Gender differences in behavioral changes elicited by prenatal methamphetamine exposure and application of the same drug in adulthood

The aim of the present study was to compare the response to sub‐chronic application of methamphetamine (MA) in adulthood in male and female rats prenatally exposed to the same drug. The spontaneous locomotor activity and exploratory behavior of adult male and female rats prenatally exposed to 5 mg/kg MA or saline (SAL) were tested in a Laboras apparatus (Metris B.V., Netherlands) for five consecutive days, 1 hr daily. MA 1 mg/kg or SAL were used as a challenge prior to testing. Our results showed that rats prenatally exposed to MA were more sensitive to sub‐chronic administration of MA in adulthood than prenatally SAL‐exposed rats. However, this sensitizing effect of prenatal MA exposure was manifested differently in males and females. In contrast, prenatal MA exposure decreased baseline locomotion in females. This study indicates that gender plays an important role in the sensitivity to MA during prenatal development and in adulthood. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 232–242, 2013     

Phosphodiesterase type 1 inhibition improves learning in rats exposed to alcohol during the third trimester equivalent of human gestation

Deficits in learning and memory have been extensively observed in animal models of fetal alcohol spectrum disorders (FASD). Here we use the Morris maze to test whether vinpocetine, a phosphodiesterase type 1 inhibitor, restores learning performance in rats exposed to alcohol during the third trimester equivalent of human gestation. Long Evans rats received ethanol (5 g/kg i.p.) or saline on alternate days from postnatal day (P) 4 to P10. Two weeks later (P25), the latency to find a hidden platform was evaluated (2 trials per day spaced at 40-min inter-trial intervals) during 4 consecutive days. Vinpocetine treatment started on the first day of behavioral testing: animals received vinpocetine (20 mg/kg i.p.) or vehicle solution every other day until the end of behavioral procedures. Early alcohol exposure significantly affected the performance to find the hidden platform. The average latency of ethanol-exposed animals was significantly higher than that observed for the control group. Treatment of alcohol-exposed animals with vinpocetine restored their performance to control levels. Our results show that inhibition of PDE1 improves learning and memory deficits in rats early exposed to alcohol and provide evidence for the potential therapeutic use of vinpocetine in FASD.     

Sex differences in anxiety-like behavior and locomotor activity following prenatal and postnatal methamphetamine exposure in adult rats

The aim of the present study was to investigate the impact of prenatal and postnatal methamphetamine (MA) exposure on behavior and anxiety in adult male and female rats. Mothers were daily exposed to injection of MA (5 mg/kg) or saline (S): prior to impregnation and throughout gestation and lactation periods. On postnatal day 1, pups were cross-fostered so that each mother raised 6 saline-exposed pups and 6 MA-exposed pups. Based on the prenatal and postnatal exposure 4 experimental groups (S/S, S/MA, MA/S, MA/MA) were tested in the Open field (OF) and in the Elevated plus maze (EPM) in adulthood. Locomotion, exploration, immobility and comforting behavior were evaluated in the OF, while anxiety was assessed in the EPM. While prenatal MA exposure did not affect behavior and anxiety in adulthood, postnatal MA exposure (i.e. MA administration to lactating mothers) induced long-term changes. Specifically, adult female rats in diestrus and adult males postnatally exposed to MA via breast milk (S/MA and MA/MA) had decreased locomotion and exploratory behavior in the OF and showed increased anxiety-like behavior in the EPM when compared to female rats in diestrus or males postnatally exposed to saline (S/S and MA/S). In adult females in proestrus, postnatal exposure to MA affected only exploratory behavior in the OF when compared to rats in proestrus postnatally exposed to saline. Thus, the present study shows that postnatal exposure to MA via breast milk impairs behavior in unfamiliar environment and anxiety-like behavior of adult male and female rats more than prenatal MA exposure.     

Prenatal cocaine exposure increases heart susceptibility to ischaemia–reperfusion injury in adult male but not female rats

The present study tested the hypothesis that prenatal cocaine exposure differentially regulates heart susceptibility to ischaemia–reperfusion (I/R) injury in adult offspring male and female rats. Pregnant rats were administered intraperitoneally either saline or cocaine (15 mg kg⁻¹) twice daily from day 15 to day 21 of gestational age. There were no differences in maternal weight gain and birth weight between the two groups. Hearts were isolated from 2-month-old male and female offspring and were subjected to I/R (25 min/60 min) in a Langendorff preparation. Preischaemic values of left ventricular (LV) function were the same between the saline control and cocaine-treated hearts for both male and female rats. Prenatal cocaine exposure significantly increased I/R-induced myocardial apoptosis and infarct size, and significantly attenuated the postischaemic recovery of LV function in adult male offspring. In contrast, cocaine did not affect I/R-induced injury and postischaemic recovery of LV function in the female hearts. There was a significant decrease in PKCɛ and phospho-PKCɛ levels in LV in the male, but not female, offspring exposed to cocaine before birth. These results suggest that prenatal cocaine exposure causes a sex-specific increase in heart susceptibility to I/R injury in adult male offspring, and the decreased PKCɛ gene expression in the male heart may play an important role.     

Stress responses of adolescent male and female rats exposed repeatedly to cat odor stimuli,and long‐term enhancement of adult defensive behaviors

In order to characterize the short‐ and long‐term effects of repeated stressor exposure during adolescence, and to compare the effects of using two sources of cat odor as stressor stimuli, male and female adolescent rats (postnatal day (PND) ～ 38–46) were exposed on five occasions to either a control stimulus, a cloth stimulus containing cat hair/dander, or a section of cat collar previously worn by a cat. Relative to control stimulus exposure, activity was suppressed and defensive behavior enhanced during exposure to either cat odor stimulus (most pervasively in rats exposed to the collar). Only cloth‐exposed rats showed elevated levels of corticosterone (CORT), and only after repeated stressor exposure, but interestingly, rats exposed to the collar stimulus during adolescence continued to show increased behavioral indices of anxiety in adulthood. In this group, the time an individual spent in physical contact with a cagemate during the final adolescent exposure was negatively related to stress‐induced CORT output in adulthood, which suggests that greater use of social support during adolescent stress may facilitate adult behavioral coping, without necessitating increased CORT release. These findings demonstrate that adolescent male and female rats respond defensively to cat odor stimuli across repeated exposures and that exposure to such stressors during adolescence can augment adult anxiety‐like behavior in similar stressful conditions. These findings also suggest a potential role for social behavior during adolescent stressor exposure in mediating long‐term outcomes. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 551–567, 2013     

Swimming exercise ameliorates depression-like behaviors induced by prenatal exposure to glucocorticoids in rats

Prenatal exposure to glucocorticoids (GCs) leads to affective dysfunction in adulthood, which may be associated with the alterations in hypothalamic–pituitary–adrenal (HPA) axis. Physical exercise has been shown to ameliorate depressive symptoms. The objectives of present study were to investigate whether prenatal exposure to GCs induces depression-like behaviors in adult offspring rats, and determine whether swimming exercise alleviates the depression-like behaviors induced by this paradigm. Pregnant rats received dexamethasone (DEX) (0.1 mg/kg/day) in the last third of pregnancy or vehicle. DEX treatment reduced body weight in 1, 3, 6, 9-week old male offspring, and 3, 6, 9-week old female offspring. DEX treatment resulted in an elevated level of serum corticosterone in adult offspring (9 weeks). Female and male adult offspring rats exhibited decreased number of poking into holes and rearing and decreased central distance traveled in open field test (OFT), and reduced sucrose consumption, suggesting prenatal DEX exposure increase depression-like behaviors in the adult offspring rats. Four-week swimming exercise reduced serum corticosterone levels, and alleviated the depressive behavior by reversing the decreased number of poking into holes and rearing as well as decreased central distance traveled, and reversing the reduced sucrose consumption in male and female adult offspring. These findings suggested prenatal exposure to GCs increase the activity of HPA axis and depression-like behaviors of adult offsprings. Swimming exercise decreases HPA activity and ameliorates depression in rats exposed to DEX prenatally.     

Differences in hormonal and inflammatory parameters in male Lewis and Long Evans rats with adjuvant arthritis

The purpose of the present study was (i) to compare secretory responses of prolactin and corticosterone to the acute stress of immobilization in male rats of the Lewis and Long Evans strains and (ii) to compare secretion of the two hormones in rats with fully developed adjuvant arthritis (AA) and their relationship with the intensity of the inflammatory reaction. A short immobilization of 5 min induced equal elevations of both hormones in both strains, but 20-min immobilization produced significantly stronger responses in Long Evans rats than in Lewis rats. AA inhibited prolactin secretion equally in both strains (from 11.6 +/- 1.3 ng/ml to 4.2 +/- 0.6 ng/ml in Lewis rats, p < 0.01, and from 3.7 +/- 0.6 to 2.12 +/- 0.1 ng/ml in Long Evans rats, p < 0.05), but caused a conspiciously larger elevation of corticosterone in the Long Evans than in the Lewis animals (11.5 +/- 1.2 microg/dl in Long Evans rats versus 5.1 +/- 0.5 microg/dl in Lewis rats, p < 0.01) while basal levels were similar. The larger corticosterone response in the Long Evans rats was associated with a stronger inflammatory reaction assessed by hind paw swelling (2.3 +/- 0.1 ml for Long Evans rats versus 1.8 +/- 0.08 ml for Lewis rats, p < 0.01) and plasma levels of nitric oxide (47.5 +/- 5.7 microM for Long Evans rats versus 28.7 +/- 2.5 microM for Lewis rats, p < 0.01) than in the Lewis males with lower corticosterone levels. In conclusion, there are significant, obviously genetically based, differences in the corticosterone responses to both immobilization and AA between the two strains, with the Long Evans rats reacting more strongly than the Lewis rats. The lack of the expected inverse relationship between corticosterone levels and the intensity of the inflammation indicates that the activity of corticosterone is not its primary determinant and that other important factors are involved.     

Pacing conditions contribute to the conditioned ejaculatory preference for a familiar female in the male rat

Male rats show greater unconditioned sexual arousal and mating preference for a novel female compared to a familiar one. However, they also display a conditioned preference to ejaculate with a female bearing an odor paired previously with copulation to ejaculation, suggesting that their copulatory strategies are not fixed. The aim of the present study was to examine if males might prefer a familiar or a novel female after repeated copulation with the same female in a pacing chamber bisected by a 1-hole or a 4-hole divider. Sexually na?ve male Long Evans rats were assigned to copulate with the same almond-scented or unscented female in a 1-hole or 4-hole pacing chamber for 10 conditioning trials at 4-day intervals. Four days following the last trial, each male was given a partner preference test during which they had the choice to copulate with either the familiar or a novel scented or unscented female. Results showed that males trained to copulate in 1-hole pacing chambers developed a conditioned ejaculatory preference for their familiar almond-scented female. However, if the familiar female was not scented with almond odor or if a novel female was bearing the almond odor, 1-hole trained males failed to display conditioned ejaculatory preference. Males trained in the 4-hole condition did not display a conditioned ejaculatory preference. These findings indicate that pacing conditions in which males have restricted access to the female contribute to the conditioned ejaculatory preference for familiar females bearing a neutral odor.     

Infantile handling and sex differences in shock-elicited aggressive responding of hooded rats

Infantile handled (Days 1-20) and nonhandled, male and female Long Evans hooded rats were tested at maturity (90-100 days) over 10 daily sessions for aggressive response to footshock. Individual jump and flinch thresholds for reactivity to shock, as well as paired aggressive responding to shock, were not significantly influenced by the handling procedure, although handled females ultimately adopted higher levels of fighting than nonhandled females. Handled rats were heavier than nonhandled rats of the same sex before and after testing for social aggression. Males fought significantly more than females; the discrepancy increased with additional sessions of paired exposure to shock. Male and female fight trends over sessions were linear and positive with a greater acceleration for males. The results were interpreted as indicative of a social learning variable occurring with repeated aggressive contact and primarily affecting males.     

Effects of consanguinity, exposure to pregnant females, and stimulation from young on male gerbils' responses to pups.

In three experiments investigating variables affecting responses of male Mongolian gerbils to conspecific young, we compared the behavior directed towards pups of natural fathers, virgin foster fathers, and sexually experienced foster fathers (Experiment 1); males either previously exposed or not exposed to pregnant females (Experiment 2); and males provided or not provided with extra opportunities to huddle over pups (Experiment 3). We found no difference in responses to pups among natural fathers, virgin foster fathers, and foster fathers that had fathered litters. On the other hand, both a week of exposure to a pregnant female and opportunity to huddle over pups for an extra 15 min/day had significant effects on males' subsequent responses to conspecific young. We speculate on the reasons why a male's response to pups might be affected by his exposure to a pregnant female and stimuli from pups, but not by the probability that the pups were his own offspring.     

Effects of copulation on reproductive function in aged female rats

Old female rats in persistent vaginal estrus (PVE) were exposed to varying degrees of copulatory stimulation. While limited mating experiences had no noticeable effects on reproductive function, cohabitation with sexually vigorous males or other forms of exposure to extended mating experiences disrupted the PVE state. Prolonged diestrus, irregular cycles, pseudopregnancy and pregnancy were observed subsequent to extensive copulatory experiences. Except for a tendency to be less receptive to initial mounts old females displayed sexual behavior comparable to that observed in younger, virgin animals. Ten or more intromissions disrupted the PVE. Induction of pregnancy or pseudopregnancy appears to require 30 or more intromissions in these animals. It is concluded that the PVE observed in aged female rats is at least partly due to the absence of coital stimulation. These observations are taken to suggest that age-related changes in the reproductive capacity of female rats may be attributable to alterations in the sensitivity of ovulatory and progestational mechanisms to hormonal and sensory influences.     

Comparison of medial preoptic, amygdala, and nucleus accumbens lesions on parental behavior in California mice (Peromyscus californicus)

We have previously shown that medial preoptic area (MPOA) lesions disrupt parental behavior in both male and female California mice (P. californicus). In the present study, we compare the effects of lesions in the MPOA, with those in the basolateral amygdala (BA) and nucleus accumbens (NA) on male and female parental behaviors in the biparental California mouse. A male or multiparous female from each male-female pair was given an electrolytic or sham lesion in the MPOA, BA, or NA and tested for parental responsiveness. Since female P. californicus show postpartum estrus, they were likely pregnant during parental testing. MPOA lesions produced deficits in both male and female parental behaviors, and BA lesions disrupted male, and to a lesser extent, female parental behavior. NA lesions produced mild effects on pup-retrieval in males and no effect on parental behavior in females. However, NA lesions incompletely destroyed the NA shell, the region most relevant for maternal behavior in rats, and should be investigated further. These results support a role for the MPOA and BA in both male and female parental behaviors.     

Endothelin-1 exposure on postnatal day 7 alters expression of the endothelin B receptor and behavioral sensitivity to endothelin-1 on postnatal day 11

Endothelin (ET)-1 is a chemical mediator released by the body at sites of injury and disease and is involved in various painful states. This study examined whether ET-1 exposure in the neonatal period alters subsequent ET-1 induced nociception and expression of the ET_B receptor. ET-1 or saline was administered to postnatal day 7 rats. On postnatal day 11, ET-1 or saline was administered; a first exposure to ET-1 for one group, and a second exposure to ET-1 for another group. A statistically significant increase in ET-1 induced paw flinching was observed in postnatal day 11 male rats exposed to ET-1 for the second time as compared to male rats exposed to ET-1 for the first time. In contrast, a statistically significant decrease in ET-1 induced paw flinching was observed in postnatal day 11 female rats exposed to ET-1 for the second time as compared to female rats exposed to ET-1 for the first time. Furthermore, in males a positive correlation was found between ET-1 induced paw flinching on postnatal day 7 versus 11. In contrast, in females a negative correlation was found between ET-1 induced paw flinching on postnatal day 7 versus 11. Changes in behavioral sensitivity to ET-1 were accompanied by sex-specific ET-1 induced changes in expression of the ET_B receptor on postnatal day 11 in the plantar hind paw with a statistically significant decrease and increase in ET_B receptor expression in males and females, respectively. These findings suggest that ET-1 exposure in the neonatal period sex-specifically alters expression of the ET_B receptor and behavioral sensitivity to ET-1 whereby males show sensitization and females show de-sensitization.     

Sensory mediation of female-male mounting in the rat: II. Role of tactile and conspecific cues

Although previous research has shown that olfactory cues mediate female-male mounting (FMM) in the rat, the role of other sensory modalities on FMM has not been investigated. The present study examined the display of female mounting of castrated male rats in bilevel chambers following different tactile or locomotor activity manipulations. Female rats (N = 40) were ovariectomized (OVX), primed with estrogen (E) and progesterone (P), and given either vaginocervical stimulation (VCS), flank/perineum stimulation (FPS), combined VCS and FPS, or general handling, immediately before each test with a castrated male rat for five trials. Compared to handling, the FPS females showed an increase in FMM behavior, whereas females given VCS, or combined VCS and FPS, showed a decrease in FMM behavior. A second experiment examined the effect of a 15-min delay between stimulation and testing using identical experimental and control conditions. There were no significant differences in the amount of FMM behavior between these groups. Finally, OVX rats primed with E and P were tested with castrated males that had been given injections of a ketamine/xylazine anesthetic mixture, saline, or amphetamine, to induce three levels of conspecific locomotor activity: none, moderate, or high, respectively. A positive linear relationship was found between male activity level and FMM. These data indicate that both tactile cues and cues associated with locomotor activity of the stimulus male modulate FMM.     

Development of defensive behavior and conditioning to cat odor in the rat

Laboratory rats show a range of defensive behaviors, including freezing, avoidance, and risk assessment upon exposure to cat odor, an unconditioned but highly effective threat stimulus. This study examined defensive behaviors, and the rapid conditioning to context plus cue, of these behaviors, in 18-, 26-, and 38-day-old male and female rats exposed to cat odor. Rats were placed individually in a runway with a cloth covered (control or saturated with cat fur/skin odor) block for a 10-min trial. On the following day, a similar trial involved an odorless block. On the odor exposure day, rats of all ages showed less contact with the odor block than with the control block. The 26- and 38-day-old rats, but not the 18-day-old rats, also showed locomotor suppression, more avoidance of the area where the odor block was located, and more risk assessment than no-odor controls. On a test of conditioned behavior 24 h following exposure, 26- and 38-day-old rats exhibited defensive behavior including avoidance and reduction of locomotion while 18-day-old pups did not.     

Plasma testosterone concentration in adult male rats following acquisition of copulation-illness associations.

Prior research has identified stimuli and procedures that elicit increments in plasma testosterone in copulating male rats. In the present experiment, we demonstrate that associative inhibition of copulatory behaviors in male rats is not correlated with and cannot be attributed to a conditioned suppression of testosterone. Each male rat was paired with an inaccessible estrous female for 7 min and was then given an opportunity to copulate. Two groups received an injection of either lithium chloride (LiCl; 0.3 M, 20 ml/kg, IP) or saline (0.3 M, 20 ml/kg, IP) immediately after each of 11 pairings spaced at 3- to 4-day intervals. A third group received a noncontingent injection of LiCl 24 h after each pairing. After an initial screening for copulatory behaviors, a fourth group received only handling comparable to that received by the other three groups. Rats that received contingent LiCl gradually ceased to copulate; rats that received either noncontingent LiCl or saline remained vigorous copulators. Male rats were returned to their home cages on Trial 12 after 7-min exposure to an inaccessible female. Blood was collected by decapitation 38 min later. Testosterone levels, measured by radioimmunoassay, were significantly higher for saline than for handled control rats. Testosterone levels for handled control rats, however, were comparable to those of copulating and noncopulating rats that had received either noncontingent or contingent LiCl, respectively.     

Long maternal separation has protective effects in rats exposed to activity‐based anorexia

This study examined the effect of three neonatal treatments of maternal separation during infancy in young adult rats exposed to standard activity‐based anorexia (ABA) consisting of food restriction plus free access to an activity wheel. During the first 20 postnatal days of life rat pups were exposed to periods of either brief maternal separation (BMS, 15 min), long maternal separation (LMS, 180 min), or were non‐handled (NH). Thereafter, male and female rats were exposed to ABA. Neonatal treatment produced no significant differences in the survival time of male rats, whereas survival was greater in female rats exposed to LMS than in NH rats under ABA procedure. In conclusion, prolonged maternal separation appears to promote resistance in female animals subjected to harsh ABA life‐threatening conditions. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 616–624, 2009     

Sensory control of shock-elicited fighting in rats

Intact vibrissal organs have been implicated as requisite for normal shock-elicited fighting in paired male rats and may convey the principal sensory information contributing to conspecific intermale aggression. Anesthesia of the vibrissal pad prior to each paired footshock exposure completely blocked the attack behavior of experimentally naive rats. Suppression of fighting was effective in all pairs tested over 14 daily sessions. Devibrissaed pairs also fought less than controls but gradually attained normall levels of fighting in spite of repeated clipping of all vibrissae to prevent significant regrowth. The results demonstrate an evident behavioral distinction between anesthesia of the vibrissal pad and removal of the vibrissae. General epidermal sensation from the snout appears to be necessary for initiating social fighting between paired males exposed to irritable shock.