Effects of diazepam on conflict behaviour and on plasma corticosterone levels in male and female rats

The anxiolytic properties of diazepam and its effects on plasma corticosterone levels were compared in male and female, water deprived rats exposed to the punished (0.8 mA) drinking procedure. The effects of diazepam on unpunished licking, tested under familiar or unfamiliar conditions, and on the lick latency were also studied and a comparison between the two sexes was made. Both punished and unpunished drinking were less in females than in males. In both sexes, a clear anticonflict effect, i.e. a much greater effect on punished than on unpunished drinking, was obtained with 2 and 4 mg/kg, but not with I mg/kg, of diazepam i.p. Plasma corticosterone levels were higher in water deprived females than in males. Following the punished and unpunished drinking procedure, plasma corticosterone levels were found to have decreased more in female than in male rats, especially after administration of 1 mg/kg of diazepam. Diazepam had similar anticonflict effects in rats of both sexes but had a greater suppressive effect on the plasma corticosterone levels in female rats. There was no correlation between the anxiolytic effects of diazepam and its effect on the plasma corticosterone levels. When testing was done under unfamiliar conditions, the latency to licking was greater in female than in male rats and diazepam (1, 2 and 4 mg/kg) increased this latency in both sexes. The results suggest sex differences in the neuroendocrine, but not in the anxiolytic, effects of diazepam.     

Effects of low dosages of apomorphine on maternal responsiveness in lactating rats

Lactating rats (day 7 +/- 1 postpartum) were observed during a 1-h reunion with their pups 4 h after separation from them and 10 min after subcutaneous injection of saline (SAL; 0.1 ml) or low dosages of the dopamine agonist, apomorphine (APO; 0.1 or 0.25 mg/kg). Although APO did not affect latency to sniff pups or retrieve the first pup, there were dosage-dependent delays in onset of licking and nursing pups, and decreases in retrieval and grouping of pups, nursing duration, and litter weight gain. The alterations in maternal responsiveness among APO-treated dams were related to increased carrying and mouthing of pups and markedly increased sniffing of pups, bedding, and cage. Duration of time spent licking pups, exploring, and self-grooming did not differ between groups. Thus, certain APO-induced stereotypic behaviors interfered with the normal sequence of maternal behavior by exaggerating some components and delaying others. These results are relevant to disturbances in maternal behavior caused by hyperreactivity or by other drugs that increase dopaminergic activity, such as cocaine.     

Tetrahydrofuran: two-generation reproduction toxicity in Wistar rats by continuous administration in the drinking water.

In a two-generation reproduction toxicity study, 25 male and 25 female Wistar rats per dose group and generation were exposed continuously to tetrahydrofuran in the drinking water for at least 70 days prior to and during mating, gestation, parturition and lactation to weaning, at concentrations of 0, 1000, 3000 or 9000 ppm (approximately 100, 300 and 700 mg/kg/day in males and females premating, 100, 300 and 800 mg/kg/day in females during gestation, and 200, 500 and 1300 mg/kg/day in females during lactation) through two successive generations. In both generations and sexes, water consumption was dose-relatedly reduced at all doses; food consumption and body weight were reduced at 9000 ppm. Necropsy kidney weights were increased in 9000 ppm F0 males. Pup body weight gain during lactation was reduced in both generations (F1 and F2 pups) and eye opening delayed in the first generation (F1 pups) at 9000 ppm; there were no treatment-related malformations. The NOAEL of tetrahydrofuran in drinking water is 9000 ppm for parental fertility and reproductive performance, and 3000 ppm for systemic parental and developmental toxicity.     

Pre-weaning non-handling of rats disrupts latent inhibition in males, and results in persisting sex- and area-dependent increases in dopamine and serotonin turnover

Pre-weaning "handling" of rat pups (1-21 days) is reported to result in a number of behavioural differences from "nonhandled" pups, persisting into adult life. In general, these are associated with altered emotional reactivity. We now report the results of a replication of a previous finding that handling also affects performance on a latent inhibition (LI) task, which involves learning in the absence of motivation. The effect of 30 pre-exposures to a tone stimulus on the formation of an association from two pairings between that stimulus and footshock was determined. The association was indexed by the suppression of licking resulting from tone presentation during licking for water reward. In adult female rats, pre-exposure prevented the formation of this association (i.e. LI was present) whether they had been handled or nonhandled pre-weaning. However in adult males, pre-exposure was effective only in handled rats, and not in nonhandled. This confirms the striking pattern of results reported previously by another group (Weiner et al., 1987). The turnover of dopamine (DA) and serotonin was subsequently determined post mortem from the ratios of metabolites to amines in DA-innervated brain areas of the rats used in the present study. Pre-weaning nonhandling and female sex, were independently associated with increased dopamine turnover, and to a lesser extent with increased serotonin turnover. While these increases were not sex-specific, nonhandled males did show a pattern of increased DA turnover relative to serotonin turnover in limbic areas; previous pharmacological and physiological studies support the idea that this pattern may be associated with impairment of LI. It is concluded that preweaning nonhandling is indeed associated with an impairment of LI restricted to males, and is associated with enduring changes in DA and 5HT turnover in both sexes. Further studies are indicated to determine the precise role of these changes in the behavioural effects of pre-weaning nonhandling.     

Ethological methods to study the effects of maternal exposure to estrogenic endocrine disrupters: a study with methoxychlor

There has been increasing interest, both at the scientific and regulatory level, in the use of ethological methods for evaluating neural effects of endocrine disrupters. We present a series of ethological studies on the effects of maternal exposure to low, environmentally relevant doses (0.02, 0.2, and 2 microg/g mother bw/day) of the estrogenic pesticide methoxychlor (MXC) on behavior. From gestation day 11 to 17, female mice spontaneously drank oil with or without MXC; their maternal behavior was examined from postpartum days 2 to 15. MXC treatment during pregnancy produced slight changes in the expression of maternal behavior: females fed the lower MXC dose spent less time nursing the pups as compared to control dams. Their maternally exposed offspring were subjected to a series of behavioral tests at different ages. Maternal exposure to MXC affected behavioral responses to novelty in both sexes at periadolescence. The onset of male intrasex aggression was delayed in males prenatally exposed to low doses of MXC, since exposed males showed low levels of aggressive interactions during early adolescence but not after they reached adulthood. When adults, MXC-exposed females, but not males showed increased exploration in an unfamiliar open-field. While a sex difference was observed in the control group, with males being significantly more active in the open field than females, prenatal treatment with some MXC doses tended to decrease the sexual dimorphism in activity levels in the novel environment. Ethology, as the evolutionary study of behavior, may provide a framework for integrating a functional perspective (i.e., evolutionary significance) to studies on proximate mechanisms that can account for behavioral alterations induced by developmental exposure to endocrine disrupters.     

Sexual segregation in infancy and bi-directional benzodiazepine effects on hot-plate response and neophobia in adult mice.

In the present experiment, the hypothesis that rearing animals in conditions of sexual segregation in infancy (ISS) would affect their adult behavioral reactivity to drug or environmental challenges was tested. Outbred Swiss CD-1 mouse litters were reduced at birth to six pups according to three conditions: MM (all males), MF (sex-balanced composition), and FF (all females). At weaning (day 21), all mice were rehoused in unisexual groups. At adulthood (day 70), animals were challenged either with BDZ agonist chlordiazepoxide (CDP at 2.5- or 5.0-mg/kg dose) or BDZ receptor partial inverse agonist Ro 15-3505 (RO at 3-, 10-, or 30-mg/kg dose) and assessed in sequence for pain reactivity in a hot-plate apparatus (set at 55 +/- 1 degrees C), for locomotor activity in a Varimex apparatus, and finally for neophobia level by measuring the latency to first approach a novel object. As concerns the hot-plate test, lick latency was significantly shortened in MF females receiving CDP (5.0 mg/kg), while RO was either ineffective in MF females or induced a prominent dose-dependent analgesia in FF females. Activity was decreased by CDP (2.5 mg/kg) and enhanced by RO (3.0 mg/kg). For latency to approach a novel object, males as a whole exhibited shorter times than females. Mixed-sex animals of both sexes were less fearful, being also more explorative than their corresponding unisexually reared groups. In particular, MF males receiving either a 5.0-mg/kg CDP dose or a 3.0-mg/kg RO dose explored the object more often than MM males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine antagonists during parturition disrupt maternal care and the retention of maternal behavior in rats

Brief contact with pups at parturition enables the female rat to establish and retain the full repertoire of maternal behaviors, allowing her to respond rapidly to pups in the future. To determine whether the dopamine system is involved in the retention of maternal behavior, females were continuously infused with dopamine antagonists during the periparturitional period and then allowed either a brief interaction period with pups (3 h) or no interaction with pups (pups removed as they were born). Females were exposed to either the D1-like antagonist SCH 23390 (0.1 or 1.0 mg/kg/day) or the D2-like antagonist clebopride (0.5 or 1.0 mg/kg/day). The high dose of either DA antagonist resulted in significant attenuation of maternal care immediately postpartum. When tested for the retention of maternal behavior 7 days later, however, only the females exposed to the D2 antagonist displayed a delayed response to shown full maternal behavior (FMB) towards donor pups. Thus, while both dopamine receptor subtypes appear necessary for the full and rapid expression of maternal behavior during the early postpartum period, only the D2 receptor subtype appears to be involved in the retention of this behavior.     

Male olfactory cues affect mothers’ behavior in mice: effects of benzodiazepines

Rationale: Threatening social stimuli were used in this study as aversive conditions to test anxiety in lactating female mice. The odors of potential infanticidal males or the ”stress odor” left by restrained mice represented two aversive conditions that have been suggested to modulate the time spent by the mothers to reach their pups after 30 min of separation. Objectives: The effects of drugs acting at the benzodiazepine receptors were evaluated on the behavior of mothers exposed to different threatening social cues. Methods: Lactating mice of the NMRI outbred strain with 8-day old pups were treated with (1) chlordiazepoxide (CDP) 2.5, 5.0 and 10 mg/kg i.p.; (2) flumazenil 10 mg/kg i.p. and (3) methyl β-carboline-3-carboxylate (β-CCM) 3.0 mg/kg i.p. Results: The odors left by stressed females changed the mothers’ exploratory behavior, but not the latency to reach pups. The latency was higher in the presence of cues from potentially infanticidal males. CDP (5.0 mg/kg) reduced the time spent to contact pups, whereas the other CDP doses did not modify the dam’s behavior. Flumazenil, given in combination with CDP (5.0 mg/kg) antagonized the latter anxiolytic effect. In addition, in the presence of cues from potentially infanticidal males β-CCM had anxiogenic activity, increasing latency to reach pups. The same CDP and β-CCM doses were ineffective in the presence of cues from stressed females and in the absence of olfactory cues from conspecifics. Conclusions: This study provides behavioral and pharmacological validation of a new model of anxiety specifically designed for lactating females. Received: 21 January 1999 / Final version: 22 April 1999     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat. I. Reproductive toxicity

The reproductive toxicity of toluene was evaluated in a 2-generation test in which male and female Sprague–Dawley rats, parental (F0) and first generation (F1), were exposed to toluene via whole body inhalation, 6 h/day, 7 days/week for 80 days premating and 15 days of mating at concentrations of 0, 100, 500 and 2000 ppm (0, 375, 1875 and 7500 mg/m³). Toluene was administered at 2000 ppm to both sexes, or to females or males only to be mated with untreated partners. Pregnant females at all dose levels were exposed from gestation day (GD) 1–20 and lactation day (LD) 5–21. At LD5, females were removed from their litters for daily exposure and returned when 6 h of exposure was completed. F1 pups selected to produce the F2 generation were treated for 80 days beginning immediately after weaning (LD21) and initially mated at a minimum of 100 days of age. F2 pups were not exposed to toluene by inhalation.

Toluene exposure did not induce adverse effects on fertility, reproductive performance, or maternal/pup behaviors during the lactation period in males and females of the parental or first generation, but did inhibit growth in F1 and F2 offspring in the 2000 ppm (both sexes treated) and 2000 ppm (females only treated) groups. Caesarean section of selected 2000 ppm (both sexes treated) dams at GD20 showed reduced fetal body weight and skeletal variations. Exposure to toluene caused decreased pup weights throughout lactation in F1 and F2 2000 ppm (both sexes treated), and 2000 ppm (females only treated) groups. Exposure at 2000 ppm to male parents only did not induce similar weight inhibition in offspring. The toluene offspring NOAEL is 500 ppm in groups in which maternal animals were exposed, and 2000 ppm for male only treated groups.     

The actions of diazepam and serotonergic anxiolytics vary according to the gender and the estrous cycle phase

The anxiolytic effect of diazepam (0.5, 1.0 and 2.0 mg/kg), buspirone (2.5 and 5.0 mg/kg), indorenate (2.5 and 5.0 mg/kg) and ipsapirone (5.0 and 10.0 mg/kg) was evaluated in male and female rats during the proestrus and metestrus phases. The burying behavior test was used to measure the anxiety levels. In this test, increases in the behavior latency are interpreted as prolonged reactivity, while reductions in the burying behavior are considered to reflect anxiolytic states. Diazepam increases in burying behavior latency were consistently higher than those observed after serotonergic anxiolytics. Buspirone, at no dose tested, affected the burying behavior latency, while indorenate and ipsapirone had only minor effects. Male individuals were more sensitive than females to the actions of diazepam on burying behavior. The serotonergic anxiolytics produce similar responses in both sexes. Metestrus females were much less sensitive to the action of all anxiolytics on burying behavior latency than proestrus females. Proestrus females were highly sensitive to the actions of diazepam on burying latency as compared both with males and metestrus females. Data show that a larger gender and within females variation occurs after treatment with diazepam as compared with the serotonergic anxiolytics. The results are discussed considering the relationships between ovarian hormones and the GABA-benzodiazepinic and serotonergic systems.     

Influence of sex on the pharmacokinetics of tolmetin in the rat

The purpose of this study was to investigate sex-related differences in the pharmacokinetics of tolmetin, a potent nonsteroidal anti-inflammatory drug, in the rat. Male and female Wistar rats received oral tolmetin at two dose levels, 3.2 and 10 mg/kg. Blood samples were drawn at selected times after drug administration, and tolmetin concentration in whole blood was determined. Tolmetin was rapidly absorbed in all cases. C(max) increased with the dose, but was similar in both sexes. Notwithstanding, tolmetin half-life was significantly prolonged in females compared with males. As a result of the prolonged half-life, area under the curve values were significantly higher in females than in males. Tolmetin clearance was significantly reduced in females. The present results strongly suggest sex-related differences in the pharmacokinetics of tolmetin in the rat. Tolmetin elimination appears to be impaired in females, compared with males. The existence of sex-related differences in tolmetin pharmacokinetics in other species, including humans, requires further investigation.     

Sex differences in the burying behavior test in middle-aged rats: effects of diazepam

The full behavioral profile displayed during the burying behavior test was studied in middle aged (11-14 months) males, females with irregular estrous cycles, and females in persistent diestrus, with and without diazepam (0.5-2.0 mg/kg). Ambulation and motor coordination were also tested to discern behavioral changes from general motor alterations. Without diazepam treatment, middle-aged males showed longer burying behavior latencies, more prod explorations and less freezing than both groups of females. Untreated middle aged males also showed less cumulative burying and more immobility compared to females with irregular cycles. None of the parameters showed any difference between the female groups. Diazepam (0.5 and 1.0 mg/kg) increased burying behavior latency in females, but had no effect on any parameter in middle aged males. However, a higher dose (2.0 mg/kg) of diazepam increased immobility, freezing and the number of prod shocks and decreased prod explorations and groomings, but impaired motor coordination in males. In contrast with young males and females, diazepam at any dose reduced cumulative burying. Data are discussed on the bases of (1) sex and age differences in burying behavior and on (2) the anxiolytic-like action of diazepam and its side effects.     

Effects of dopamine on the secretion of glycoproteins from the functional segments of the rat submandibular gland

The action of dopamine (DA) on salivation and the secretion of marker glycoproteins (GP) from secretory cells of the rat submandibular gland (SMG) was investigated using various blockers at doses of 1 or 2 mg/kg (i.v.). DA at doses from 5 to 40 mg/kg (i.p.) dose-dependently increased salivation and the concentration of protein in SMG saliva. The order of inhibitory potency on salivation was propranolol (PPR) greater than phentolamine (PHN) much greater than haloperidol (HAL) when DA was administered i.p. at a dose of 10 mg/kg and PHN much greater than HAL much greater than PPR when the dose of DA was 40 mg/kg. The concentration of protein in saliva after pretreatment with HAL or PHN increased significantly at a dose of 40 mg/kg of DA, but did not increase at a dose of 10 mg/kg of DA. Moreover, pretreatment with PPR decreased it at both doses of DA. The electrophoretic profiles of GP in DA-evoked saliva showed two characteristic main bands of GP I (130 KDa) and GP IV (21.5 KDa) contained in the acinar cells (AC) and a minor band of GP III (31 KDa) which originated from the granular tubular cells (GT). The profile was not changed by pretreatment with PHN and HAL when DA was administered at a dose of 10 mg/kg, but at a dose of 40 mg/kg, the intensity of band I increased. Pretreatment with PPR, when DA was administered at 40 mg/kg, caused an increase in the intensity of band III and a reduction in that of band I. These results suggest that DA, at low doses, affects the AC, whereas at a higher dose, it affects both the AC and GT.     

Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats

Genistein is a naturally occurring isoflavone that interacts with estrogen receptors and multiple other molecular targets. Human exposure to genistein is predominantly through consumption of soy products, including soy-based infant formula and dietary supplements. A dose range-finding study was conducted as a prelude to a multigeneration bioassay to assess potential toxicities associated with genistein consumption. Genistein was administered in a soy- and alfalfa-free diet at 0, 5, 25, 100, 250, 625, or 1250 ppm to pregnant dams starting on Gestation day 7 and continuing throughout pregnancy. Dietary exposure of the dams continued through lactation, and pups were maintained on the same dosed feed as their mother after weaning until sacrifice at Postnatal day 50. Body weight and feed consumption of the treated dams prior to parturition showed a decreasing trend with a significant reduction at the highest dose. Litter birth weight was depressed in the 1250 ppm dose group, and pups of both sexes in that dose group had significantly decreased body weights relative to controls at the time of sacrifice. The most pronounced organ weight effects in the pups were decreased ventral prostate weight in males at the 1250 ppm dose and a trend toward higher pituitary gland to body weight ratios in both sexes. Histopathologic examination of female pups revealed ductal/alveolar hyperplasia of the mammary glands at 250 to 1250 ppm. Ductal/alveolar hyperplasia and hypertrophy also occurred in males, with significant effects seen at 25 ppm and above. Abnormal cellular maturation in the vagina was observed at 625 and 1250 ppm, and abnormal ovarian antral follicles were observed at 1250 ppm. In males, aberrant or delayed spermatogenesis in the seminiferous tubules relative to controls was observed at 1250 ppm. There was a deficit of sperm in the epididymis at 625 and 1250 ppm relative to controls, although testicular spermatid head counts and epididymal spermatozoa counts did not show significant differences from controls at these doses. Both sexes showed an increase in the incidence and/or severity of renal tubal mineralization at doses of 250 ppm and above. Dietary genistein thus produced effects in multiple estrogen-sensitive tissues in males and females that are generally consistent with its estrogenic activity. These effects occurred within exposure ranges achievable in humans.     

Reproduction Study of Dimethylacetamide following Inhalation in the Rat

Reproduction Study of Dimethylacetamide following Inhalationin the Rat. Ferenz, R. L., and Kennedy, G. L., Jr. (1986). Fundam.Appl Toxicol. 7, 132-137. Groups of 10 male and 20 female Crl:CD(SD)BRrats were exposed to vapors of dimethylacetamide (DMAC) at concentrationsof 0 (control), 30, 100, or 300 ppm. Exposures were conductedfor 6 hr/day, 5 days/week for 10 weeks (prebreeding), then 7days/week for 7 to 8 weeks (through breeding, gestation, andlactation). The exposure period was interrupted for female ratsbetween gestation Day 21 and postpartum Day 4. No compound-relatedeffects on body weight, survival, or clinical signs were detectedin parental rats. Liver weight to body weight ratios were increasedin groups where both males and females were exposed to 300 ppmbut not in groups where only males or only females were exposedto 300 ppm. No significant differences were observed betweencontrol and test rats with respect to mating performance, fertility,length of gestation, progeny numbers, structure, and viability.At 21 days postpartum, pups derived from matings involving exposureof both sexes to 300 ppm or exposure of parental females to300 ppm had lower body weights than did the controls. Grosspathologic examination of representative pups and evaluationof liver and gonad weight data did not reveal any DMAC-relatedchanges. It is concluded that reproduction in rats was not alteredby repeated inhalation exposure to up to 300 ppm DMAC.     

Enriched environment and acceleration of visual system development

Rearing mice from birth in an enriched environment leads to a conspicuous acceleration of visual system development appreciable at behavioral, electrophysiological and molecular level. Little is known about the possible mechanisms of action through which enriched environment affects visual system development. It has been suggested that differences in maternal behavior between enriched and non-enriched conditions could contribute to the earliest effects of enriched environment on visual development and that neurotrophins, BDNF in particular, might be involved. Here, we examined Brain Derived Neurotrophic Factor (BDNF) levels in the visual cortex during development and showed that an increase occurs in the first week of life in enriched pups compared to standard reared pups; BDNF levels at birth were equal in the two groups. This suggests a postnatal rather than a prenatal effect of environment on BDNF. A detailed analysis of maternal care behavior showed that pups raised in a condition of social and physical enrichment experienced higher levels of licking behavior and physical contact compared to standard reared pups and that enhanced levels of licking were also provided to pups in an enriched environment where no adult females other than the mother were present. Thus, different levels of maternal care in different environmental conditions could act as indirect mediator for the earliest effects of enrichment on visual system development. Some of the effects of different levels of maternal care on the offspring behavior are long lasting. We measured the visual acuity of differentially reared mice at the end of the period of visual acuity development (postnatal day 45) and at 12 months of age, using a behavioral discrimination task. We found better learning abilities and higher visual acuity in enriched compared to standard reared mice at both ages.     

Behavioral effects of prenatal haloperidol exposure

Pregnant albino rats were exposed to vehicle (CON), 2.5 mg/kg (LOW) or 5.0 mg/kg (HIGH) haloperidol (HAL) from the sixth through the twentieth day of gestation. The effect of prenatal HAL exposure on offspring was assessed with the following five behavioral measures: 1) milk-induced behavioral activation on the sixth postnatal day (PND 6), 2) shock-precipitated wall climbing (PNDs 9, 11, 13, 15 and 17), 3) amphetamine-induced stereotypies (PND 30), 4) apomorphine-induced stereotypies (PND 30) and 5) duration of barbiturate anesthesia (PNDs 34 and 62). Measures taken very early in life indicated that prenatal HAL reduced arousal. Inactivity scores were elevated in HAL-exposed pups on PND 6 during milk-induced behavioral activation. Shock-precipitated wall climbing was reduced in the HAL animals on PNDs 9 and 11, but not thereafter. At PND 30, no prenatal treatment effect was detectable on stimulant-induced stereotypies or on duration of barbiturate anesthesia. On PND 62, barbiturate anesthesia duration was significantly reduced in both sexes of HIGH HAL animals. These findings suggest that prenatal HAL effects follow a dynamic, changing course as the exposed rat pup matures. Early reductions in arousal (milk-induced behavior and shock-precipitated wall climbing) wane with age, perhaps to be replaced by an actual increase in arousal as HAL pups approach adulthood.     

Sex differences in hyperalgesia during morphine infusion: effect of gonadectomy and estrogen treatment

Morphine treatment can paradoxically increase nociception (i.e. hyperalgesia). Since there are putative sex differences in nociception and morphine sensitivity, we compared nociception in male and female mice using the tail-withdrawal test during continuous infusion of two morphine doses (1.6 and 40.0 mg/kg/24 h). Both doses caused hyperalgesia in both sexes, but onset in females always preceded that of males. Although the larger dose initially evoked analgesia, naltrexone (NTX) pellets implanted prior to morphine infusion abolished analgesia but not hyperalgesia. Distinct sex differences also characterized each morphine dose. Specifically, the lower morphine dose caused hyperalgesia that dissipated after 6 days in males but persisted in females for a minimum of 14 days. Despite this difference, N-methyl-d-aspartate (NMDA) receptor antagonists reversed hyperalgesia in both sexes. In contrast, the higher morphine dose evoked hyperalgesia that resolved concurrently in both sexes, but hyperalgesia was reversed by NMDA receptor antagonists in males only. Ovariectomy (OVX), but not OVX followed by estrogen treatment, abolished both sex differences, and resulted in females exhibiting the male-typical pattern. This study thus demonstrates NTX-insensitive morphine hyperalgesia in females as previously reported for males. However, females utilized hyperalgesic mechanisms which were distinct from those employed by males. Data from females subject to OVX/estrogen replacement further indicate that females possess functional male-typical hyperalgesic mechanisms, but are diverted from their use by ovarian sex steroids. Finally, the finding that each morphine infusion dose was characterized by a unique sex difference provides additional evidence for distinct multiple hyperalgesic systems.     

Octyl methoxycinnamate: two generation reproduction toxicity in Wistar rats by dietary administration.

Wistar rats continuously received octyl methoxycinnamate (OMC) in the diet through two successive generations at nominal doses of 0, 150, 450 or 1000 mg/kg bw/day. OMC had no adverse effects on estrous cycles, mating behavior, conception, parturition, lactation and weaning, sperm and follicle parameters, macropathology and histopathology of the sexual organs. 1000 mg/kg bw/day reduced parental food consumption and body weight (-14% to -16% in males, -4% to -5% females), increased liver weight, produced hepatic cytoplasmic eosinophilia and erosion/ulceration of glandular stomach mucosa. and led to a slightly decreased implantation rate in the top dose F0 and F1 dams. The high dose F1 and F2 pups had reduced lactation weight gain and organ weights and delayed sexual maturation landmarks. There was no evidence of a selective influence of the test compound on pups' sexual landmarks. The NOAEL (no observed adverse effect level) is 450 mg/kg bw/day for fertility and reproductive performance, for systemic parental and developmental toxicity.     

Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats

Male and female rats were given perfluorooctadecanoic acid (PFOdA) by gavage at 40, 200 or 1,000 mg/kg/day, and each female was mated with a male in the same dose group after 14-day administration. Males were dosed for 42 days and females were dosed throughout the gestation period until day 5 of lactation. One female given 1,000 mg/kg/day was euthanized on day 18 of gestation due to a moribund condition; however, no other treatment-related clinical signs of toxicity were observed. Body weights fell at 1,000 mg/kg/day from day 28 through the administration period in males and throughout gestation and lactation in females. Red blood cell count, hemoglobin level and hematocrit were decreased at 200 and 1,000 mg/kg/day in males and activated partial thromboplastin time was prolonged at 1,000 mg/kg/ day in females. Histopathological examination revealed hepatic changes, such as centrilobular hypertrophy and necrosis, in males given 200 and 1,000 mg/kg/day and in females given 1,000 mg/kg/day. Pancreatic zymogen granule was decreased in both sexes at 1,000 mg/kg/day. As for reproductive and developmental toxicity, there were decreases in the number of corpora lutea, implantation, total number of pups born and the number of live pups on postnatal days 0 and 4 at 1,000 mg/kg/day. At this dose, birth weights of pups were decreased and postnatal body weight gain was inhibited. Based on these findings, the NOAEL of PFOdA was considered to be 40 mg/kg/day for repeated dose toxicity and 200 mg/kg/day for reproductive/developmental toxicity.