The effects of cocaine on maternal behaviors in the rat.

Although recent research has focused on the behavioral teratology of cocaine, there has been little attention centered on the effects of cocaine use on parenting behaviors after birth. This experiment investigated the effects of cocaine on parental (generally termed maternal) behavior in the rat. Four types of adult rats were tested for these effects over a 10-day testing period: lactating primiparous female dams, primiparous females, nulliparous females, and males. Subjects were injected daily with cocaine (5 mg/kg) or saline. Ten minutes postinjection each subject was placed in a cage with three stimulus pups and nesting material, and observed for several measures of maternal behavior for 5 minutes, including sniffing, licking, and retrieving pups. Subjects were also rated on a maternal behavior scale at 60 minutes and 24 hours postinjection, and on nest quality. Cocaine reduced both the total number and duration of sniffing and licking maternal behaviors, and resulted in a lower maternal behavior rating at 60 minutes compared to saline-treated subjects. Among those subjects that retrieved pups within the first 5 minutes, cocaine-injected subjects retrieved for a longer duration. These results also suggest impaired maternal behavior, since rapid retrievals would have been more efficient in maintaining a nest huddle. Thus, cocaine impaired the parenting ability of both male and female rats, with and without previous parenting experience.     

The reproductive stage and experience of sexually receptive mothers alter their preference for pups or males

Female rats show postpartum estrus, a unique stage in their reproductive cycle in which they are able to display maternal and sexual responses at the same time. To assess the relative value of pups or males for sexually receptive mothers with different hormonal profiles and reproductive experiences, we employed a 3-point star maze with 3 choice compartments containing: pups, a sexually active male, or no stimulus (neutral). Cycling maternal and nonmaternal females in late proestrus, independently of their previous reproductive experience, strongly preferred the male to the pups, although most postpartum estrous dams did not exhibit preference for the male. The majority of the postpartum primiparous females did not prefer the litter's chamber either, but a previous reproductive experience strongly determined their preference for the pups. These results suggest that the hormonal changes of the proestrus, in contrast to those of the postpartum estrus, promote a strong preference for the male that is not diminished by the maternal condition. Conversely, the endocrine changes of the postpartum facilitate the effect of previous reproductive experience in strengthening the incentive value of the pups.     

The medial preoptic area is necessary for motivated choice of pup- over cocaine-associated environments by early postpartum rats

Converging evidence suggests that the motivation to seek cocaine during the postpartum period is significantly impacted by the competing incentives of offspring, a stimulus unique to this life stage. In the present study, the functional role of the medial preoptic area (mPOA), a critical site involved in maternal responsiveness, on processing incentive value of pup-associated cues and influencing response allocation for pup- over cocaine-associated environments was investigated using a concurrent pup/cocaine choice conditioned place preference (CPP) paradigm. Early postpartum females with bilateral guide cannulae aimed into the mPOA or into anatomical control sites were conditioned, from postpartum days (PPD) 4 to 7, to associate different uniquely featured environments with pups or cocaine. CPP was tested on PPD8 following intra-mPOA infusions of either 2% bupivacaine or saline vehicle. In two additional experiments, the effects of intra-mPOA infusions of bupivacaine on expression of conditioned responding induced by environments associated with either pups or cocaine were examined separately. Transient inactivation of the mPOA selectively blocked the conditioned preferences for pup-associated environments, significantly contrasting the robust pup-CPP found in non-surgical and intra-mPOA vehicle-treated females. In contrast, mPOA inactivation failed to alter cocaine-CPP in postpartum females. When given a choice between environments associated with pups or cocaine, transient functional inactivation of the mPOA altered choice behavior, biasing the preference of females toward cocaine-associated environments, such that almost all preferred cocaine- and none the pup-associated option. The anatomical specificity was revealed when inactivation of adjacent regions to the mPOA did not affect CPP responses for pups. The findings support a critical role for the mPOA in mediating pup-seeking behavior, and further suggest that the competing properties of pups over alternative incentives, including drugs of abuse, rely on mPOA integrity to provide relevant pup-related information to the circuitry underlying the choice behavior between pups and alternative stimuli.     

Development of cocaine sensitization before pregnancy affects subsequent maternal retrieval of pups and prefrontal cortical activity during nursing

Pups are a highly rewarding stimulus for early postpartum rats. Our previous work supports this notion by showing that suckling activates the mesocorticolimbic system in mothers. In the present study, we tested whether development of behavioral sensitization to cocaine before pregnancy affects the neural response to pups during the early postpartum days (PD). Virgin rats were repeatedly administered cocaine for 14 days (15 mg kg(-1)) and withdrawn from treatment during breeding and pregnancy. The neural response to suckling was measured at PD 4-8 using blood-oxygen-level-dependent (BOLD) MRI or microdialysis. Our results show that BOLD activation in the medial prefrontal cortex (PFC), septum and auditory cortex was curtailed in cocaine-sensitized dams. No differences between cocaine sensitized and saline control dams were observed in the nucleus accumbens, olfactory structures, or in 48 additional major brain regions that were analyzed. Baseline, but not pup-stimulated, dopamine (DA) levels in the medial PFC were lower in cocaine-sensitized dams than in controls. When tested for maternal behaviors, cocaine-sensitized dams showed significantly faster retrieval of pups without changes in other maternal behaviors such as grouping, crouching and defending the nest. Taken together, the present findings suggest that maternal motivation to retrieve pups was enhanced by repeated cocaine exposure and withdrawal, a result reminiscent of 'cross-sensitization' between the drug and a natural reward. Changes in retrieval behavior in cocaine-sensitized mothers might be associated with a hypo-responsive medial PFC.     

Establishment of pheromonal bonds and diet choice in young rats by odor pre-exposure

Rat pups reared by mothers maintained on a diet inhibiting maternal pheromone production do not exhibit a tendency to approach the pheromone excreted by normally maintained lactating females. The results of the present experiments indicate that following exposure in isolation to the smell of maternal pheromone, rat pups reared by dams not producing maternal pheromone exhibit a strong preference for the odor of maternal pheromone. Furthermore, pups reared by non-pheromone producing dams, and exposed in isolation to an arbitrary odor, exhibit both a preference for that odor and a preference for a diet with which that odor is associated. These results are discussed as demonstrating the importance of stimulus familiarity, rather than association learning, in the development of pheromonal bonds and socially transmitted diet preferences.     

Experience-dependent cell survival in the maternal rat brain

Postpartum maternal experience produces long-lasting changes in maternal behavior in the mother rat, which can be altered by early-life isolation. Postpartum experience also affects the regulation of adult neurogenesis in the neural circuit underlying maternal behavior, in a region-specific manner. Female rats were reared either with their mothers (MR) or in isolation in an artificial rearing (AR) paradigm. In adulthood, rats were mated and separated from their pups at birth. The following day, dams were injected with a mitotic marker and either allowed to interact with pups (maternal experience) or left alone. Results show that MR rats that acquire a later maternal experience show increases in cell survival in parts of the excitatory limb of the maternal neural network (bed nucleus of the stria terminalis and nucleus accumbens), but no changes in the inhibitory limb (amygdala). In comparison to AR inexperienced rats, AR maternally experienced rats show no increases in cell survival in the excitatory limb, but a striking reduction in cell survival in the inhibitory limb. The results suggest that early preweaning maternal isolation alters the structural plasticity that occurs following a postpartum maternal experience.     

Behavioral and neural correlates of postnatal olfactory conditioning: I. Effect of respiration on conditioned neural responses

Following olfactory classical conditioning, infant rats exhibit a preference for the conditioned odor and exhibit enhanced uptake of focal 14C 2-deoxyglucose (2-DG) within the olfactory bulb. The present experiments assessed the role of respiration on the expression of the enhanced 2-DG uptake response. Pups were conditioned from postnatal day (PN) 1-18 with an olfactory stimulus paired with a reinforcing tactile stimulus which mimics maternal contact (Odor-Stroke). Control pups received odor only or tactile stimulation only. On PN 19, pups received 1 of 3 tests: 1) a two-odor choice test, 2) an odor/2-DG test with normal respiration allowed, or 3) an odor/2-DG test with respiration experimentally controlled. The results indicated that: 1) Odor-Stroke pups learned the conditioned odor preference, 2) Odor-Stroke, normally respiring pups exhibited enhanced olfactory bulb 2-DG uptake when compared to control pups. No difference in respiration rate was detected between groups in normally respiring pups. 3) Odor Stroke pups whose breathing was experimentally controlled exhibited enhanced olfactory bulb 2-DG uptake when compared to control pups with an identical number of respirations. Together, these results demonstrate that modified respiration during testing is not required for the expression of a modified olfactory bulb response to learned attractive odors. Therefore, the data suggest that the olfactory system itself is modified by early learning.     

Mother-Infant Interactions in Rats Lacking CCK(A) Receptors

Mediation of mother-infant interactions by the brain-gut peptide cholecystokinin (CCK) was examined by observing behavior of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which lack functional CCKA receptors because of a genetic abnormality. OLETF (n = 10) and control (Long-Evans Tokushima Otsuka [LETO] n = 10) dams interacted with 1 pup of each line on Postpartum Days 6-9. OLETF pups received more body and anogenital licking and emitted substantially more ultrasonic vocalizations than LETO pups. OLETF dams carried pups less frequently and showed a nursing position more frequently than LETO dams. No significant Pup X Dam Line interactions or line differences in dams' activity were detected. The results provide convergent validity to previous pharmacological studies implicating CCK mediation of both infant and maternal behavior.     

Selective breeding for infant vocal response: A role for postnatal maternal effects?

N:NIH rats were selectively bred on the basis of high or low rates of ultrasonic vocalization (USV) response to isolation at 10 days of age (Brunelli et al., 1997: Dev Psychobiol 31:255-265). To examine the possibility of postnatal maternal effects in the generational transmission of divergent traits, pups were cross-fostered shortly after birth between dams of the two lines (Low- and High-USV). Controls were fostered to dams of the same line (in-fostered). Additional (population) control data were obtained from the entire 13th generation of the selectively bred lines. USV rates of cross-fostered pups in each line were not significantly different from rates of in-fostered pups of the same line. High USV line pups cross-fostered to Low USV line dams weighed significantly less than in-fostered pups, on the day of testing. The results provide no evidence for a postnatal maternal contribution to the USV phenotype. Prenatal and/or perinatal maternal effects have not been ruled out.     

Effects of prenatal cocaine exposure and maternal separation on heart rate,orienting response habituation,and retention

Effects of the presence or absence of the dam during testing and the retention interval on pretone heart rate (HR) and habituation and retention of an HR orienting response to tone were examined in prenatally cocaine-exposed and nontreated Sprague Dawley rat pups in two experiments. On postnatal day 16, each pup received two test sessions, separated by a 4-hr retention interval during which pups were either isolated or placed with their dam and siblings. For testing, each pup was placed in the test apparatus in the presence or absence of an anesthetized dam where, after a 15-min adaptation period, 10 tone presentations were given, each separated by a 65-s intertrial interval, with HR measured during a 5-s pretone period and throughout the 10-s tone for each trial. Experiment 1 used offspring from the regular breeding colony and observed the typical HR lowering effect of maternal presence during testing, an effect that was surprisingly potentiated, however, following the retention interval in animals that were isolated during this interval. This apparent potentiation by prior isolation of the HR lowering effect of the dam was confirmed in Experiment 2 in nontreated offspring, but did not emerge convincingly in offspring of either dams subcutaneously injected with 40 mg/kg of cocaine HCl daily from gestational days 8 to 20 (C40) or dams injected with saline and pair-fed 4 days (PF4) to mimic the acute anorexic effects of cocaine administration. Consistent with prior work, C40 offspring also were found to exhibit better retention of the habituated orienting response than offspring of NT dams and to some extent PF4 dams as well, a retention effect that was not significantly influenced, however, by social context during the retention interval.     

The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: evidence for the reward comparison hypothesis

Rats suppress intake of a saccharin conditioned stimulus (CS) when it is paired with an aversive unconditioned stimulus (US), an appetitive US, or a drug of abuse such as morphine or cocaine. It is unclear, however, whether the reduction in intake induced by these drugs is mediated by their aversive or their rewarding properties. The present set of experiments addressed this question by comparing the suppressive effects of a known aversive US (LiCl), a known reinforcing US (sucrose), and a drug of abuse (cocaine) in two strains of rats (i.e., Lewis and Fischer 344 rats) that differ in their preference for rewarding stimuli. The results show that, although both strains readily acquired a LiCl-induced conditioned taste aversion (CTA), the suppressive effects of sucrose and cocaine were robust in the drug-preferring Lewis rats and absent in the Fischer rats. These data argue against a CTA account and in favor of the reward comparison hypothesis.     

Exposure to PCB 77 affects partner preference but not sexual behavior in the female rat

In rats, exposure to the polychlorinated biphenyl congener 3, 4, 3′, 4′-tetrachlorobiphenyl (PCB 77) affects the brain and behavior of the offspring as well as the maternal behavior of the dams. In the present study, a cross-fostering design was used to examine the effects of pre- and/or postnatal exposure to PCB 77 on sexual behavior and partner preference in female rats, and to determine the role of altered maternal behavior in the mediation of these effects. Pregnant rats were treated with oil or PCB dissolved in oil (2 mg/kg b.w.) on gestation days 6-18 and then given pups that had been exposed to either the oil vehicle or PCB during gestation. As adults, the female offspring were tested for partner preference (that is, whether they preferred to spend time with a sexually receptive female or a sexually active male) and sexual behavior. None of the treatments affected female sexual behavior. However, both double exposure and postnatal exposure diminished the animals' preference for a male over a female stimulus, but partner preference was not affected by prenatal exposure alone. There were no significant correlations between the changes in partner preferences due to PCB exposure and the amount of maternal grooming and licking received by the treated litters. Thus, female partner preference is affected by early PCB exposure, and the effects depend upon whether the exposure is in utero or via lactation and may be independent of any effects of the PCB on maternal care.     

Effects of stress during pregnancy on maternal behavior in mice

The effects of stress experienced during pregnancy and raising stressed offspring on maternal behavior were investigated in Swiss-Webster mice. Dams were either stressed or not stressed during pregnancy, and raised either prenatally stressed or nonstressed cross-fostered pups. Maternal behaviors such as grooming, nursing, pup retrieval and maternal aggression were assessed during the first 4 days after birth. Nonstressed dams raising stressed pups and stressed dams raising nonstressed pups groomed and nursed their pups significantly less than did control dams (stressed dams raising stressed pups and nonstressed dams raising nonstressed pups). Nonstressed dams raising stressed pups were also the slowest to retrieve both the first and last pup in retrieval tests. Nonstressed dams raising nonstressed pups were significantly less aggressive than other dams. In contrast, stressed dams raising stressed pups exhibited high levels of nursing and grooming, retrieved their pups rapidly and were very aggressive towards an intruder. These results indicate that raising stressed pups, or experiencing stress during a pregnancy can have significant effects on maternal behaviors. Stressed dams raising stressed pups exhibit maternal care comparable to that of nonstressed dams raising nonstressed pups at least for nesting/nurturing behaviors, and show increased levels of aggression and pup retrieval.     

Behaviorally functional opioid systems in infant rats: I. Evidence for olfactory and gustatory classical conditioning

In order to characterize behavioral function of opioid systems in neonatal rats, two series of experiments were initiated. In one, the reinforcing properties of exogenous opioids were investigated in 5-day-old pups. Specifically, the infant's ability to associate the novel taste of saccharin, received while suckling, with ip morphine injections was assessed. Rats that received 0.5 ml of saccharin prior to morphine administration ingested considerably more saccharin on Day 10 than did control rats. The second set of experiments was conducted to determine whether rat pups could associate a novel odor with morphine administration. Five days after conditioning, that stimulus was highly preferred by morphine-treated pups compared with saline control pups. Thus positive associations were formed with either a novel taste stimulus experienced while suckling or with an odor experienced during social isolation. Conditioning was cue specific and was retained for at least 5 days. The formation of these associations was blocked with opioid antagonists given prior to conditioning. These data suggest behaviorally functional opioid receptors and raise the possibility of a functional role of the endogenous opioids in motivational processes in infant rats.     

Parturition influences initial pup preferences at later onset of maternal behavior in primiparous rats

Initial maternal responsiveness as a function of varying pup stimuli was assessed in primiparous Long-Evans rats. Pups were removed during parturition and the dams tested beginning 24 hr later. These dams were most likely to respond maternally towards newborn (0-2-day-old) rat pups (100%) and 6-8-day-old hamsters, which are the size of newborn rats (83.3%). In contrast, dams were significantly less likely to respond maternally towards newborn hamsters (50%) and 8-10-day-old rats (16.7%), pups which are half as large and twice as large, respectively, as newborn rats; indeed, dams were likely to attack these pups (33.3% and 25%, respectively). The maternal response (less than or equal to 1 hr) to dead newborn rats was similar to that towards live newborn rats, except that fewer dams retrieved dead pups rapidly (less than or equal to 1 min). Cesarean-delivered dams did not display higher maternal responsiveness towards 0-2 than towards 8-10-day-old rats. Further, whereas no parturition-experienced dam displayed infanticide towards newborn rats, 21.9% of primiparous Cesarean-delivered dams did. Thus, the exogenous and/or endogenous stimuli associated with parturition enhance selective maternal responsiveness and diminish infanticide towards pups the size of newborn rats.     

The early presence of food-oriented appetitive behavior in developing rats.

The appetitive behavior of 3- to 6-day-old rat pups was studied by testing their ability to direct their ingestive behavior to a restricted food source. We found that, from 3 days of age, pups were able to feed efficiently from such a source. More specifically, pups that were deprived of nutrition but not of maternal care as well as pups that were dehydrated ingested significantly more than nondeprived animals, and did so whether liquid diet was spread over the entire floor surface beneath them or restricted to a fraction of the floor surface. However, pups that had been nutritionally and maternally deprived were not able to direct their feeding. The general locomotor activation of pups in this latter group appeared to interfere with their ability to direct their behavior to the restricted source. These results indicate that from early ages, developing rats possess the appetitive competence to guide their behavior and suggest that previous findings of poorly directed behavior were a confound of the behavioral activation shown by pups tested in a state of maternal deprivation.     

The behavioral response to novelty is altered in rats neonatally exposed to cocaine

It has recently been suggested that the effects of in utero cocaine exposure may result in subtle deficits related to a challenging environment, including exposure to novelty or stress. This study used a neonatal drug-exposure model to examine the behavioral response to a novel environment in rodents. Subjects were artificially reared (AR) from postnatal Days 4-10. There were four treatment groups; AR 40 mg/kg/day cocaine, AR 20 mg/kg/day cocaine, AR control group receiving no drug, and a normally reared control. In Experiment 1, subjects were tested for their preference of maternal home-cage or clean wood-chip odors in a T-maze on postnatal Day 15. Subjects from all treatment groups preferred the maternal odor. In Experiment 2, subjects were habituated to four familiar odors and tested with a novel odor in an open field (postnatal Days 16-21). Neonatal exposure to 20 mg/kg/day cocaine led to an overall increase in exploratory behavior during testing, whereas 40 mg/kg/day did not, supporting the hypothesis that developmental exposure to cocaine at some doses may alter the offspring's response to a changing environment.     

Ultrasonic vocalization responses of rat pups to acute separation and contact comfort do not depend on maternal thermal cues

In order to assess the importance of maternal thermal cues in controlling the acute USV responses of rat pups to contact with her body (the contact comfort response) and to separation from her, we drastically altered maternal temperature by inducing severe hypothermia so that maternal rectal and flank temperatures averaged more than 20°C below normal and 10°C below ambient levels during testing. Isolated 12- to 13-day-old pups showed reductions in USV when these cold dams were presented and brisk USV accelerations when the cold dams were removed from the test chamber. These responses closely resembled those of other pups tested with warm (36°C) anesthetized dams. No significant differences were found in pups' USV contact comfort responses to cold and warm dams. For acute separation, prior maternal thermal properties and other factors were found to modulate the relative intensity of the marked USV increase elicited by this event © 1993 John Wiley & Sons, Inc.     

Determinants of mother-young contact in Norway rats

Rat dams choose to care for their pups in a relatively warm area, apparently because they have an elevated thermal set point for the regulation of their body temperature. Since the duration of their contact bouts with their pups is limited by an acute hyperthermia that they experience while on the pups, their choice limits the time that they can spend with their pups. When dams could choose the temperature at which they cared for their young they spent only about half the time in contact with their offspring as did dams caring for their pups at the ambient temperature of the laboratory. We conclude that rat dams do not attempt to maximize the duration of their contact bouts with their offspring. Dams also do not attempt to minimize the amount of time that they spend away from their offspring. The duration of the intervals between contact bouts was influenced by the ability of the dams to dissipiate the heat gained during the contact bout with the pups. Again, dams did not seek out a cool area in which to spend their interbout intervals, preferring to remain in relatively warm areas. Their thermal preference facilitated the retention of their body heat and prolongation of the interbout intervals. Dams may return to the nest periodically for brief bouts during which the state of the pups is monitored. Pups were found to play both passive and active roles in modulating the overall pattern of maternal contact, for dams maintained contact with pups if the pups were cool, but failure to attach to the nipples soon after contact was established frequently led to rapid bout termination, particularly with warm pups. Contact is maintained if the pups are cool or if they attach to the nipples. Finally, it was found that pups could actively curtail interbout intervals by emitting ultrasonic vocalizations.