Fetal female rats are masculinized by male littermates located caudally in the uterus.

Female rats are masculinized in utero by male littermates sharing the same uterine horn. Increased anogenital distances in neonatal females and mounting behavior in adult females are related to the presence of males on the caudal side of the females in the uterine horn. Contrary to current beliefs, interamniotic diffusion may not be responsible for the exchange of masculinizing agents among fetuses. Since uterine blood flow in the rat is from the direction of the cervix toward the ovary, masculinizing hormones secreted by fetal males may be carried via the uterine vasculature to female littermates located further downstream.

Sexual behavior induction of c-Fos in the nucleus accumbens and amphetamine-stimulated locomotor activity are sensitized by previous sexual experience in female Syrian hamsters.

Dopamine transmission in the nucleus accumbens can be activated by drugs, stress, or motivated behaviors, and repeated exposure to these stimuli can sensitize this dopamine response. The objectives of this study were to determine whether female sexual behavior activates nucleus accumbens neurons and whether past sexual experience cross-sensitizes neuronal responses in the nucleus accumbens to amphetamine. Using immunocytochemical labeling, c-Fos expression in different subregions (shell vs core at the rostral, middle, and caudal levels) of the nucleus accumbens was examined in female hamsters that had varying amounts of sexual experience. Female hamsters, given either 6 weeks of sexual experience or remaining sexually naive, were tested for sexual behavior by exposure to adult male hamsters. Previous sexual experience increased c-Fos labeling in the rostral and caudal levels but not in the middle levels of the nucleus accumbens. Testing for sexual behavior increased labeling in the core, but not the shell, of the nucleus accumbens. To validate that female sexual behavior can sensitize neurons in the mesolimbic dopamine pathway, the locomotor responses of sexually experienced and sexually naive females to an amphetamine injection were then compared. Amphetamine increased general locomotor activity in all females. However, sexually experienced animals responded sooner to amphetamine than did sexually naive animals. These data indicate that female sexual behavior can activate neurons in the nucleus accumbens and that sexual experience can cross-sensitize neuronal responses to amphetamine. In addition, these results provide additional evidence for functional differences between the shell and core of the nucleus accumbens and across its anteroposterior axis.

Changes in gene expression within the nucleus accumbens and striatum following sexual experience.

Sexual experience, like repeated drug use, produces long-term changes including sensitization in the nucleus accumbens and dorsal striatum. To better understand the molecular mechanisms underlying the neuroadaptations following sexual experience, we employed a DNA microarray approach to identify genes differentially expressed between sexually experienced and sexually naive female hamsters within the nucleus accumbens and dorsal striatum. For 6 weeks, a stimulus male was placed in the home cage of one-half of the hormonally primed, ovariectomized female hamsters. On the seventh week, the two experimental groups were subdivided, with one half paired with a stimulus male. In comparison with sexually naive animals, sexually experienced hamsters receiving a stimulus male on week 7 exhibited an increase in a large number of genes. Conversely, sexually experienced female hamsters not receiving a stimulus male on week 7 exhibited a reduction in the expression of many genes. For directional changes and the categories of genes regulated by the experimental conditions, data were consistent across the nucleus accumbens and dorsal striatum. However, the specific genes exhibiting changes in expression were disparate. These experiments, among the first to profile genes regulated by female sexual behavior, will provide insight into the mechanisms by which both motivated behaviors and drugs of abuse induce long-term changes in the mesolimbic and nigrostriatal dopamine pathways.

-Fos expression in female hamster brain following sexual and aggressive behaviors.

The goal of these experiments was to use c-Fos immunocytochemistry to determine areas of the female hamster brain that are active during lordosis and aggression. Ovariectomized hamsters were given (i) estradiol and progesterone, plus a lordosis test, (ii) estradiol and progesterone, but no lordosis test, (iii) oil, plus an aggressive behavior test, or (iv) oil, but no behavior test. Results showed that following lordosis, there was increased c-Fos expression in the medial bed nucleus of the stria terminalis, medial accumbens, medial preoptic nucleus, paraventricular nucleus and medial amygdala. Following a single aggression test, c-Fos was significantly increased only within the medial amygdala. There was no effect of lordosis or aggression on c-Fos expression within the lateral or central ventromedial hypothalamus, suprachiasmatic nucleus or dorsal midbrain central gray. In a second experiment, ovariectomized female hamsters were given (i) repeated aggressive experience, (ii) a single aggression test or (iii) no aggression test. Because some females were not aggressive towards males, they became a separate group post hoc. The number of cells expressing c-Fos was higher in the medial preoptic nucleus and medial amygdala of females given a single aggressive test and in non-aggressive females vs control females. Females given prior aggressive experience showed higher c-Fos expression only in the medial preoptic nucleus. These results demonstrate that increased neural activation in several forebrain nuclei is seen after sexual or aggressive behaviors in female hamsters. However, because the pattern of c-Fos staining in the non-aggressive females was similar to the pattern in aggressive females, this questions previous conclusions regarding the behavioral specificity of these effects and suggests instead that such activation is common to social interactions in general.

Brain region specificity in estradiol effects on neuronal ultrastructure in rats.

The effects of long-term (15 days) and short-term (3 days) treatment with estradiol benzoate (EB) on stacking of rough endoplasmic reticulum in neurons of four brain regions (medial preoptic nucleus, ventromedial hypothalamus, arcuate nucleus and midbrain central gray) were investigated. These regions were chosen for their role in reproduction in female rats and/or the presence of estradiol-concentrating cells. Long-term EB treatment increased the proportion of neurons in the ventromedial hypothalamus (by 30%) and medial preoptic nucleus (by 17%) that contained stacks of rough endoplasmic reticulum. Short-term EB affected stacking only in ventromedial hypothalamic neurons. EB was without effect on neurons of the arcuate nucleus of the hypothalamus or midbrain central gray. The degree of stacking of rough endoplasmic reticulum in neurons of the ventromedial hypothalamus was positively related to the level of sexual behavior (lordosis) activated by these hormone treatments.

Localization of protein Ser/Thr phosphatase 5 in rat brain.

Protein phosphatase 5 is a recently discovered Ser/Thr phosphatase that is structurally related to calcineurin and protein phosphatases 1 and 2. Northern blot and in situ hybridization studies have shown that protein phosphatase 5 mRNA is present at high levels in brain and is localized to discrete regions. In the present study, we used immunocytochemistry and immunoblot analyses to examine the regional and subcellular distribution of this enzyme in brain. Our work demonstrates that protein phosphatase 5 is widely expressed throughout brain, but is not uniformly distributed. The most intense staining occurred in neurons of the cerebellum, cerebral cortex, and the supraoptic nucleus of the hypothalamus. Other areas also contained immunoreactive cell bodies, including the globus pallidus, hippocampus, thalamus, lateral preoptic area of the hypothalamus, substantia nigra and other brainstem nuclei. Staining in these cells was observed primarily in perikarya and proximal processes.

Recovery of masculine copulatory behavior from lesions of the medial preoptic area: effects of age versus hormonal state.

The present experiments tested the hypothesis that one consequence of the hormonal activation of the onset of copulation in male rats is a reduction in the plasticity of the medial preoptic area (MPOA) with respect to its role in copulation. In Experiment 1, one group of male rats received 1 mg of testosterone propionate daily from 10 to 45 days of age, and a second group received oil injections. Males in each of these groups received either bilateral MPOA lesions (MPOAX) or a sham operation as juveniles (28-31 days of age). The proportions of MPOAX males copulating as adults did not differ for males previously injected with oil or testosterone. In Experiment 2, male rats were castrated at 15 days of age. These castrated males as well as gonadally intact males received bilateral MPOA lesions or a sham operation in adulthood. Following testosterone replacement, MPOAX males displayed copulatory impairments regardless of hormonal state during development. Taken together, the results of these experiments suggest that the plasticity (with respect to copulation) of the neural system encompassing the MPOA is a function of some aspect of chronological age unrelated to the animal's developmental hormonal condition prior to the time of the lesion.

Forebrain sites of estradiol-17 beta action on sexual behavior and aggression in female Syrian hamsters.

The effects of intracranial implants of estradiol in the ventromedial hypothalamus (VMH), the anterior hypothalamus (AH), or the medial amygdala (AMG) on aggression, sexual behavior, and serum estradiol were examined in female Syrian hamsters. Estradiol implants in the VMH, followed by systemic progesterone, stimulated sexual behavior and inhibited aggression. Estradiol implants in other intracranial sites activated sexual behavior but did not reliably inhibit aggression. Intracranially implanted and systemically treated animals had equivalent peripheral estradiol concentrations at sacrifice. These results suggest that: (a) the VMH is an important neural site for estradiol actions on sexual and aggressive behavior, (b) the caudal AH and AMG also may be sites of estradiol action on sexual behavior, and (c) these intracranial implants may only be effective given systemic estradiol exposure or the concurrent stimulation of multiple brain areas.

Mechanisms for oliguria in acute renal failure.

Warm ischemic (90 minutes) acute renal failure (ARF) was evaluated in the dog and found to cause polyuric ARF in the injured kidney if the opposite normal kidney was removed. In contrast, if the normal kidney were left intact, oliguric ARF was noted in the injured kidney. To further evaluate the mechanisms for oliguria and polyuria, chronic reinfusion of urine from a normal kidney into the inferior vena cava (ureterocaval anastomosis) resulted in polyuria in the opposite warm ischemic injured kidney; whereas chronic reinfusion of urine into the portal vein (ureteroportal anastomosis) resulted in profound oliguria in the opposite injured kidney. In separate additional experiments, urine acutely infused into the inferior vena cava at a rate of 0.38 ml/minute caused a significantly greater diuretic and renal hemodynamic response than seen with urine infused into the portal vein. Acute infusions of urea solution (0.38 ml/minute) with the same osmolality of urine were completely devoid of diuretic and renal hemodynamic effects. These studies reveal that urine contains a powerful hemodynamic and diuretic factor which appears to convert oliguric to polyuric ARF following warm ischemic renal injury in the dog. This factor is not urea and can be destroyed by the liver.

High-dose intravenous gamma globulin: does it have a role in the treatment of severe erythroblastosis fetalis?

The role of high-dose intravenous (IV) gamma globulin in the treatment of erythroblastosis fetalis was assessed in five pregnancies with severe Rh (four) or Kell (one) isoimmunization. These women were treated with IV gamma globulin (1.0 g/kg body weight) once a week. In addition, fetal blood transfusions were performed when indicated. In four patients with Rh sensitization, high-dose IV gamma globulin treatment had no apparent effect on the total number of intrauterine transfusions required, the interval between transfusions, or the volume of blood required at each transfusion. The treatment did not prevent fetal hydrops and had no effect on maternal antibody titers. In one patient with Kell sensitization, however, the course of the disease was less severe than anticipated, suggesting that IV gamma globulin treatment may have modified the severity of the disease. We conclude that high-dose IV gamma globulin does not appear to be useful in the treatment of severe Rh disease. Its role in Kell and other types of red-cell isoimmunization deserves further evaluation.

Sexual experience sensitizes mating-related nucleus accumbens dopamine responses of female Syrian hamsters.

We examined the effects of prior sexual experience on extracellular concentrations of dopamine in the nucleus accumbens of female hamsters. Nucleus accumbens dopamine was measured by in vivo microdialysis during mating in female Syrian hamsters that had previously been given six prior sexual encounters with a male, three prior encounters, or were sexually naive. High levels of sexual behavior were observed in all three groups, which were accompanied by increases in dialysate dopamine during periods when the male was present. However, females that received six prior sexual encounters had significantly elevated and prolonged increases in dialysate dopamine compared with those of the sexually naive females or females with only three prior sexual encounters with a male. The data indicate that the mesolimbic system can be sensitized by repeated experiences associated with a motivated behavior.

A microdialysis study of ventral striatal dopamine during sexual behavior in female Syrian hamsters.

Microdialysis was used to study the effects of exposure to a male hamster on extracellular concentrations of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in the ventral striatum of ovariectomized female Syrian hamsters pretreated with either estradiol and progesterone, or a similar regimen of oil injections. The hormone-treated females showed high levels of lordosis throughout the hour of exposure to the male. In hormone-treated females, there was a rapid elevation of dialysate dopamine within the first 15 min of exposure to the male. Dialysate dopamine gradually declined over the next 45 min, though remaining significantly above baseline during the entire period of exposure to the male. None of the oil-treated females showed any indication of lordosis, and the addition of the male produced only a small increase in dopamine at 30 min, after which dopamine returned to pre-male basal levels. DOPAC, HVA, and 5-HIAA were all elevated following introduction of the male for both groups of females. These results suggest that ovarian hormones modulate the responsivity of ventral striatal dopamine to incentive stimuli associated with mating behavior in females, although extracellular levels of dopamine in the ventral striatum do not seem to be directly coupled to the display of lordosis.

Induction of hindlimb stepping movements in rats spinally transected as adults or as neonates.

Rats were spinally transected as adults or as neonates. When their hindlimbs were held off the ground and tail pinch was applied, both groups of animals exhibited a strong tendency to step with alternating limbs. The most striking difference between the groups was in the rate of stepping, the neonatal spinals being significantly faster than the adult spinals. To our knowledge, this is the first evidence that adult-transected rats retain a degree of locomotion-related coordination.

Progesterone effects on sexual behavior and neuronal ultrastructure in female rats.

Treatment of female rats with a low dose of estradiol (5% estradiol in a 5 mm Silastic capsule) and progesterone (0.5 mg) increased the percentage of neurons in the ventromedial nucleus of the hypothalamus that contained stacks of rough endoplasmic reticulum, as compared with female rats receiving either estradiol alone or no treatment. Only females treated with both estradiol and progesterone displayed any sexual behavior, with these females responding at maximal levels. These results support the relationship between stacking of rough endoplasmic reticulum in ventromedial hypothalamic neurons and levels of sexual behavior in female rats, and provide evidence that progesterone can produce rapid changes in the morphology of hypothalamic neurons in estrogen-treated animals.

Dopamine receptor antagonists attenuate conditioned place preference following sexual behavior in female Syrian hamsters.

We assessed the effects of the dopamine D2 receptor antagonists, sulpiride and raclopride, on conditioned place preference produced by sexual behavior in female Syrian hamsters. Female hamsters treated with sulpiride or raclopride showed high levels of sexual behavior (lordosis) that were equivalent to control females receiving vehicle injections. The degree of place preference conditioning for sulpiride-treated females was marginally reduced, whereas females treated with raclopride showed no evidence of conditioning. These results indicate that conditioned place preference is a useful means for probing the appetitive components of female sexual behavior, and that dopamine D2 receptors are involved in this appetitive process.

Estradiol increases the dendritic length of ventromedial hypothalamic neurons in female Syrian hamsters.

We examined the effects of ovarian hormones on dendritic architecture of neurons in the ventromedial nucleus of the hypothalamus in female Syrian hamsters. Treatment with 10 micrograms of estradiol benzoate for two days, or estradiol benzoate for two days followed by an injection of 500 micrograms of progesterone, increased the total dendritic length of ventromedial nucleus neurons by almost 50% compared with neurons from the ventromedial nucleus of ovariectomized, oil-treated females. Neurons in a control region, the dorsomedial nucleus of the hypothalamus, were unaffected by these hormone treatments. These results demonstrate that steroids can induce changes in dendritic structure within 48 hr, suggesting that such morphological reconfiguration of hypothalamic neurons may underlie variations in behavior associated with the female's 4-day estrous cycle.

RNA and protein synthesis inhibitors: effects on sexual behavior in female rats.

Biochemical evidence indicates that many steroid hormone effects on target tissues are mediated via actions on the genome. Studies on the hormonal control of reproductive behavior have demonstrated several effects of RNA or protein synthesis inhibitors on female sexual behavior in rats. In female rats treated with estrogen and progesterone, intracranial application of actinomycin-D (an RNA synthesis inhibitor) can disrupt lordosis responding if the drug is given in conjunction with estrogen, but not with progesterone. Protein synthesis inhibitors (cycloheximide or anisomycin) applied intracranially at the time of estrogen also disrupt lordosis, with anisomycin antagonizing the progesterone-facilitation of lordosis. Possible neural sites of action of these drugs are considered, as are alternative modes of action of these synthesis inhibitors. Whereas the effects of estrogen on lordosis include the synthesis of some, as yet unidentified, proteins, the exact role for protein synthesis in the mediation of progesterone's actions on lordosis remains less certain.

Conditioned place preference in female hamsters following aggressive or sexual encounters.

Prior studies have demonstrated the utility of conditioned place preference procedures for examining the motivational or rewarding properties of behavior. The purpose of this experiment was to assess whether female Syrian hamsters would show evidence of conditioned place preference for aggression or sexual behaviors. Weekly conditioning sessions were conducted for three groups of female hamsters for 5 weeks. One group of female hamsters engaged in sexual activity with a male hamster in the gray compartment of a place preference apparatus. A second group of females experienced aggressive interactions with a male when placed together also in the gray compartment. Females in each of these conditioning groups were placed alone in the white compartment within 1 h of the behavioral interactions. A control group of hormone-treated females was placed alone in both compartments of the apparatus. Following the conditioning sessions, all females were given free access to the conditioning apparatus. Females with prior sexual or aggressive experience spent significantly more time in the gray compartment than they did before conditioning. Control females did not show any significant change in their preference for either compartment of the apparatus. The results suggest that female hamsters prefer an environment associated with the prior rewarding properties of sexual or aggressive interactions.

Progesterone inhibition of sexual behavior is accompanied by an activation of aggression in female Syrian hamsters.

Previous studies have shown that progesterone can have biphasic activational and inhibitory roles in the regulation of sexual behavior in female Syrian hamsters. The purpose of this study was to determine whether these biphasic effects on sexual behavior are mirrored in a reciprocal regulation of aggression. Ovariectomized female Syrian hamsters were treated with estradiol followed 2 and 3 days later by either 1) two oil injections (O-O), 2) an oil and a progesterone injection (O-P), 3) a progesterone and oil injection (P-O), or 4) two progesterone injections (P-P). Females were tested for aggression and sexual behavior in conjunction with these hormone treatments. On the final test session, P-P females had significantly lower lordosis durations than did O-P females, confirming the progesterone inhibition of sexual behavior previously reported. Without hormone treatment all females showed high baseline levels of aggression. On the last behavioral test, aggression in O-O females and P-O females was comparable to their baseline levels of aggression. In contrast, aggression in P-P females was significantly higher than the baseline levels of aggression. These results suggest that like its effects on sexual behavior, progesterone can have both inhibitory and activational effects on aggression in female Syrian hamsters.

Anisomycin does not disrupt the activation of penile reflexes by testosterone in rats.

A possible role of protein synthetic processes in the testosterone-activation of penile reflexes in rats was examined in these experiments. In Experiment 1, long-term castrated male rats were injected with 250 micrograms testosterone propionate (TP) and tested for penile reflexes 24 hr later. Fifteen minutes prior to TP these males received a systemic injection of the protein synthesis inhibitor anisomycin (ANI) or the saline vehicle. ANI had no disruptive effect on the activation of penile reflexes by TP; in fact, ANI facilitated erection frequency. In Experiments 2 and 3, a series of three ANI or saline injections were given at 2 hr intervals beginning with the injection of 250 micrograms TP, with no significant effect on any reflex parameters tested 12 or 24 hr after TP. In Experiment 4, the penile reflexes of male rats were stimulated by implanting a Silastic capsule containing testosterone subcutaneously for 2 weeks. A series of ANI or saline injections were spaced 3 hr apart, with penile reflexes tested 6 and 12 hr after the first injection. There were no significant differences between ANI and saline-treated males at 6 hr, whereas at 12 hr ANI-treated males had significantly shorter reflex latencies and significantly more penile flips than did males injected with saline. In a final experiment (Experiment 5), the Silastic capsules were removed from the males in the previous experiment. Three injections of ANI or saline were given at 4 hr intervals beginning with the removal of the Silastic capsule.(ABSTRACT TRUNCATED AT 250 WORDS)