Behavior Genetics, Vol. 32, No. 4, July 2002 (© 2002)
Prenatal Cocaine Exposure Alters Maternal Retrieval Behavior in Mice Christopher W. Hess,1,2 Martin E. Hahn,1 Robert H. Benno,1 and Norman Schanz1 Received 13 Aug. 2001—Final 9 Apr. 2002
Previous studies have demonstrated alterations in maternal retrieval behavior as a result of direct cocaine exposure. To establish the influence of prenatal cocaine exposure on pup retrieval, we exposed pups of three F1 genotypes by injecting their mothers (all C57BL/10J strain) with 20 mg/kg cocaine hydrochloride or saline subcutaneously on gestation days 7 to 17. When those pups became adults, control and exposed females were mated with males of the same genotype and tested for pup retrieval on postpartum days 4 and 5. Because ultrasonic calls are known to be elicitors of maternal retrieval behavior, the rate of ultrasonic calling was measured. Prenatal cocaine exposure exerted a significant effect upon retrieval latency on day 4. No relationship was found between genotype and retrieval latency. KEY WORDS: Prenatal cocaine; pup retrieval; maternal behavior; ultrasonic calls; mice.
INTRODUCTION
rats exposed prenatally to cocaine (Molina et al., 1994; Spear et al., 1998). Though these alterations may not be observable under normal conditions, these studies demonstrate a decrease in adaptability that can be “unmasked” by stressful situations. We have observed such behavioral alterations in our laboratory in studies of dominance and agonistic behavior and prenatal cocaine exposure, and have demonstrated that genotype can interact with condition in mediating the effects of prenatal cocaine exposure on aggression and ultrasonic calls in mice (Hahn et al., 1997a; Hahn et al., 2000). Behavioral alterations that result from prenatal cocaine exposure are arguably of particular relevance when they are social behaviors that influence offspring development, such as maternal behavior. Maternal behavior can be defined as those activities in which a mother engages to optimize the development and increase the likelihood of survival of her offspring (Zimmerberg and Gray, 1992). In the rodent, these behaviors can be separated into non-infant and infant directed behaviors (Numan, 1990). Non-infant directed behaviors include nest building, maternal aggression toward intruders, lactational hyperphagia, and the consumption of pup urine. Infant-directed behaviors include crouching over the litter, nursing, anogenital licking, and pup retrieval.
In the past two decades, the possible consequences of cocaine abuse by a pregnant mother for her unborn child has been a topic of societal concern and debate. Current clinical research continues to identify intrauterine growth retardation, neurological abnormalities, and deficiencies in motor development associated with prenatal cocaine exposure in humans (Arendt et al., 1999; Chiriboga et al., 1999). However, these results may be produced by cocaine in conjunction with other factors (such as polydrug abuse or genotype) and not cocaine alone (Franks et al., 2001). Rodent models have proven particularly useful in isolating behavioral changes directly attributable to cocaine. Studies have demonstrated disruptions in olfactory conditioning in rats and mice (Goodwin et al., 1992; Wilkins et al., 1998) and both age-dependent alterations of some stress-related behaviors (such as normal immobility responses to footshock and forced swim) and alterations in agonistic responses to stressful situations in 1 2
William Paterson University, Wayne, New Jersey 07470, USA. To whom correspondence should be addressed at Department of Biology, William Paterson University, Wayne, NJ 07470, USA. Tel: (973) 720-2480. Fax: (973) 720-2338. e-mail:
[email protected]
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The behavior on which we will focus is the search for and retrieval of pups. A pup can be separated from the safety of the home nest by a number of circumstances. When disturbed, rodent dams sometimes relocate their litter and nest, and pups can be dropped or left behind during relocation. Separation can also result from the mother’s reactions to disturbances in the environment. Stimuli can cause a nursing mother to leave the nest abruptly, scattering the nursing pups along the way. In addition, older pups will occasionally wander out of the nest, or wander away while the mother is relocating the litter (King, 1963; Rosenblatt and Lehrman, 1963). Pups who remain separated from their home nest for extended periods have a poor chance of survival and are at risk for being attacked by aggressive adults or predators, or they may perish from hypothermia (Okon, 1970; Nagy, 1993). It is therefore crucial that mothers search for and retrieve pups soon after they are displaced. To date, studies examining the effects of cocaine exposure on rodent maternal behaviors have focused upon adult female rats (Petruzzi et al., [1997] is the exception and used mice) directly exposed to cocaine. A majority of these studies have established that cocaine does alter maternal behavior. However, the findings of these studies vary according to dosage, the behaviors being tested, the presence of cocaine in the blood at the time of testing, and whether maternal behavior had been established at the time of testing (Heyser et al., 1992; Zimmerberg and Gray, 1992; Johns et al., 1994; Kinsley et al., 1994; Vernotica et al., 1996; Quinones-Jenab et al., 1997; Nelson et al., 1998). Of the studies that specifically examined pup retrieval, some found no significant effect of cocaine exposure (Sobrian et al., 1990; Heyser et al., 1992; Johns et al., 1994; Nelson et al., 1998), while other studies found that cocaine increased latency to retrieve one or more pups and reduced the number of dams engaging in retrieval (Zimmerberg and Gray, 1992; Kinsley et al., 1994; Vernotica et al., 1996). The lack of a reliable effect of cocaine on pup retrieval may be due to a number of factors, including differences in the testing procedure and factors previously listed. The purpose of the present study was to determine if prenatal cocaine exposure alters the maternal retrieval behavior of the adult mouse. Because it has been shown that direct cocaine exposure can alter maternal retrieval, and we have previously demonstrated that adult mouse behaviors (such as aggression) that are altered by direct cocaine can also be affected by prenatal exposure to cocaine (Hahn et al., 1997a), we predict that prenatal exposure to cocaine will impair pup retrieval
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behaviors in adult female subjects caring for their own litters. We are aware of no previous studies that examine the effects of prenatal cocaine exposure on subsequent adult maternal behavior. Further, since we have shown genotype to interact with prenatal cocaine in influencing adult behavior (Hahn et al., 1997a) and infant behavior (Hahn et al., 2000), we predict that this effect will be genotype dependent. Because the ultrasonic calls of isolated pups have been shown to play an important role in the eliciting of a retrieval response (Sales and Smith, 1978; Ehret and Haack, 1984), we also studied the frequency of calls produced by pups and examined their role in the retrieval process. METHOD Subjects The subjects in this study were 62 female mice from a total of 34 litters. Each litter contributed an average of two females. Female subjects were the F1 generation of a cross between C57/BL10J females and a male from the DBA/2J, BALB/cJ, or SJL/J strain (B10D2F1/J, B10CF1/J, and B10SJLF1/J, respectively). We chose these particular strains to produce F1 progeny because we have an extensive database on their ultrasonic call characteristics (Hahn et al., 1997b; Hahn et al., 2000). All mice in the study were born and raised in the mouse laboratory of William Paterson University. The conditions in the laboratory are maintained according to the highest standards of animal care set forth by the U.S.D.A. and the N.I.H. Subjects were maintained in 30 ⫻ 20 ⫻ 15 cm clear plastic colony cages with stainless steel cage tops in colony rooms that were maintained at 68–72 ºF on a 12:12 hour light/dark schedule, with lights on at 0800. ProLab Rat, Mouse, and Hamster 3000 Laboratory Chow and tap water were available ad libitum for all subjects. Production and Prenatal Cocaine Exposure of the F1 Test Subjects Following the procedures of Hahn et al. (2000), nulliparous female progenitors of the test subjects were weighed and placed with their assigned breeding males in a neutral cage in the afternoon and separated the following morning, approximately 18 hours later. Females were then checked for the presence of a vaginal plug and weighed daily to confirm pregnancy. We randomly assigned pregnant females to one of two groups that received injections of either 20 mg/kg cocaine hydrochloride or saline administered by subcutaneous injec-
Prenatal Cocaine and Pup Retrieval
tion from gestation days 7 through 17. We injected the females once daily at approximately 1100 and systematically varied the injection site across the back of the subjects to reduce local tissue necrosis. Pregnant females were checked for births daily at 0900. For females in the process of giving birth at 0900, day of birth was recorded as the following day. We recorded the weight of the litter, and dam weight was recorded from day 16 until parturition. The average pup weights were then calculated from the weight of the litters. As in previous studies in our laboratory, there were no significant differences found in weight gained by the mothers during gestation or weight of the pups at birth as a result of the 20 mg/kg cocaine treatment. Breeding of the F1 Test Subjects Both male and female F1 pups generated and prenatally exposed to cocaine by the above procedure were weaned at 21 days of age and group housed for 14 to 18 days. We individually isolated female subjects and breeding males 1 week prior to mating. At approximately 45 days of age (range ⫽ 42– 46), breeding males were paired with female subjects of the same F1 genotype. Female subjects were placed in a neutral cage with a male at 0930, and males were removed 24 hours later, which was again designated as day 0 of gestation. Day of birth was defined as the day on which all pups had been delivered before 0900. In litters that had been partially delivered by 0900, day of birth was assigned as the following day. The subjects of the study then were the females of three F1 genotypes who had been exposed to cocaine or saline prenatally and their F2 litters. Apparatus Previous investigations of maternal retrieval have employed a variety of procedures and apparatuses, none of which could be considered a standard. In our laboratory, we found that a linear apparatus made of tubes, a modification of that employed by Ehret (1992), and an open-field apparatus were both effective in differentiating the behavior of mice of different inbred strains. Because the effects of prenatal cocaine exposure are known to be small or subtle, we decided to employ both apparatuses, the tube apparatus on day 4 and the open-field on day 5. The apparatuses used for testing retrieval behavior are shown in Fig. 1. The day 4 testing apparatus was made of Plexiglas and consisted of one center chamber and two lateral chambers, each with a removable top and bottom. Con-
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necting tubes joined the center and lateral chambers. The center and lateral chambers were 12.7 cm in diameter and 10.2 cm in height. Connecting tubes had a diameter of 6.0 cm and measured 61 cm long. Removable gates confined the test subject to the center chamber during preparations for a given trial. The open-field apparatus used on day 5 consisted of a wooden box 86 cm ⫻ 86 cm ⫻ 38 cm. During testing, pups were placed into plastic bins measuring 12.7 ⫻ 10.5 cm, with a height of 7.6 cm. The bins were placed in the four corners of the open field, and ultrasonic detectors were suspended 2 cm above the bins. Pup ultrasonic calls were recorded using Ultra Sound Advice Mini-3 Ultrasonic Detectors (Ultra Sound Advice, London) fixed at 70 kHz and the Noldus Audiofilter 1 and Observer Basic software program (Noldus Information Technologies, Wageningen, Netherlands). The Observer program was run on a Dell Latitude Pentium II laptop computer.
PROCEDURE Day 4 Testing: Two-Choice Paradigm We tested subjects on day 4 between 1100 and 1430. Dam weight, litter weight, and calculated average pup weight were recorded at 0900. Between 1 and 2 hours before testing, we placed the mother and her pups in the center chamber of the two-choice apparatus with a significant portion of the home nest material and approximately half of a chow nugget, which weighed approximately 2.5 g. During the acclimation period, the mother was free to explore the entire apparatus. After completion of the acclimation period, we removed the mother and all pups and returned them to the home cage. We then replaced the mother in the center of the apparatus, which was partitioned from the connecting tubes by removable gates. Any nest material that had been displaced into the tubes in the center chamber was replaced. We randomly chose two pups and assigned them to either the left or the right lateral chambers. After assignment, we determined the sex of the pups and placed them into the chambers simultaneously. We then placed an ultrasonic detector atop the lid of each lateral chamber, in which a hole approximately 1 cm wide allowed detection of ultrasonic calls. We initiated time and ultrasound frequency recording devices simultaneously with gate removal. Latency to pup retrieval and the number of ultrasonic calls were recorded for the 10-minute testing period. In both day 4 and day 5 testing, retrieval occurred when any part
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Hess, Hahn, Benno, and Schanz
Fig. 1. Day 4 and day 5 testing apparatuses.
of the retrieved pup crossed the plane of the opening to the center chamber. Pups that were not retrieved within the 10 minute testing period were assigned the maximum time of 10 minutes.
Day 5: Open-Field Paradigm Subjects were tested on day 5 between 1100 and 1700. Dam weight, litter weight, and average pup weight were recorded at 0900. The mother and pups were given a 1 to 2 hour acclimation period as described for day 4 testing. Pup bins were added to each corner of the apparatus just before testing, and ultrasonic detectors were placed about 2 cm above the bins.
Four pups were randomly chosen and placed into the bins. Time and ultrasound detecting devices were initiated simultaneously with gate removal. Latency to pup retrieval and number of ultrasonic calls were recorded for the 10-minute testing period. RESULTS Retrieval The mean latencies to retrieval of both pups on day 4 are shown in Fig. 2. There appears to be an effect of condition on retrieval latency, but the strength of the effect seems inconsistent across the genotypes tested. The effect seems most pronounced in the B10CF1/J genotype
Prenatal Cocaine and Pup Retrieval
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Fig. 2. Panel a. The effect of condition on mean latency to retrieval on day 4. Panel b. The effect of condition on mean latency to retrieval on day 5.
and nearly absent in the B10D2F1/J genotype. Mean latencies to retrieval on days 4 and 5 are shown in Fig. 2. We conducted a 2 ⫻ 3 (condition ⫻ F1 genotype, the mother’s genotype) GLM (General Linear Models) procedure on the latency to retrieval of both pups on day 4. Condition exerted a reliable effect on latency to retrieval, (F(2,56) ⫽ 5.21, P ⫽ .026). Cocaine exposure accounted for slightly over 9% of the total sum of squares, SScondition/SStotal ⫽ .093. The mean latencies for retrieval on day 5 do not appear to differ greatly between control and treatment subjects. A 2 ⫻ 3 (condition ⫻ F1 genotype) GLM procedure confirmed this lack of a reliable difference due to condition, (F(2,55) ⫽ .28, P ⫽ .991). Ultrasonic Calls Because ultrasonic calls have been reported to be strong elicitors of retrieval behavior, the mean num-
bers of calls per minute produced by pups of the treatment and control subjects were also examined. The day 4 and day 5 mean rates of ultrasonic calls per minute are shown in Table I. There appears to be an effect of F 2 genotype on the number of calls produced per minute. Within genotypes, prenatal cocaine exposure of the mothers seems to have increased the number of calls per minute of pups in the B10CF2/J and B10SJLF2/J genotypes. We tested the rates of ultrasound production on days 4 and 5 with 2 ⫻ 3 (condition ⫻ F2 genotype) GLM procedures. On day 4, there was a reliable effect of genotype on the number of calls per minute, (F(2,116) ⫽ 10.4, P ⬍ .0001). Genotype accounted for approximately 15% of the total sum of squares, SScondition/SStotal ⫽ .150. The effects of condition and condition by genotype were not significant. On day 5, genotype exerted a reliable effect on the number of calls per minute, (F(2,220) ⫽
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Hess, Hahn, Benno, and Schanz
Fig. 2. (continued)
14.989, P ⬍ .0001), and the effects of condition and condition by genotype were not significant. DISCUSSION We studied the effect of prenatal cocaine exposure upon maternal retrieval behavior in mice of three hybrid genotypes: the F1 offspring of C57/BL10J females
and a male of the DBA/2J, BALB/cJ, or SJL/J genotype (B10D2F1/J, B10CF1/J, and B10SJLF1/J respectively). We also examined the effect of genotype and condition on the rate of ultrasonic calling. Cocaine exerted a significant effect on total retrieval in the twochoice apparatus on day 4. Given the ubiquitous effects of genotype on behavior, it is surprising to see that genotype did not alter
Table I. Mean Ultrasonic Calls per Minute of F2 Hybrid Pups on Days 4 and 5 Day 4 Genotype B10D2F2/J B10CF2/J B10SJLF2/J
Day 5
Saline
Cocaine
Saline
Cocaine
56.76 ⫾ 14.14 24.83 ⫾ 6.550 1.31 ⫾ 0.840
54.83 ⫾ 8.200 37.48 ⫾ 10.31 18.38 ⫾ 6.960
42.73 ⫾ 7.970 27.70 ⫾ 5.480 9.76 ⫾ 3.13
44.73 ⫾ 5.61 28.92 ⫾ 4.48 10.47 ⫾ 2.34
Prenatal Cocaine and Pup Retrieval
any of the measures of pup retrieval we employed. A previous study employing 11 inbred strains found strain differences using some of the same measures we employed but in a different setting (Carlier et al., 1982). However, these differences between strains were not large, and in a subsequent study using 2 of the 11 strains, those same investigators found no differences in measures of retrieval (Cohen-Salmon et al., 1985). Our failure to find strain differences in this study is possibly because of the particular genotypes we studied. The methods that have been used to study the various aspects of rodent pup retrieval are not standardized. In previous studies, investigators have scattered pups within the home cage (Giordano et al., 1990; Carlier et al., 1982; Kinsley et al., 1994; Zimmerberg and Gray, 1992) and utilized retrieval apparatuses such as the open field (e.g., Petruzzi et al., 1997), a two-choice running board emanating from a central nest area (Ehret and Haack, 1984; Ehret, 1992), and circular platforms placed on top of the cage (Deviterne and Desor, 1990). As described above, we chose to use both a two-choice and an open-field apparatus on successive testing days. It is possible that we found no effects of prenatal cocaine or genotype in the openfield apparatus on postnatal day 5 because the test females were distracted by non-relevant cues in the openfield apparatus. We also examined the effects of genotype and treatment of the mother on the number of ultrasonic calls produced by the pups. The strong effect of genotype found on the number of calls produced per minute has already been established in the literature (Hahn et al., 1997b; Hahn et al., 1998; Cohen-Salmon et al., 1985). Despite a considerable difference in mean calls per minute in the B10SJLF2/J genotype, there was no significant effect of condition or an interaction found between genotype and condition on the number of calls per minute. Although Hahn et al. (2000) demonstrated a significant effect of condition on the rate of ultrasonic calling in pups who were prenatally exposed to cocaine, the lack of a significant effect of the exposure status of the mother on the number of ultrasonic calls produced by the unexposed offspring indicates that the effect of cocaine on ultrasonic calls does not extend beyond the prenatally exposed individual to her offspring. The focus of this study was the effect of prenatal cocaine exposure on maternal retrieval behavior. With regard to prenatal cocaine exposure, the results of this study are in agreement with previous studies in both direction and size, indicating that the effects of prena-
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