2008; 20(2):188-98. · 3.14 Impact Factor
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ABSTRACT: To assess how early can estrogens induce female mating behaviors, rat pups 8-29 days old (D8-D29, respectively) were injected twice daily with estradiol benzoate (E) or oil (O) followed by progesterone (P) or oil, and then observed for the estrogen-dependent ear wiggling (EW) and lordosis in response to natural stimulation from male rats. In female pups treated with E + E + P, the incidence of EW appeared as early as D13 and increased gradually to reach maximum at D18, when all pups tested showed EW. EW also occurred in E + E + O females, but never in O + O + P females or in any E + E + P male. Lordosis in E + E + P, as well as E + E + O, female pups occurred later, starting at D15. O + O + P females or E + E + P males never display lordosis. To explore the possibilities that the age and gender differences are due to distribution and/or function of estrogen receptor-alpha (ERalpha) or progesterone receptor (PR), separate pups were used for immunocytochemical (ICC) staining of these receptors in the hypothalamic ventromedial nucleus (VMN). There was no age difference in female pups in the density of ERalpha or the induction of PR between D11/D12, when no sexual behavior was observed, and D19/D20, when almost all pups tested performed the behaviors. There were gender differences: male pups had less ERalpha than females at D19/D20, though not at D11/D12, and did not respond to E in the induction of PR in the VMN. These results show that ERs and their signaling systems in the VMN of rat pups are functional at least after D11 but only in females, and that the gender differences appeared to be due to differences in the molecular biology of ERalpha.
Endocrine 01/2008; 32(3):287-96. · 1.42 Impact Factor
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ABSTRACT: Social recognition, processing, and retaining information about conspecific individuals is crucial for the development of normal social relationships. The neuropeptide oxytocin (OT) is necessary for social recognition in male and female mice, with its effects being modulated by estrogens in females. In previous studies, mice whose genes for the estrogen receptor-alpha (alpha-ERKO) and estrogen receptor-beta (beta-ERKO) as well as OTKO were knocked out failed to habituate to a repeatedly presented conspecific and to dishabituate when the familiar mouse is replaced by a novel animal (Choleris et al. 2003, Proc Natl Acad Sci USA 100, 6192-6197). However, a binary social discrimination assay, where animals are given a simultaneous choice between a familiar and a previously unknown individual, offers a more direct test of social recognition. Here, we used alpha-ERKO, beta-ERKO, and OTKO female mice in the binary social discrimination paradigm. Differently from their wild-type controls, when given a choice, the KO mice showed either reduced (beta-ERKO) or completely impaired (OTKO and alpha-ERKO) social discrimination. Detailed behavioral analyses indicate that all of the KO mice have reduced anxiety-related stretched approaches to the social stimulus with no overall impairment in horizontal and vertical activity, non-social investigation, and various other behaviors such as, self-grooming, digging, and inactivity. Therefore, the OT, ER-alpha, and ER-beta genes are necessary, to different degrees, for social discrimination and, thus, for the modulation of social behavior (e.g. aggression, affiliation).
Genes Brain and Behavior 11/2006; 5(7):528-39. · 3.48 Impact Factor
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ABSTRACT: Acute estradiol (E2) can potentiate the excitatory responses of hypothalamic ventromedial nucleus (VMN) neurons to neurotransmitters. To investigate the mechanism(s) underlying the potentiation, the whole-cell patch voltage clamp technique was used to study VMN neurons in hypothalamic slices prepared from female juvenile (3–5 weeks) rats. A voltage step and/or ramp was applied every 5 min to evoke whole-cell currents before, during and after a treatment with E2 (10 nM), corticosterone (10 nM) or vehicle for up to 20 min. Acute E2 increased inward currents in 38% of neurons tested. Their average peak inward current amplitudes started to increase within 5 min and reached the maximum of 163% of pretreatment level (Pre) at 20 min of treatment before recovering toward Pre. These increases are significantly greater than the Pre and corresponding vehicle controls and non-responsive neurons. Outward currents were decreased significantly by E2 in 27% of E2-treated cells, down to 60% of Pre levels. E2 also appeared to affect the kinetics of the inward and outward currents of estrogen-responsive neurons. Whenever observed, the effects of acute E2 were reversible after a 5- to 10-min washing. Probability analysis indicates that E2 affected the inward and the outward currents independently. The E2 effects are specific in that they were not produced by similar treatment with vehicle or corticosterone. Pharmacological characterizations using ion replacement and channel blockers showed that the inward currents were mediated practically all by Na+ and the outward currents mainly by K+. Thus, acute E2 can enhance inward Na+ and attenuate outward K+ currents. Since both effects will lead to an increase in neuronal excitability, they may explain our previous observation that E2 potentiates the excitation of VMN neurons.
Brain Research 11/2006; · 2.73 Impact Factor
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ABSTRACT: Rapidly emerging evidence suggests that glial cells in the central nervous system are sensitive to oestrogen actions. However, the functional consequences of the cellular mechanisms of these cells have proven difficult to study in vivo because of the intimate relationships between neurones and glia. Microarray technology offers the potential to uncover steroid hormone regulation of glial-specific genes that may play a role in hormone-dependent neuronal-glial interactions. Analysis of transcriptomes from the medial basal hypothalamus (MBH) of oestradiol and vehicle-treated adult ovariectomised mice revealed an up-regulation of several glial specific genes by oestradiol, including glutamine synthetase (GS), which facilitates the conversion of glutamate to glutamine and plays an integral role in amino acid neurotransmission. In situ hybridisation confirmed that oestradiol treatment resulted in an up-regulation of GS gene expression in the arcuate and ventromedial nuclei of the MBH, as well as the medial amygdala and hippocampus. Moreover, oestradiol increased protein expression of GS in both the MBH and hippocampus. Neurones are incapable of de novo net synthesis of glutamate from glucose and are dependent on glial-provided precursors such as glutamine to renew their amino acid transmitter pools. Thus, oestradiol induced expression of GS suggests a significant role for glial cells in hormonal modulation of glutamatergic neurotransmission important to female reproductive behaviours, neuroendocrine physiology and cognitive functions.
Journal of Neuroendocrinology 10/2006; 18(9):692-702. · 3.14 Impact Factor
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ABSTRACT: Estrogens modulate almost all aspects of female behavioral arousal; however, apart from that of sexual behavior, the neurobiology of female arousal remains unclear. Because orexins-hypocretins are neurotransmitters known to be important for behavioral arousal, the authors hypothesized that orexins may be a target for estrogen. Gonadectomized female mice received an intracerebral injection of either phosphate-buffered saline, the neurotoxin saporin (SAP), or the orexin-2-saporin conjugate (OXSAP) in the lateral hypothalamus. SAP- and OXSAP-treated mice were also divided into groups receiving either estradiol capsules or oil capsules. Mice were tested in 3 behavioral tests measuring different modes of arousal: sensory responsiveness, running wheel activity, and fearfulness. OXSAP mice showed decreases in sensory responsiveness and fearfulness concomitant with a reduction in orexin cell number. Estradiol affected all behaviors tested but decreased fearfulness only when combined with OXSAP treatment. These data indicate that estrogens modulate orexins' effects on fearfulness.
Behavioral Neuroscience 03/2006; 120(1):1-9. · 2.62 Impact Factor
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ABSTRACT: Previous research has indicated the importance of sex in mediating the larger magnitude of mu-opioid receptor agonist-induced analgesia in male relative to female rodents. Whereas manipulations involving the adult activational effects of gonadal hormones minimally alter these analgesic sex differences, manipulations involving neonatal organizational effects of gonadal hormones have previously been shown to profoundly affect morphine analgesia. Thus, adult male rats neonatally castrated on the first day after birth displayed reductions in morphine analgesia relative to sham-operated males, and adult female rats neonatally treated with testosterone propionate on the first day after birth displayed enhancements in morphine analgesia relative to vehicle-treated females. Because neonatal androgenization in female rats produces an anovulatory syndrome that could change their adult hormonal milieu, the present study examined whether adult ovariectomy altered the magnitude of systemic morphine analgesia (1-5 mg/kg) in neonatal androgenized female rats relative to neonatal vehicle-treated female rats as well as gonadal steroid hormone replacement with estradiol benzoate. Intact male rats displayed significantly greater magnitudes and potencies (2- to 2.3-fold leftward shift) of systemic morphine analgesia than female rats treated neonatally with either vehicle (1-5 mg/kg) or testosterone (1.7-5 mg/kg). In turn, neonatal androgenized female rats displayed significantly greater magnitudes of systemic morphine (1, 5 mg/kg) analgesia than vehicle-treated female rats accompanied by a smaller 20% leftward shift in potency. Adult ovariectomy minimally affected morphine analgesia in neonatal vehicle-treated females, while significantly reducing the magnitude (1 mg/kg), but not the potency of morphine analgesia in neonatal androgenized female rats. Estradiol replacement therapy significantly increased the magnitude of morphine analgesia in both groups at some doses, but only changed the potency (20-30%) in females treated neonatally with vehicle. Taken together, these data suggest a limited organizational-activational gonadal hormone interaction in the mediation of systemic morphine analgesia in female rats.
Brain Research 11/2005; 1059(1):13-9. · 2.73 Impact Factor
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ABSTRACT: Regulated gene expression in single neurons can be linked to biophysical events and behavior in the case of estrogen-regulated gene expression in neurons in the ventrolateral portion of the ventromedial nucleus (VMN) of the hypothalamus. These cells are essential for lordosis behavior. What genes are coexpressed in neurons that have high levels of mRNAs for estrogen receptors (ERs)? We have been able to isolate and measure certain mRNAs from individual VMN neurons collected from rat hypothalamus. Large numbers of neurons express mRNA for ERalpha, but these neurons are not identical with the population of VMN neurons expressing the likely gene duplication product, ERbeta. An extremely high proportion of neurons expressing either ER also coexpress mRNA for the oxytocin receptor (OTR). This fact matches the known participation of oxytocin binding and signaling in sexual and affiliative behaviors. In view of data that ER and OTR can signal through PKCs, we looked at coexpression of selected PKCs in the same individual neurons. The most discriminating analysis was for triple coexpression of ERs, OTR, and each selected PKC isoform. These patterns of triple coexpression were significantly different for male vs. female VMN neurons. Further, individual neurons expressing ERalpha could distribute their signaling across the various PKC isoforms differently in different cells, whereas the reverse was not true. These findings and this methodology establish the basis for systematic linkage of the brain's hormone-sensitive signaling pathways to biophysical and behavioral mechanisms in a well studied mammalian system.
Proceedings of the National Academy of Sciences 11/2005; 102(40):14446-51. · 9.68 Impact Factor
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ABSTRACT: Compared to results from a generation of neuropharmacological work, the phenotype of mice lacking the oxytocin (OT) peptide gene was remarkably normal. An important component of the current experiments was to assay OT-knockout (OTKO) and wild-type (WT) littermate control mice living under controlled stressful conditions designed to mimic more closely the environment for which the mouse genome evolved. Furthermore, our experimental group was comprised of an all-female population, in contrast to previous studies which have focused on all-male populations. Our data indicated that aggressive behaviors initiated by OTKO during a food deprivation feeding challenge were considerably more intense and diverse than aggressive behaviors initiated by WT. From the measures of continuous social interaction in the intruder paradigm, it emerged that OTKO mice were more offensively aggressive (attacking rumps and tails) than WT. In a test of parental behaviors, OTKO mice were 100% infanticidal while WT were 16% infanticidal and 50% maternal. Finally, 'alpha females' (always OTKO) were identified in each experiment. They were the most aggressive, the first to feed and the most dominant at nesting behaviors. Semi-natural environments are excellent testing environments for elucidating behavioral differences between transgenic mice and their WT littermates which may not be ordinarily discernible. Future studies of mouse group behavior should include examining female groupings in addition to the more usual all-male groups.
Genes Brain and Behavior 07/2005; 4(4):229-39. · 3.48 Impact Factor
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ABSTRACT: In a previous behavioral study, brief application of a membrane-limited estrogen to neurons in rat hypothalamic ventromedial nucleus (VMN) facilitated lordosis behavior-inducing genomic actions of estrogen. Here, electrophysiological recordings from single neurons were employed to characterize these membrane-initiated actions. From rat hypothalamic slices, electrical activity was recorded from neurons in the ventrolateral VMN, the cell group crucial for estrogen induction of lordosis. In addition to the resting activity, neuronal responses to histamine (HA) and N-methyl-d-aspartate (NMDA) were also recorded before, during, and after a brief (10-15 min) application of estradiol (E, 10 nM). These two transmitters were chosen because their actions are mediated by different mechanisms: HA through G protein-coupled receptors and NMDA by ligand-activated ion channels. Vehicle applications did not affect either resting activity or neuronal responses. In contrast, acute E exposure modulated neuronal responses to transmitters, with no significant effect on the resting activity. It potentiated excitatory responses to HAs (20 out of 48 cells tested) and to NMDA (10 out of 19 cells), but attenuated inhibitory responses to HA (3 out of 6 units). Both of these hormonal actions would increase VMN neuronal excitation. In separate experiments, neuronal excitation was found to be suppressed by anesthetics, which would block E's induction of lordosis when administered at the time of estrogen application. These data are consistent with the notion that increasing electrical excitation of VMN neurons can be a mechanism by which acute E exposure facilitates the lordosis-inducing genomic actions of estrogens.
Brain Research 06/2005; 1043(1-2):124-31. · 2.73 Impact Factor
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ABSTRACT: We examined the distribution of estrogen receptor (ER)-alpha and ER-beta immunoreactive (ir) cells in the dorsal (DRN) and median/paramedian (MPRN) raphe nuclei in male mice. ER-alpha ir neurons were scattered across the three subdivisions (ventral, dorsal, and lateral) of the DRN and the MPRN. Robust ER-beta ir cells were observed throughout the raphe nuclei, and were particularly abundant in the ventral and dorsal subdivisions of the DRN. Using dual-label immunocytochemistry for ER-alpha or ER-beta with tryptophan hydroxylase (TPH), the rate-limiting enzyme for 5-hydroxytryptamine (5-HT) synthesis, over 90% of ER-beta ir cells exhibited TPH-ir in all DRN subdivisions, whereas only 23% of ER-alpha ir cells contained TPH. Comparisons of ER-alpha knockout (alphaERKO) as well as ER-beta knockout (betaERKO) mice with their respective wild-type (WT) littermates revealed that gene disruption of either ER-alpha or ER-beta did not affect the other ER subtype expression in the raphe nuclei. In situ hybridization histochemistry revealed that there was a small but statistically significant decrease in TPH mRNA expression in the ventral DRN subdivision in betaERKO mice compared with betaWT mice, whereas TPH mRNA levels were not affected in alphaERKO mice. These findings support a hypothesis that ER-beta activation may contribute to the estrogenic regulation of neuroendocrine and behavioral functions, in part, by acting directly on 5-HT neurons in the raphe nuclei in male mice.
Neuroscience 02/2005; 130(2):445-56. · 3.38 Impact Factor
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ABSTRACT: Arousal, the activation of brain and behavior, is a fundamental component of behavior. While sex differences in behavior are pervasive, it is unknown whether they could be due to an underlying dimorphism in arousal mechanisms. Because histamine (HA) acting through histamine 1 (H1) receptors is one essential component of arousal neural circuitry, the aim of the current experiment was to measure sex differences in behavioral arousal following treatment with the H1 receptor antagonist, pyrilamine (PYRL). Castrated male and ovariectomized female Swiss-Webster mice were treated subcutaneously with either 15 or 35 mg/kg of PYRL. The effect of drug treatment was determined in an array of behaviors: sensory responsiveness, running wheel activity, and fearfulness. Surprisingly, the lower dose of PYRL increased some aspects of arousal, sensory responsiveness, and anxiety-like behavior, while the higher dose of PYRL resulted in decreases in arousal across tests, indicating that antagonism of histamine receptors does not have a linear relationship with arousal. Females were more sensitive to the arousal-reducing effects of PYRL than males in sensory and running wheel tasks but not in tests of emotion. In conclusion, antagonism of H1 receptors can alter arousal in a sex-dependent manner, independent of circulating gonadal steroids, in mice.
Pharmacology Biochemistry and Behavior 12/2004; 79(3):563-72. · 2.53 Impact Factor
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ABSTRACT: Social behavior involves both the recognition and pro-duction of social cues. Mice with selective deletion(knockout) of either the gene for oxytocin (OT) or genes for the estrogen receptor (ER) -c or -B display impaired social recognition. In this study we demonstrate that these gene knockout mice also provide discriminably different social stimuli in behavioral assays. In an odor choice test, which is a measure of social interest and discrimination, outbred female Swiss-Webster mice discriminated the urine odors of male knock-outs IKO: OTKO, alphaERKO, betaERKO) from the odors of their wildtype littermates (WT: OTWT, alphaERWT, betaERWT). Females showed marked initial choices of the urine odors of OTWT and betaERWT males over those of OTKOand PERKO males, and alphaERKO males over alphaERWT males. The odors of OTKO and betaERKO males also induced aversive, analgesic responses, with the odors of WTs having no significant effects. Odors of both the alphaERWT andalphaERKO males induced aversive, analgesic responses,with the odors of the WT inducing significantly greater analgesia. The odors of restraint stressed WT and KO males also elicited analgesia with, again, females dis-playing significantly greater responses to the odors of stressed OTKO and betaERKO males than their WTs, and significantly lower analgesia to the odors of stressedalphaERKO than alphaERWT males. These findings show that the KO mice are discriminated from their WTs on the basis of odor and that the various KOs differ in the relative attractiveness/aversiveness of their odors. Therefore, in behavioral assays one causal route by which gene inactivation alters the social behavior of knockout mice may be mediated through the partners'modified responses to their odors.
Genes Brain and Behavior 09/2004; 3(4):189-95. · 3.48 Impact Factor
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ABSTRACT: Genes induced by estrogens in the mammalian forebrain influence a variety of neural functions. Among them, reproductive behavior mechanisms are very well understood. Their functional genomics provide a theoretical paradigm for linking genes to neural circuits to behavior. We propose that estrogen-induced genes are organized in modules: Growth of hypothalamic neurons; Amplification of the estrogen effect by progesterone; Preparative behaviors; Permissive actions on sex behavior circuitry; and Synchronization of mating behavior with ovulation. These modules may represent mechanistic routes for CNS management of successful reproduction. Moreover, new microarray results add estrogen-dependent genes, including some expressed in glia, suggesting possible hormone-dependent neuronal/glial coordination.
Molecular Psychiatry 07/2004; 9(6):550-6. · 13.67 Impact Factor
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ABSTRACT: Although various types of group living are widespread in mammals, including humans, the study of the hormonal and genetic underpinnings of nonsexual social behaviour, is in its infancy compared to the analysis of sexual behaviour mechanisms. Oxytocin, vasopressin and gonadal hormones certainly play an important role. Social recognition, where animals identify and recognize other individual conspecifics, is a crucial prerequisite for the occurrence of a wide range of social behaviours. Social recognition is also important for coping with one major cost of life in a group: the increased risk of exposure to parasites and infection. We review recent functional genomic studies on the involvement of oxytocin and oestrogen-receptor genes in the regulation of social recognition in mice and in the ecologically relevant context of parasite recognition and avoidance. Based on quantitative studies of social recognition with gene-knockout mice and with antisense DNA, we propose a four-gene micronet contributing to social recognition. This micronet involves the genes coding for oestrogen receptors alpha (ER-alpha), beta (ER-beta), oxytocin and the oxytocin receptor. In this model, circulating oestrogens promote transcription of (i) oxytocin in the paraventricular nucleus of the hypothalamus through ER-beta and (ii) oxytocin receptor in the amygdala through ER-alpha. This model forms the core around which increasingly complex genetic, hormonal and neural interactions associated with social behaviours and recognition can be organized.
Journal of Neuroendocrinology 05/2004; 16(4):383-9. · 3.14 Impact Factor
