The influence of methamphetamine on maternal behavior and development of the pups during the neonatal period

Since it enters breast milk, methamphetamine (MA) abuse during lactation can not only affect the quality of maternal behavior but also postnatal development of pups. The aim of the present study was to examine the effect of injected MA (5 mg/kg) on maternal behavior of rats and the differences in postnatal development, during postnatal days (PD) 1–11, of pups when the pups were directly exposed (i.e., injected) to MA or received MA indirectly via breast milk. Maternal behavior was examined using observation test (PD 1–22) and pup retrieval test (PD 1–12). The following developmental tests were also used: surface righting reflex (PD 1–12), negative geotaxis (PD 9), mid-air righting reflex (PD 17), and the rotarod and beam-balance test (PD 23). The weight of the pups was recorded during the entire testing period and the day of eye opening was also recorded. MA-treated mothers groomed their pups less and returned the pups to the nest slower than control dams. The weight gain of pups indirectly exposed to MA was significantly slower. In addition, pups indirectly exposed to MA were slower on the surface righting reflex (on PD 1 and PD 2) and the negative geotaxis test. In females, indirect exposure to MA led to earlier eye opening compared to controls. At the end of lactation, males who received MA indirectly via breast milk performed worse on the balance beam test compared to males who received MA directly. However, direct exposure to MA improved performance on rotarod relative to controls. Our results suggest that indirect MA exposure, via breast milk, has a greater impact than direct MA exposure.     

Hormonal basis during pregnancy for the onset of maternal behavior in the rat

This article reviews the current state of our knowledge about the hormonal basis of maternal behavior in the rat. Considered are the ovarian hormones estrogen and progesterone, the pituitary hormones beta-endorphin and prolactin, and the hormone oxytocin, secreted by several hypothalamic nuclei and associated brain regions. The hormones of pregnancy, estrogen and progesterone, prime the female to respond to a terminal rise in estrogen that stimulates a high level of maternal responsiveness even before parturition begins. Studies on the role of prolactin, using hypophysectomy, prolactin release blockers and anterior pituitary and prolactin replacement, indicate that prolactin is required for the ovarian hormones to be effective in stimulating maternal behavior. During the latter half of pregnancy, placental lactogen may displace prolactin in this role. Although prolactin serves as a chronic stimulus for maternal behavior, it also may act over a short period. Oxytocin stimulates maternal behavior in a specific strain of rat, but not in other strains, and only when administered introcerebroventricularly (ICV) in estrogen-primed females. The decline in the high brain levels of beta-endorphin around parturition has been proposed as a requirement for the onset of maternal behavior; morphine blocks the onset of maternal behavior and disrupts ongoing maternal behavior and maternal aggression in lactating females. However, blocking beta-endorphin action at parturition interferes with pup cleaning and eating of the placenta as well.     

Effects of prenatal stress on maternal behavior in the rat

Some authors reported a link between maternal stress and disturbances in their infants. Because of difficulties due to human research, the effects of prenatal stress have to be examined in animal models. Our approach was original in that the stressor was an ecological one and was applied at a given gestational day. Indeed, the stressor was a cat and the effects of stress on maternal behavior were investigated in five groups of 10 female rats: two groups were composed of females which were acutely stressed either at the 10th or the 14th gestational day; two other groups were composed of females which were repeatedly stressed either at the 10th or the 14th gestational day; the fifth group comprised non-stressed females. Plasma corticosterone concentrations measured in blood samples collected from dams just after stress were significantly higher than in controls showing that cat represents an efficient stressor for rats. Maternal behavior was recorded during 30 min at the 2nd, 4th, and 6th postnatal days. In all cases, stressed dams' activities directly directed towards the pups (retrieving, sniffing and licking), those non-directly directed towards the pups (carrying its tail and digging the sawdust), and those directed towards themselves (eating, drinking and resting) were altered to different degrees. These alterations in maternal behavior can explain, at least in part, the mortality and the low growth rate observed in pups born from stressed dams.     

Repeated morphine administration during pregnancy attenuates maternal behavior

The present study tested the hypothesis that repeated administration of morphine on days 11-18 of pregnancy alters maternal behavior. Saline- and morphine-treated mothers were observed with their pups in two experiments. Rats were always tested twice a day during the light and dark phases of the reverse light/dark cycle. In Experiment 1, 12 types of activities and three types of nursing positions of mothers were recorded ten times during each 50-minute session for the 23-day lactation period. A decrease in nursing and active maternal behavior, and an increase in self-care, rearing and sniffing was found in morphine-treated mothers. Additionally, both saline- and morphine-treated mothers exhibited significantly more maternal behavior during the light, and non-maternal activities during the dark sessions of each day. Moreover, both saline- and morphine-treated mothers displayed significantly less maternal behavior and more non-maternal activities as postpartum time progressed. In Experiment 2, a different group of mothers was tested for pup retrieval from postnatal days 1 through 12. Morphine-treated mothers were slower than saline-treated mothers in retrieving all pups into the nest. However, there were no differences in latency to carry the first pup and return him/her to the nest. No unusual maternal behaviors were observed during the retrieval tests. Thus, the present study suggests that morphine administration during the second half of pregnancy attenuates some components of maternal behavior and increases non-maternal activities of mothers.     

Firing patterns of maternal rat prelimbic neurons during spontaneous contact with pups

Extracellular single unit activity was recorded from medial prefrontal cortex (mPFC) of postpartum dams over the course of 3 days while they engaged in spontaneous pup-directed behaviors and non-specific exploratory behavior. Out of 109 units identified over the course of the experiment, 15 units were observed to be pup-responsive and 15 increased their discharge rates non-specifically while not attending to pups. An association between neuronal activity and typical maternal behaviors (e.g., retrieval, pup-grooming, nursing) was not observed. Instead, brief bouts of snout contact with pups were accompanied by phasic increases and decreases in spike rates. The observed pup contact responsive cells might play a role in processing of sensory feedback from pups or the transmission of modulatory output to other subcortical maternal brain areas.     

The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression

Depression is associated with hippocampus (HC) volume loss. Chronic mild stress (CMS) in rats is a model of depression. Antidepressants attenuate HC volume loss and reverse the depression-like symptoms of stressed animals. We evaluated the effect of CMS and the selective serotonin reuptake inhibitor, fluoxetine (FLX) treatment on behavioral and cognitive parameters in rats, and on HC and frontal cortex (FC) neurotrophic factors levels. Male rats were exposed sequentially, over a period of 5 weeks, to a variety of mild stressors. FLX (5 mg/kg/day ip) was administered to the stressed group and controls (unstressed). After 5 weeks of CMS, animals were tested using the Morris Water Maze (MWM). In the MWM, we observed that FLX had a transitory effect on unstressed rats. CMS reduced insulin-like growth factor-1 receptor (IGF-1R) levels in the HC whereas after FLX treatment these levels reverted to normal range. CMS rats revealed a significant decrease in extracellular signal-regulated kinase (ERK) phosphorylation in both HC and FC regions, while FLX normalized these levels. This study suggests that IGF-1R and ERK may have a role in mediating the neural stress response and the mode of action of FLX. This role seems to be independent of the BDNF alterations.     

Repeated restraint stress and corticosterone injections during late pregnancy alter GAP-43 expression in the hippocampus and prefrontal cortex of rat pups

In the offspring of prenatal stress animals, overactivity and impaired negative feedback regulation of the hypothalamic–pituitary–adrenal axis are consistent finding. However, little was known about how prenatal stress can permanently alter developmental trajectories of pup's brain. Growth-associated protein-43 (GAP-43) is a presynaptic membrane phosphoprotein whose expression increases during developmental events such as axonal outgrowth or remodeling and synaptogenesis. Phosphorylation of GAP-43 by protein kinase C was correlated with enhanced axonal growth and transmitter release. In adult animals, increase of GAP-43 correlated with monoaminergic deficit in neuropsychiatric disorders. The present study examines the effects of repeated maternal restraint stress on the level of GAP-43 in the brain of rat pups. The results showed that prenatal stress significantly increased GAP-43 level in the PFC of rat pup during PND 7–14 as compared to control but not significant difference when observed at PND 21. Increased GAP-43 expression was also observed in the pup's hippocampus during the same postnatal periods. However, when observed at PND 60, pups born from stressed mother showed a significant lower (p < 0.001) GAP-43 expression as compare with control group. These changes indicate the direct effect of corticosteroid hormone, since repeated maternal injection with corticosterone (CORT, 40 mg/kg) during GD 14–21 also gave the same results. PND 7–14 is the peak period of synaptogenesis in these brain areas and abnormal axon sprouting and reorganization may lead to a defect in synaptic pruning at later stage of life. The results suggested that maternal stress is harmful to the developing brain and upregulation of GAP-43 indicated a protective mechanism against the toxicity of maternal stress hormone. Prenatal stress alter the normal developmental trajectories in the pup's brain may underlies the mechanism link between early life stress and neuropsychopathology in later life.     

Administration of 17alpha-ethinylestradiol during pregnancy elicits modifications of maternal behavior and emotional alteration of the offspring in the rat

Intraperitoneal administration of 17alpha-ethinylestradiol (15 microg.kg(-1)) in pregnant rats, every day from day 9 to day 14 of pregnancy, elicited a high percentage of abortions. Quantification of maternal behavior showed that treated dams took better care of their pups than control dams, injected with the vehicle only, did. Postnatal reflexes, which reflect maturational rate, were established more promptly in the offspring of treated dams than in the offspring of control dams. However, when adult, the rats born from treated dams developed anxiety- and depressive-like behaviors. All these results are explained by the effects of the exogenous estrogen on the developing brain of the fetuses.     

The effects of genetic liability for schizophrenia and maternal smoking during pregnancy on obstetric complications

The purpose of this study was to determine whether a genetic vulnerability for schizophrenia and/or health-risk behaviors among schizophrenic pregnant women were associated with an increased incidence of obstetric complications (OCs). METHOD: A high-risk birth cohort was formed by searching the Finnish Perinatal Register for all births from 1991-2000 with arterial cord pH values below 7.20, an indication of fetal asphyxia. This database was merged with national hospital discharge registries to determine psychiatric morbidity of the mothers and the mothers' first-degree relatives. Mothers were divided into 3 groups: women diagnosed with schizophrenia/schizoaffective disorder (n=53), mothers with a first-degree relative with schizophrenia/schizoaffective disorder (n=590) and healthy controls (n=36,895). RESULT: Schizophrenic women had significantly more OCs than mothers with a first-degree schizophrenic relative and controls. These women had significantly increased rates of eclampsia, premature delivery, prenatal hospitalizations, and marginally significant increases in high blood pressure. Offspring of schizophrenic mothers had significantly decreased APGAR scores and birth weight and increased medical complications after birth. In contrast, women with a schizophrenic first-degree relative had no significant increases in OCs compared to controls. Schizophrenic mothers also smoked more than the other groups and smoking was found to mediate the relationship between maternal schizophrenic status and decreased birth weight among offspring. CONCLUSIONS: Maternal schizophrenia during pregnancy leads to an increased risk of OCs, possibly due to engagement in health-risk behaviors during pregnancy, such as smoking, whereas genetic susceptibility to schizophrenia, by itself, does not appear to be related to incidence of OCs.     

Bisphenol-A exposure during pregnancy and lactation affects maternal behavior in rats

In mammals, endogenous estrogens are crucial for sexual differentiation during the perinatal period, and the modulation in adulthood of many neuroendocrine and behavioral functions involved in reproduction. In rats, the estrogenic environment during pregnancy and lactation affects directly maternal behavior. This experiment was aimed to test whether the exposure to the estrogenic compound bisphenol-A (BPA; 0.040 mg/kg/die, orally) of adult female rats, from mating to weaning of the pups, could alter maternal behavior. An appropriate methodology was applied to reveal differences in the behavior of dams directed to male and female pups, testing the dams on postnatal days 3-4 and 8-9. Results show different maternal behavioral patterns towards male and female pups of control mothers, with more ano-genital licking to males than to females. Exposure of mothers to BPA modified their behavior, reducing specific components of maternal behavior, both active and passive, irrespective of the sex of pups and the period of observation. This experiment shows that maternal behavior is affected by a prolonged exposure to a low dose of BPA during pregnancy and lactation, thus suggesting an effect on neural circuits in adulthood.     

Early weaning deprives mouse pups of maternal care and decreases their maternal behavior in adulthood

Weaning is one of the most important events in the early stage of life, and recently we have found that precocious weaning augments anxiety and aggressiveness in mice. Maternal behavior has been reported to be transmitted from one generation to the next; that is, female pups that received intensive maternal care showed higher maternal behavior in their adulthood. In the present study, the following three experiments were conducted to understand maternal behavior transmission in early-weaned mice that were separated from the dam on postnatal day 14. First, the maternal behavior observed from the postpartum day 15 to 21, which was deprived in the early-weaned mice, were analyzed. Mothers spent 3% of their time on licking/grooming and arched-back nursing of their pups on postpartum day 15, and the time spent on these behaviors was gradually decreased until postpartum day 21; however, they spent 50% of their time attending to their pups through postpartum days 15-21. Simultaneously, the behavior of the pups was monitored, and it was found that the early-weaned mice had higher activity and lower resting behavior over the period from postnatal day 15 to 21. Secondly, the early- and normally weaned female mice were subjected to an elevated plus maze test at the age of 8 weeks to assess their anxiety level. The early-weaned mice showed a lower frequency of entering the open arms, and a shorter duration of time spent within them, as compared to the normally weaned mice, suggesting that early-weaned females had a higher anxiety level. In the third experiment, the two groups of female mice were paired with adult male mice for 2 weeks, and the mother's maternal behavior was analyzed. The early-weaned female mice showed lower frequency of licking/grooming and arched-back nursing of their pups as compared to the normally weaned mice, whereas the time of mother-off pups and attending to pups were not different between groups. These results suggest that early-weaning manipulation deprives offspring of a certain level of maternal care, and as a consequence, the offspring show higher anxiety levels and lower maternal behavior in their own adulthood.     

Interacting effects of oxazepam in late pregnancy and fostering procedure on mouse maternal behavior

The present study was designed to assess the proactive effects of late pregnancy benzodiazepine (BDZ) treatment on maternal behavior in the postpartum period, using cross-fostering procedures to control for the role of changes produced prenatally in the offspring. Outbred CD-1 mouse dams were treated with either oxazepam (OX, 15 mg/kg PO twice/day on pregnancy days 12-16) or vehicle (VEH). After parturition, entire litters were exchanged either within treatments (in-fostered groups, IF) or between treatments (cross-fostered groups, CF), while additional litters were left undisturbed (un-fostered groups, UF). The behavior of lactating dams was observed in their home cages at 4, 8, and 12 days postpartum. Maternal responses, particularly nursing, were reduced in the OX-UF and OX-CF conditions and either normal or enhanced in the OX-IF condition. Correspondingly, locomotor/exploratory activity was markedly enhanced in the former conditions and close to the control level in the latter condition. In sum, the fostering variable appeared to determine whether pups raised by dams treated previously with BDZ receive either insufficient or exaggerated maternal care. This points to the need for a better understanding of mother/pup interactions in studies aimed at characterizing drug and toxicant effects on offspring development.     

Anti-inflammatory agents attenuate the passive responses of guinea pig pups: evidence for stress-induced sickness behavior during maternal separation

A previous study found that intracerebroventricular (ICV) infusion of 25 microg of alpha-MSH reduced the passive responses (crouched stance, eye-closing, piloerection) of guinea pig pups during a 3-h isolation in a novel environment. Because alpha-MSH has broad anti-inflammatory properties, the results suggested that proinflammatory factors play a role in mediating the behavior of isolated infants. The present study further investigated this possibility. In Experiment 1, injection of lipopolysacchride (LPS) increased the number of 60-s intervals in which pups expressed the same three responses during a 1-h test, and ICV infusion of alpha-MSH significantly reduced the effect of LPS on crouching and piloerection. In Experiment 2, the prostaglandin synthesis inhibitor indomethacin (10 mg/kg) reduced the number of 60-s intervals in which pups exhibited both crouching and the full suite of passive responses during a 3-h isolation in a novel environment. Together these results provide further support for the hypothesis that the passive behaviors exhibited during prolonged isolation are "stress-induced sickness behaviors" mediated by proinflammatory factors.     

Second generation effects of maternal alcohol consumption during pregnancy in rats

1. Previous studies have shown that when female rats are administered alcohol during pregnancy there are adverse effects on their progeny, including decreased birth weight and delayed neuromotor development. Evidence from several sources suggests alcohol exposure may contribute to cytogenetic abnormalities, suggesting the possibility of cross generational effects from prenatal exposure. 2. On day 1 of gestation female rats were randomly allocated to the Alcohol group, which received a liquid diet containing 5% (v/v) ethanol solution until parturition, the Sucrose control group, which received an identical diet, except that sucrose had been isocalorically substituted for ethanol, or the Chow control, which received standard laboratory chow. 3. When the offspring of these rats reached adulthood they were mated with drug-free rats and the development of their offspring was monitored. 4. In comparison with female pups whose sires had been exposed to alcohol in utero, the weight of pups descended from fetally-exposed dams increased more slowly from day 1 to day 7. 5. At five days of age, significant differences favouring the two control groups were found in latency to right for pups descended from fetally-exposed dams. 6. These data suggest that the effects of prenatal exposure to alcohol are more pervasive than previously thought and affect female pups to a greater extent than males.