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BEHAVIORAL PHARMACOLOGY

Early Postnatal Stress Alters Place Conditioning to Both µ- and -Opioid Agonists

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia

Received August 8, 2007; accepted January 17, 2008.

	Abstract

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Clinical literature has established a link between early childhood incidents of neglect and trauma and adult problems with substance abuse. In rats, such early life stress has been modeled using a maternal separation (MS) paradigm in which rat pups were removed from their mothers for a few hours daily during the first two postnatal weeks. In this study, we used the MS model to investigate the effects of early postnatal stress on place conditioning to both µ- and -opioid agonists in male and female Long-Evans rats. Offspring of both rearing conditions [MS or nonhandled (NH)] were conditioned using a biased procedure to saline, the µ-opioid agonist morphine (3.0, 5.6, and 10 mg/kg s.c.), or the -opioid agonist spiradoline (0.3, 1.0, and 3.0 mg/kg) for 3 days, followed by a drug-free place-conditioning test 24 h later. Saline was administered in the morning, 30 min before confinement in one compartment, whereas morphine or spiradoline was administered in a similar manner 6 h later in the opposite compartment. MS offspring spent significantly more time in the morphine-paired compartment than NH offspring, indicating a greater place preference for the µ-opioid agonist. In the case of spiradoline, NH offspring spent significantly less time in the spiradoline-paired compartment, indicating a greater aversion to the -opioid agonist in these animals than in MS offspring. These findings indicate that early postnatal stress can significantly alter the rewarding or aversive value of µ- and -opioid agonists when measured using place conditioning.

MS has been successfully used to model many of the physiological and behavioral effects of early life trauma (Plotsky and Meaney, 1993; Caldji et al., 2000; Ladd et al., 2000). In the MS model, rat pups are separated from their mother for varying lengths of time during the first two postnatal weeks and then tested as adults. The most pronounced physiological result of this manipulation is a long-term dysregulation of the hypothalamic-pituitary-adrenal axis (Plotsky and Meaney, 1993; Ladd et al., 2000; Kalinichev et al., 2002a). As adults, MS animals exhibit elevated corticotropin-releasing factor mRNA in the hypothalamus as well as greater plasma corticosterone levels compared to nonhandled (NH) rats (Plotsky and Meaney, 1993). After a mild stress, MS offspring exhibit enhanced corticotropin-releasing factor depletion in the hypothalamus, increased cerebrospinal fluid adrenocorticotropic hormone levels, and greater increases in blood plasma corticosterone levels (Caldji et al., 2000; Kalinichev et al., 2002a; Plotsky et al., 2005). In addition, MS animals exhibit distinct behavioral differences from NH offspring on measures of fear, anxiety, and stress (Ladd et al., 2000; Huot et al., 2001; Kalinichev et al., 2002a).

MS also seems to affect other aspects of the central nervous system, including the mesolimbic dopamine (DA) and endogenous opioid systems. In the mesolimbic DA system, MS results in increased DA release as well as a decrease in the number of D₂-dopamine receptors in the ventral tegmental area and lowered DA transporter levels in the nucleus accumbens (Meaney et al., 2002). Both the µ- and -opioid systems are altered by MS. MS offspring show increased locomotor sensitization after repeated administration of morphine (µ-opioid agonist), a decreased response to morphine in tests of antinociception (Kalinichev et al., 2001a,2001b, 2002), and altered levels of dynorphin B, an endogenous ligand for -opioid receptors, in multiple brain areas (Ploj and Nylander, 2003; Vazquez et al., 2005).

Behavioral measures of both reward and reinforcement involving both dopamine and endogenous opioids are also altered (Meaney et al., 2002; Matthews and Robbins, 2003). In general, MS offspring exhibit increased intake of sucrose solution and acquisition of cocaine self-administration, and they show a decreased response to intracranial self-stimulation compared to NH offspring (Matthews and Robbins, 2003; Michaels and Holtzman, 2006; Moffett et al., 2006; Michaels et al., 2007). Although the effect of MS on the above measures has been investigated, no one has explored how MS affects place conditioning to either µ-or -opioid agonists.

Place conditioning has been used extensively to study the rewarding or aversive value of compounds (Campbell et al., 2000). During place conditioning, the effects of a drug and a set of environmental cues are paired, while a completely separate set of cues is paired with a nondrug treatment (saline). When subjects are subsequently tested in the absence of the drug, these cues elicit an approach or avoidance response to the drug-paired compartment. The amount of time spent in the drug-paired environment postconditioning compared to the time spent before conditioning indicates either a preference/aversion to the drug-paired compartment and a measure of the reward or aversive value of the drug (Carr et al., 1989; Randall et al., 1998; Tzschentke, 1998; Sanchis-Segura and Spanagel, 2006). The advantages of using place conditioning to measure reward value are that it allows for testing in a drug-free state, bypassing any side effects the drug may have on behavior, while exposing subjects to the drug only a few times (Campbell et al., 2000).

Although correlations between early postnatal stress and substance abuse are well documented in clinical literature, direct experimental evidence of a link using animal models is less established. In this study, we continued to investigate the link between early postnatal stress (modeled by MS) and measures of reward and reinforcement by using place conditioning to both µ- and -opioid agonists (morphine and spiradoline, respectively). To our knowledge, this is the first study to examine the impact of MS on place conditioning to opioid compounds.

	Materials and Methods

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Subjects
Subjects consisted of 202 adult Long-Evans hooded rats, 96 males and 106 females (Blue-Spruce; Harlan, Indianapolis, IN). During testing, rats were housed singly in standard polycarbonate cages, had free access to both food and water throughout the study, and were maintained on a 12:12 light/dark cycle. Male rats weighed 350 to 500 g at the time of testing, whereas females weighed 200 to 300 g. This study was conducted in accordance with the Institute of Laboratory Animal Resources (1996) as well as with approval from the Institutional Animal Care and Use Committee of Emory University.

Maternal Separation Procedure
A variation of a well established maternal separation procedure was used in this study (Plotsky and Meaney, 1993; Caldji et al., 2000; Kalinichev et al., 2000; Michaels and Holtzman, 2007). Timed pregnant dams were shipped to our facility on day 12 of pregnancy and gave birth 10 days later. After birth, on postnatal day 1 (P1; birth day = P0), dams were removed from their cages and pups were gendered, culled to litters of 10 (50% male and 50% female), and cross-fostered to another dam. These litters were then randomly assigned to one of two conditions, MS or NH. On the following day, P2, pups in the MS litters were taken from their dams and placed in a bedding-lined container, which was subsequently placed in an incubator (Veterinary water-lined warmer; ThermoCare Inc., Incline Village, NE) for 24 h. At the end of this separation period, pups were returned to their cage and their foster dam. On P3, no separation took place. From P4 to P12, alternating 3- and 6-h periods of separation occurred. Pups of NH litters were placed with their foster dam after group assignment and left undisturbed until weaning, with the exception of necessary cage maintenance. Pups were weaned on P21 and housed in same-gender, same-litter groups of two or three until time of testing on approximately P90 (see Fig. 1).

View larger version (10K): [in this window] [in a new window]   Fig. 1. Timeline depicting the maternal separation procedure. Manipulations were performed on postnatal days 2 to 12 (P2–12), and offspring were tested at P90+. For more detail see Maternal Separation Procedure under Materials and Methods.

Apparatus
The place-conditioning apparatus consisted of a 40 x 40 x 30-cm Plexiglas chamber made up of two compartments, divided by a removable panel with a doorway (14.5 x 13 cm), which allowed for access to both compartments. One compartment was gray with a roughly textured floor, whereas the second was checkered with black and white squares and had a smooth floor. A solid barrier without a doorway was used to confine animals to one side of the chamber during place conditioning.

Place-Conditioning Procedure
General. On the first day of experimentation (pretest), rats were placed in the chamber and allowed to freely explore both compartments for 15 min. Locomotion and location within the chamber were monitored using Digiscan activity monitors (AccuScan Instruments Inc., Columbus, OH), with the aid of VersaMax software (version 1.30; AccuScan Instruments Inc.) and a desktop computer. The time each rat spent in a compartment was noted. All rats showed a preference for one side or the other. To lessen variability and control for a ceiling effect (spending the maximal amount of time in a given side), a biased procedure was used during place conditioning.

Morphine-Induced Place Conditioning. For place conditioning involving morphine, the initially preferred side was paired with saline injection, whereas the nonpreferred side was paired with morphine. After the pretest, three conditioning days occurred. In the morning of these days, rats received s.c. injections of saline 30 min before being confined to one compartment of the chamber for 30 min. Six hours later, in the afternoon, rats received injections with morphine (3.0–10 mg/kg; randomly assigned per animal) 30 min before being restricted to the opposite compartment for 30 min. Twenty-four hours after the last conditioning session, on test day, rats were given full access to the entire chamber for 15 min, and the amount of time spent in each compartment was recorded.

Spiradoline-Induced Place Conditioning. For place conditioning involving the -agonist spiradoline, the initially preferred side of the chamber was paired with spiradoline (0.3–3.0 mg/kg) injections, whereas the nonpreferred side was paired with saline injection. Conditioning was similar to that with morphine, involving three conditioning days as well as saline injections in the morning 30 min before conditioning, followed by spiradoline injections 6 h later (30 min before the afternoon conditioning session). Twenty-four hours after the final conditioning session, rats were given free access to both sides of the chamber for 15 min, and the time spent in each compartment was recorded.

Data Analysis
Results were converted to difference scores by subtracting the time (seconds) spent in the drug-paired compartment during the pretest from the time spent in the drug-paired compartment during the postconditioning test (Bardo et al., 1995). Saline-saline group data were analyzed using a one-way analysis of variance (ANOVA) as well as one-sample t-tests comparing times to 0. Data were analyzed using a three-way ANOVA in which gender, rearing, and drug dose were between-subjects measures. When applicable, a Newman-Keuls or Dunnett's test was used for multiple post-hoc comparisons. The t-tests were also conducted, comparing each dose between rearing groups and between genders. The level set for all comparisons was p 0.05.

	Results

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Saline-saline control groups from place conditioning involving morphine and spiradoline were combined for comparisons. There was no statistical difference between rearing groups or gender [F(1,3) = 0.6]. In addition, no group differed from 0, indicating no conditioned place preference (CPP) in any group [M-NH, t(5) = 0.4; M-MS, t(5) = 0.1; F-NH, t(7) = 0.3; and F-MS, t(7) = 0.7, where M and F indicate male and female, respectively].

Across all morphine doses, MS offspring spent a significantly greater amount of time in the morphine-paired compartment compared to NH offspring, indicating a greater preference for the morphine-paired compartment [F(1,3) = 10.9]. Post-hoc comparisons revealed that M-MS offspring, on average, spent twice as much time in the morphine-paired compartment than did M-NH offspring (Fig. 2, top). In contrast, at no dose of morphine did F-MS offspring differ from their F-NH counterparts (Fig. 2, bottom). No main effect of gender was found during morphine conditioning. Morphine dose had a significant effect on difference scores [F(3,90) = 15.0]; as the morphine dose increased, animals in all four groups spent more time in the morphine-paired compartments. Both M-MS and F-MS offspring exhibited a significant place preference compared to saline at all morphine doses, whereas M-NH and F-NH offspring only exhibited a significant difference from saline at 5.6 and 10 mg/kg (Fig. 3). A significant gender x rearing interaction was detected, with M-MS offspring spending approximately 50 to 100 s more time in the morphine-paired compartment than F-MS offspring [F(3,90) = 11.4] (Fig. 3, top). No rearing x dose, gender x dose, or gender x rearing x dose interactions were observed.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Place conditioning in MS and NH male (top) and female (bottom) offspring across a range of morphine doses. Time difference is the time spent (in seconds) in the morphine-paired compartment postconditioning – time spent in the same compartment before conditioning. MS males spent significantly more time in the morphine-paired compartment versus NH males; however, no rearing effect was observed in females. MS offspring of both genders exhibited a significant place preference at all doses, but NH offspring only exhibited a preference at 5.6 and 10.0 mg/kg. Mean ± S.E.M.; n = 6 to 8/group. *, p < 0.05 compared same rearing condition saline. #, p < 0.05 compared to same dose, same gender NH.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Gender comparisons in morphine-induced place conditioning in MS (top) and NH (bottom) male and female offspring. Time difference is the time spent (in seconds) in the morphine-paired compartment post-conditioning – time spent in the same compartment before conditioning. A significant gender x rearing interaction was detected, with male offspring exhibiting an increased time in the morphine-paired compartment compared to females only in the MS-rearing condition. Mean ± S.E.M.; n = 6 to 8/group. *, p < 0.05 compared same rearing condition saline. #, p < 0.05 compared to same dose, same rearing condition female offspring.

NH offspring spent less time in the spiradoline-paired compartment compared to MS offspring, indicating a greater conditioned place aversion [F(1,80) = 8.7]. In M-NH offspring, all three doses of spiradoline elicited a significant place aversion compared to saline; however, in M-MS, only the lowest dose (0.3 mg/kg) elicited a significant aversion (Fig. 4, top). At the highest dose of spiradoline (3.0 mg/kg), M-NH offspring spent approximately twice as much time avoiding the spiradoline-paired compartment as did M-MS. In females, all three doses of spiradoline produced a significant place aversion in offspring of both rearing conditions (Fig. 4, bottom). No main effect of gender was determined (Fig. 5). A significant spiradoline-dose effect was also found [F(3,80) = 20.4], with time spent avoiding the spiradoline-paired compartment increasing by approximately 200 s as the dose increased to 3.0 mg/kg. A gender x rearing interaction was also discovered [F(3,80) = 3.9]; however, there was no rearing x dose or gender x rearing x dose interaction (Fig. 5, bottom). (For a list of significant statistical comparisons, see Table 1.)

View larger version (17K): [in this window] [in a new window]   Fig. 4. Place conditioning in male (top) and female (bottom) offspring of both rearing conditions across a range of spiradoline doses. Time difference is time spent in the spiradoline-paired compartment postconditioning – time spent in the spiradoline-paired compartment before conditioning. NH males spent less time in the spiradoline-paired compartment at all spiradoline doses than MS males, whereas NH females and MS females spent approximately equal time. Mean ± S.E.M.; n = 6 to 8/group. *, p < 0.05 compared same rearing condition saline. #, p < 0.05 compared to same dose, same gender NH.

View larger version (22K): [in this window] [in a new window]   Fig. 5. Place-conditioning gender comparisons in MS (top) and NH (bottom) offspring across a range of spiradoline doses. Time difference is time spent in the spiradoline-paired compartment postconditioning – time spent in the spiradoline-paired compartment before conditioning. In NH offspring, male offspring spent less time in the spiradoline-paired compartment than females; however, no difference was noted in MS offspring. Mean ± S.E.M.; n = 6 to 8/group. *, p < 0.05 compared same rearing condition saline. #, p < 0.05 compared to same dose, same rearing condition female offspring.

	Discussion

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The most striking of our findings was that rearing altered place conditioning to both the µ-opioid agonist morphine and the -opioid agonist spiradoline in a gender-dependent manner (see Table 2). MS male rats spent more time in the morphine-paired compartment than did NH males, suggesting that the drug was more rewarding in the former group than it was in the latter one. In contrast to µ-opioid agonists, -opioid agonists typically condition avoidance of the drug-paired compartment (Shippenberg and Herz, 1987; Smith et al., 2003), which occurred with spiradoline. However, avoidance of the spiradoline-paired compartment was significantly attenuated in MS male offspring relative to NH offspring.

Again, in males, morphine dose significantly affected time spent in the drug-paired compartment, with the low morphine dose (3.0 mg/kg), yielding a significant place preference in MS but not in NH males. This is inconsistent with what has previously been reported involving morphine-induced CPP, in which repeated pairings of a 3.0 mg/kg morphine dose result in a significant place preference (Bardo et al., 1995; Randall et al., 1998; Campbell et al., 2000). Some parallels are evident between our morphine results and those using other behavioral measures of drug and nondrug reward. Across a range of methods, MS offspring seem to be more sensitive to drug effects and nondrug measures of reward than their NH counterparts (see Introduction). Therefore, the cumulative results of this and other studies further support the possibility of a dysregulation within the reward systems of MS animals, leading these animals to express an altered response to rewarding stimuli.

The gender-dependent aspect of morphine-induced place conditioning was striking; only males were affected by maternal separation. This finding is in contrast to what has been noted in the literature, as well as with what we have determined in other experiments. In general, females have been more affected by maternal separation than males (Slotten et al., 2006). For example, Slotten et al. (2006) noted gender dependence in their measure of locomotor activity, as well as in plasma corticosterone levels, with MS female offspring exhibiting higher levels than MS male offspring. Likewise, we observed a gender dependence in our experiments involving intracranial self-stimulation (Michaels et al., 2007). During these experiments, a rearing effect was only noted in females during the experiments involving a progressive ratio schedule of reinforcement. The estrus cycle is known to affect the activity of female rats, and the influence of cycling hormone levels in the female rats tested may have blunted the impact of maternal separation stress in those offspring (Priest and Pfaff, 1995; Quinones-Jehab et al., 1999).

Regardless of the influence of maternal separation itself, gender differences have not generally been observed using morphine-induced place conditioning or place conditioning induced by other drugs such as heroin, cocaine, and amphetamine (Bardo et al., 1995). For example, Randall et al. (1998) looked at morphine-induced CPP in both genders in preweanling and adult rats and found no gender difference in time spent in the morphine-paired compartment at either age. Likewise, Campbell et al. (2000) looked for gender-related differences in cocaine and morphine-induced place conditioning, but they found no difference in place conditioning to either drug. Whereas most studies have not found gender differences in time spent in the drug-paired compartment, others have found that females require a lower number of drug pairings to elicit a significant place preference compared to males (Russo et al., 2003). Perhaps measuring the number of pairings required to elicit a significant place preference or aversion is more sensitive to gender differences than measuring time spent in the drug-paired chamber. MS could enhance any existing small gender difference, making it easier to measure using a pre- and/or postconditioning time difference and explaining why a consistent gender difference was observed only in MS offspring.

An aversion to spiradoline was found in animals of both genders and rearing conditions. MS offspring exhibited a lesser aversion to the -opioid agonist spiradoline than NH offspring, and this aversion was most pronounced in male offspring (regardless of the rearing group). In addition, only the lowest spiradoline dose (0.3 mg/kg) conditioned a significant aversion in MS male offspring. The possibility exists that, in MS males, the dose-response curve to spiradoline may have been shifted to the left, and if we had tested additional lower doses in these animals, we may have uncovered a more distinct dose response. Regardless, -opioid agonists in general, including spiradoline, are known to produce pronounced aversions in both place-conditioning and taste-conditioning paradigms (Shippenberg and Herz, 1987; Smith et al., 2003). Prior studies have examined other stressors and environmental factors on spiradoline-induced place aversion; however, our study is the first to examine how early postnatal stress alters this conditioning.

Some parallels can be made between our study and that of Smith et al. (2003), which examined the influence of environmental enrichment during the first 7 weeks postweaning on spiradoline-induced place aversion. In this study, animals from enriched environments exhibited an increased aversion to spiradoline compared to those from a nonenriched environment. If we consider the presence of the mother an environmental enrichment, our results are quite similar, if not more striking because of the lower doses we used and the greater aversion (time-wise) they generated.

Both changes in the -opioid system or dopamine system could account for the differences observed between groups. Changes in the density or distribution of -opioid receptors in the brain or their ligands are possible explanations for the differences found. Along these lines, Ploj and Nylander (2003) investigated changes in endogenous -opioids after maternal separation, finding increased dynorphin B binding in areas such as the hypothalamus and periaqueductal gray. Such changes in endogenous ligands could limit the impact of exogenously administered -opioid agonists, resulting in the observed decreased place aversion. The D₁-dopamine receptor is also known to play a role in conditioning to -opioid agonists (Shippenberg and Herz, 1987). Blocking the D₁-dopamine receptor during conditioning results in an abolition of place aversions to -opioid agonists, and, therefore, changes in D₁-dopamine receptor distribution or density may also play a key role in the observed differences between rearing conditions.

The results of this study suggest that early postnatal stress, as modeled by maternal separation, can lead to changes in place conditioning to µ- and -opioid agonists, indicating a change in the rewarding or aversive properties of such compounds. However, the changes seem to be gender-dependent with regard to µ- and -opioid agonists, indicating that gender may alter or interact with the impact of early postnatal stressors. Future directions for this research would be to examine whether this effect generalizes to other µ- and -opioid compounds or to explore place conditioning in these animals using other drugs of abuse, such as cocaine or amphetamine. Research in both of these directions would help yield a more complete picture of early postnatal stress and its link to substance abuse, shedding light on the mechanisms involved, and allowing for the possible development of new treatments for drug addiction.

	Acknowledgements

 
We thank Dr. Alvin C. Harmon and Mi Zhou for assistance in generating maternally separated offspring.

	Footnotes

 
This work was supported by National Institutes of Health Grant DA14122.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.107.129908.

ABBREVIATIONS: MS, maternal separation; NH, nonhandled; DA, dopamine; P, postnatal day; ANOVA, analysis of variance; CPP, conditioned place preference.

Address correspondence to: Dr. Clifford C. Michaels, Emory University, Department of Pharmacology, 1510 Clifton Road, Suite 5074, Atlanta, GA 30322. E-mail: ccmicha{at}emory.edu

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