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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Neuropeptides. Author manuscript; available in PMC 2009 Oct 1.
Published in final edited form as:
Neuropeptides. 2008; 42(5-6): 641–652.
Published online 2008 Jun 24. doi: 10.1016/j.npep.2008.05.003
PMCID: PMC2614125
NIHMSID: NIHMS84138
PMID: 18579201

IMPACT OF GESTATIONAL COCAINE TREATMENT OR PRENATAL COCAINE EXPOSURE ON EARLY POSTPARTUM OXYTOCIN mRNA LEVELS AND RECEPTOR BINDING IN THE RAT

M.S. McMurray,1 E.T. Cox,2 T.M. Jarrett,4 S.K. Williams,2 C.H. Walker,3 and J.M. Johns1,2,3,4
Author information Copyright and License information Disclaimer

Abstract

Prior research reported decreased oxytocin levels in specific brain regions correlated with disruptions in maternal care following gestational cocaine treatment in rats. Similarly, prenatal exposure to cocaine impaired subsequent maternal behavior in adulthood, but behavioral alterations were not associated with decreases in oxytocin levels in the same brain regions as were found in their cocaine-treated rat dams. To determine if other aspects of the oxytocin system are disrupted by cocaine treatment or prenatal exposure to cocaine during critical time points associated with maternal care, oxytocin mRNA transcription and receptor binding were examined on postpartum day two in relevant brain regions following gestational treatment with, or prenatal exposure to, either cocaine or saline. We hypothesized that oxytocin mRNA levels and receptor binding would be differentially affected by cocaine in the early postpartum period of dams and their offspring. Our findings indicate that gestational cocaine treatment resulted in significant increases in oxytocin mRNA levels in only the paraventricular nucleus of cocaine-treated dams, with almost significant increases in both generations in the supraoptic nucleus, but no significant effects of cocaine on receptor binding in either generation of dams. These findings indicate that in addition to oxytocin levels, cocaine treatment or prenatal exposure primarily affects oxytocin mRNA synthesis, with little effect on receptor binding in specific brain regions associated with maternal behavior in the early postpartum period of the rat.

Keywords: Oxytocin Receptor, Oxytocin mRNA, Cocaine, Intergenerational, Maternal Behavior

INTRODUCTION

Adequate maternal care is unquestionably critical for the normal development of mammalian offspring and the survival of the species as a whole. Rodent models of maternal behavior are particularly useful for the study of this important behavioral set. Rodent offspring are born blind and unable to thermoregulate, defecate, urinate, or protect themselves from attack (Numan, 1994), thus requiring considerable maternal care to survive. Importantly, rodent maternal behavior has been well characterized behaviorally, but has only recently begun to be understood in terms of neurobiological mechanisms.

The onset of maternal behavior is thought to stem primarily from hormonal changes that occur at parturition (Insel and Harbaugh, 1989; Numan and Insel, 2003; Van Leengoed et al., 1987), while the maintenance of established maternal behavior appears to be less hormone-dependent. The onset of maternal behavior is characterized by a dramatic drop in progesterone levels accompanied by a rise in estrogen, which remains elevated through much of the postpartum period (Terkel and Rosenblatt, 1968; Terkel and Rosenblatt, 1972). In addition to estrogen and progesterone, one of the primary hormonal mediators of maternal behavior is the nonapeptide oxytocin, synthesized primarily in the paraventricular and supraoptic nucleus of the hypothalamus (Numan and Insel, 2003). These two regions contain two oxytocin-producing neuronal subtypes: magnocellular and parvocellular. Magnocellular neurons within both of these regions project to the posterior pituitary for secretion to the peripheral circulatory system. Peripheral oxytocin initiates contractions during labor, facilitates milk letdown during the postpartum period, and modulates the stress response in both humans and rats (Petersson et al., 1996; Russell and Leng, 1998). The parvocellular neurons are found only in the paraventricular nucleus, and project centrally to the bed nucleus of the stria terminalis, medial preoptic area of the hypothalamus, ventral tegmental area, amygdala, hippocampus, olfactory bulbs, and nucleus accumbens, as well as other regions in the brain (Bale et al., 2001; Ingram and Moos, 1992; Numan and Corodimas, 1985; Pedersen, 1997). The function of oxytocin in these regions appears to play a role in the onset of pup-directed maternal behavior, maternal aggression, social and affiliative behaviors, and stress reactivity.

Interestingly, oxytocin release, receptor number, and mRNA transcription increase several fold throughout the brain at parturition (Insel, 1990; Lightman and Young, 1987; Neumann et al., 1993), implying an increase in the functional importance of oxytocin during the early postpartum period. Oxytocin is particularly important to the onset of maternal behavior (proposed as postpartum days one through three in rats), and is essential for the switch from the avoidance of pups to the approach of pups (Fleming et al., 1980; Numan and Insel, 2003). Intracerebroventricular oxytocin antagonist administration (Pedersen et al., 1982), or lesions of specific oxytocin-containing brain regions, including the paraventricular nucleus (Insel and Harbaugh, 1989), medial preoptic area (Numan, 1986; Numan, 1994), hippocampus (Kimble et al., 1967), and ventral tegmental area (Gaffori and LeMoal, 1979; Numan and Smith, 1984) have been shown to disrupt maternal behavior during this period. Similarly, oxytocin anti-sense administration into the paraventricular nucleus has been shown to disturb aspects of maternal behavior (Giovenardi et al., 1998). Conversely, intracerebroventricular administration of oxytocin in rodents has been shown to dose-dependently increase maternal behavior in usually non-maternal virgin female rats (Pedersen et al., 1982). Despite oxytocin’s importance to the onset period of maternal behavior, its role in maintaining maternal behavior through the later postpartum periods is poorly understood.

Gestational cocaine treatment has been shown to disrupt multiple aspects of early postpartum maternal behavior dose dependently (Nelson et al., 1998; Vernotica et al., 1996). These behavioral alterations have been associated with decreased oxytocin levels in some of the brain structures implicated in maternal behavior and/or maternal aggressive behavior, including the medial preoptic area, ventral tegmental area, and hippocampus (Johns et al., 1997). When administered directly into the medial preoptic area and nucleus accumbens, cocaine has been shown to disrupt multiple aspects of maternal behavior (Vernotica et al., 1999). Thus, it has been suggested that cocaine’s effect on the onset of maternal behavior may stem primarily from its effect on oxytocinergic systems, either directly or indirectly via other neurotransmitter effects (Elliott et al., 2001; Johns et al., 1994; Johns et al., 1998). Given oxytocin’s role in the normal induction of maternal behavior, it seems that oxytocin is a likely candidate for mediation of cocaine’s effects on this behavioral set.

Johns et al. (2005) demonstrated that poor maternal care given by cocaine-treated rat dams rearing untreated foster pups was subsequently reflected in the maternal behavior of these offspring, who exhibited less pup-directed maternal care when they became mothers. A variety of disruptions in maternal behavior that resulted from rearing condition or prenatal cocaine exposure were demonstrated in offspring, but rearing by cocaine-treated dams was correlated with increased oxytocin levels in the medial preoptic area following pup exposure. This was unlike the consistent decreases in oxytocin levels seen in the medial preoptic area of the cocaine-treated dams. Given the importance of the oxytocin system in maternal care, it seems likely that other oxytocin system dynamics might play a role in the altered maternal behavior of offspring prenatally exposed to cocaine.

The purpose of this project was to examine two aspects of the oxytocin system that have not been systematically examined in the early postpartum period following gestational treatment with cocaine or prenatal exposure to cocaine: oxytocin mRNA levels in the paraventricular and supraoptic nucleus, and oxytocin receptor binding in the medial preoptic area, ventral tegmental area. Since the focus of this paper concerned oxytocin changes following cocaine treatment or exposure, brain regions containing oxytocin receptors or mRNA that have been shown to be directly affected by cocaine and are relevant to specific aspects of maternal care were chosen. As discussed above, these regions have been associated with changes in oxytocin levels following gestational cocaine treatment, and will thus be the focus of this paper. It was hypothesized that gestational treatment with cocaine would result in increased oxytocin mRNA production in the paraventricular and supraoptic nucleus, and would alter oxytocin receptor binding in the medial preoptic, ventral tegmental and hippocampal brain regions. These changes were expected to occur in response to other cocaine-induced changes in the oxytocin system dynamics previously reported. Additionally, based on previous behavioral and biochemical studies implicating oxytocin system involvement, it was hypothesized that prenatal exposure to cocaine would alter oxytocin mRNA levels and receptor binding in the same brain regions assessed in the original dams.

METHODS

Subjects

Virgin female Sprague–Dawley rats (200–250 grams) were group housed in a temperature and humidity controlled room for a one-week habituation period prior to mating. Females were then singly housed with a sexually mature male until conception was noted by the presence of a sperm plug and, if necessary, confirmation via vaginal smear. On the day of conception, designated as gestation day (GD) zero, the female was removed from the breeding cage, randomly assigned to a treatment group, and individually housed. Pregnant females were maintained on a reverse 12-hour light-dark cycle (lights on at 2100 hours for seven days), then transferred to a room with a regular light cycle (lights on at 0700 hours for the remainder of the experiment); a procedure that results in the majority of dams delivering during daylight hours (Mayer and Rosenblatt, 1998). All procedures were conducted under federal and institutional animal care and use committee guidelines for the humane treatment of laboratory animals.

Treatment

Original Dams

On GD zero, pregnant females were randomly assigned to either chronic cocaine (CC) or chronic saline (CS) groups (eight per group). CC- and CS-treated dams received subcutaneous injections twice daily throughout gestation (GD 1–20) on alternating flanks, of 15.0mg/kg cocaine HCL (Sigma-Aldrich, St. Louis, MO) dissolved in 0.9% normal saline (1.0ml/kg total volume), or 1.0ml/kg normal saline respectively, at approximately 0800 and 1600 hours. CC-treated dams had free access to water and food (rat chow). To control for the anorexic effects of cocaine, CS-treated dams were food yoked (pair fed) to match consumption of food by CC-treated dams, as previously described (Johns et al., 1994; Johns et al., 2005).

First Generation Dams

First generation offspring of the cocaine and saline treated dams were immediately cross-fostered to untreated surrogate dams who had given birth within hours of the treatment dams to control for differences in the care received by these two groups of pups. Offspring were weaned on postnatal day 21 and one female from each litter was bred on postnatal 60. Breeding procedures were as described above, except that no drugs were administered to first generation dams (FGDs) during gestation. All FGDs were maintained on ad libitum food and water. The focus of this paper was on the biological oxytocin response to pups and not the measurement of maternal behavior, other than the general maternal response. Thus, litters were culled to four pups following delivery (two male and two female) to ensure maternal stimulation, since litters of this size have been shown to elicit maternal care and oxytocin response (Van Leengoed et al., 1987).

Original Dam Maternal Behavior Priming

The procedure for maternal behavior priming has been previously described (Johns et al., 1994). Following delivery of their final pup, original dams and their litters were brought in their home cage to an enclosed behavioral observation room, 400cm × 460cm, where dams were removed from their cage and weighed. Their pups were removed, culled to litters of eight (four male and four female pups), and fostered to an untreated surrogate dam who had delivered within 12 hours of the treated dam. Treated dams were returned to their home cage without pups and the cage placed in a 60cm × 40cm × 50cm dimly lit testing cubicle for a 30-minute habituation period. Simultaneous with the habituation period, the untreated surrogate litters from the surrogate dams that received the treated pups were weighed and culled to four female and four male pups. Surrogate litters were then placed on top of the experimental dam’s testing cubicle in a room temperature plastic cage lined with paper towels. After habituation, nesting material (ten, 2.5cm strips of paper towel) was placed at the back of the dam’s cage and the culled surrogate litter was placed in the front of her cage. Dams were allowed access to pups for 30 minutes on postpartum day (PPD) one, and then returned with the pups to the animal colony until they were killed 24 hours later.

Brain Collection and Slice Preparation

Twenty-four hours after maternal behavior priming in original dams, subjects were decapitated, the whole brain extracted and frozen immediately on dry ice and stored at -80°C. The time of sacrifice for FGDs was matched to the original dams, but no behavioral priming occurred. Twenty μm coronal sections were collected from regions of interest as illustrated in the rat brain atlas (Paxinos and Watson, 1997). Regions of interest for in situ hybridization included the paraventricular nucleus and supraoptic nucleus of the hypothalamus (see Figure 1), while receptor autoradiography focused primarily on the medial preoptic area, ventral tegmental area, and ventral CA1 region of the hippocampus (see Figure 2). Slices were thaw mounted onto slides and returned to storage at −80°C until time of assay.

An external file that holds a picture, illustration, etc. Object name is nihms84138f1.jpg

Representative Atlas images depicting the range of slices collected for the examination of oxytocin mRNA. Shaded regions denote A) the paraventricular nucleus and B) the supraoptic nucleus, the primary production sites of oxytocin mRNA. Circles have been added to emphasize the location of the supraoptic nucleus.

An external file that holds a picture, illustration, etc. Object name is nihms84138f2.jpg

Representative Atlas images depicting the range of slices collected for the examination of oxytocin receptor binding. Shaded regions denote A) the medial preoptic area; B) the ventral tegmental area; and C) the ventral CA1 region of the hippocampus.

Oxytocin In Situ Hybridization

Sections were fixed in paraformaldehyde and rinsed in PBS. After treatment with triethanolamine and acetic anhydride, they were then defatted in chloroform and dehydrated in a series of graded ethanol concentrations. Each slide was incubated at 37°C overnight with 200μl of hybridization solution containing about 1×106cpm of a 41 base 35S-labeled oxytocin oligonucleotide probe (Invitrogen, Carlsbad, California) (GGG CTC AGC GCT CGG AGA AGG CAG ACT CAG GGT CGC AGG CG) complementary to nucleotides 906–946 of the rat oxytocin mRNA (GenBank Accession Number K01701). After the incubation, the slides were washed, dehydrated, dried, and placed on Kodak Biomax MR film for one hour and developed.

Oxytocin Receptor Autoradiography

Oxytocin receptor autoradiogaphy was performed using 125I-OTA [d(CH2)5, O-Me-Tyr2, Thr4, Tyr9, Orn8]-vasotocin as described previously (Francis et al., 2002). Sections were allowed to thaw at room temperature, immersed in a fixative at room temperature for two minutes, and then rinsed twice for 10 minutes in Tris Buffer. For tracer binding, 30mL of tracer solution containing 1,800cpm/10μl probe was applied to the sections in vertical slide holders at room temperature for 60 minutes. After tracer binding, the slides underwent three five-minute washes with Tris/MgCl buffer at room temperature, followed by one 30-minute wash in Tris/MgCl buffer, and then a final two-second wash in distilled water. Slides were then rapidly dried and, along with a series of 125I-microscale standards, were exposed on film for four days to obtain images for quantification.

Photomicrograph Production and Image Analysis

Binding was quantified from the digitized films using the NIH Image program for the Macintosh®. For the receptor binding studies, optical densities were converted to disintegrations per minute, per milligram tissue equivalents using the 125I-autoradiograph standards developed with the slide images. This conversion was not used on the mRNA film, since standards are not commercially available. Comparisons between treatment groups were based on optical density measurements. To ensure that the entire region of interest was examined, binding was measured bilaterally from an average of seven non-consecutive slides per animal taken from the PVN, nine from the SON, five from the MPOA, nine from VTA, and ten from the Ventral CA1, distributed throughout each region.

Statistical Analysis

For both in situ and autoradiography data, a mean value for each animal for each brain region was calculated after outliers were removed. As our hypothesis for the original dams was directional, we were able to use one-tailed T-tests with pooled variance to compare the mean mRNA levels of each group; however, two-tailed T-tests were used to examine mRNA levels in the FGDs, and receptor binding in both generations. Statistical significance was set at the p≤0.05 level. Data are presented as group mean optical density for in situ and DPM/mg for autoradiography, with standard error.

RESULTS

Original Dams

Gestational

As shown in Table 1, CC-treated dams gained less weight during pregnancy than CS-treated dams [F(1,16)=7.134, p≤0.05]. Cocaine-treated animals gained an average of 119.6±5.4g during the gestational period, while saline-treated animals gained an average of 139.1±4.9g. There were no between-group differences in gestation length, litter birth weight, culled litter weight, or male/female ratio.

Table 1

Gestational and Litter Data

Dam ConditionNumber of DamsGestational Weight Gain (g)Number of PupsLitter Birth Weight (g)Culled Litter Weight (g)
Original Dam TreatmentCC8119.6±5.4 *14.1±0.885.6±5.037.5±1.0
CS10139.1±4.913.9±0.785.8±4.537.3±0.9
FGD Prenatal ConditionCC8121.7±16.013.9±0.982.6±6.223.3±0.9
CS9137.4±14.912.2±0.976.8±5.824.4±0.8

Note. CC indicates treatment with/prenatal exposure to chronic cocaine, while CS indicates treatment with/prenatal exposure to chronic saline. Culled Litter Weight in Original Dams represents weight of culled untreated foster litter. Asterisk indicates significant between groups difference at the p ≤ 0.05 level.

Oxytocin In Situ Hybridization

As shown in Figure 3, CC-treated dams exhibited significantly higher mean optical density in the paraventricular nucleus compared to CS-treated animals (CC: 60.59±2.41; CS: 53.93±2.19; p=0.03), indicating higher levels of oxytocin mRNA. There was no significant difference between groups in the supraoptic nucleus, although there was a strong trend towards increased transcription in this region in cocaine-treated dams compared to controls (CC: 73.75±2.30; CS: 68.17±2.45; p=0.06).

An external file that holds a picture, illustration, etc. Object name is nihms84138f3.jpg

Oxytocin mRNA in situ hybridization in the paraventricular nucleus and supraoptic nucleus of Original Dams. Representative radiographs are coronal brain slices taken from saline-treated (A) and cocaine-treated (B) rat dams. Quantification of binding in the paraventricular nucleus (C) and the supraoptic nucleus (D) was performed using NIH Image software, and values are represented as mean optical density area + SEM. * p ≤ 0.05

Receptor Autoradiography

T-tests revealed no between group differences in autoradiographic oxytocin binding (DPM/mg) in the medial preoptic area (CC: 5484.0±428.0; CS: 5146.1±608.8; p=0.33), ventral tegmental area (CC: 12090.0±1480.9; CS: 11939.0±1143.5; p=0.47), or ventral CA1 region of the hippocampus (CC: 61064±3318.8; CS: 64028±4030.9; p=0.29) respectively.

First Generation Dams

Gestational Data

There were no differences between CC-exposed and CS-exposed FGDs on any gestational measure examined. Gestational data for FGDs is presented in Table 1.

Oxytocin In Situ Hybridization

As shown in Figure 4, CC-exposed FGDs exhibited no significant differences in mean optical density in the paraventricular nucleus compared to CS-exposed animals (CC: 73.13±1.99; CS: 74.51±0.86; p=0.25). Although there was no significant difference in the supraoptic nucleus, as in their biological mothers, CC-exposed pups exhibited a strong trend towards increased oxytocin mRNA transcription levels in this region (CC: 81.78±1.49; CS: 76.60±2.06; p=0.06).

An external file that holds a picture, illustration, etc. Object name is nihms84138f4.jpg

Oxytocin mRNA in situ hybridization in the paraventricular nucleus and supraoptic nucleus of First Generation Dams. Representative radiographs are coronal brain slices taken from saline-exposed (A) and cocaine-exposed (B) rat dams. Quantification of binding in the paraventricular nucleus (C) and the supraoptic nucleus (D) was performed using NIH Image software, and values are represented as mean optical density area + SEM.

Receptor Autoradiography

There were no significant treatment effects on autoradiographic oxytocin binding (DPM/mg) in the medial preoptic area (CC: 18174±609.91; CS: 18220±1081.9; p=0.97), ventral tegmental area (CC: 11991±1204.9; CS: 11548±608.43; p=0.73), or ventral CA1 region of the hippocampus (CC: 61776±5653.8; CS: 61969±2328.1; p=0.97) of FGDs.

DISCUSSION

The purpose of this study was to determine cocaine’s effect on postpartum oxytocin mRNA production and receptor binding in relevant brain regions following gestational treatment with, or prenatal exposure to cocaine. As predicted, we found an increase in oxytocin mRNA synthesis in the paraventricular nucleus of gestationally cocaine-treated dams, a treatment that has been shown to result in, lower oxytocin levels in brain regions indicated as important for the normal onset of maternal behavior (Johns et al., 1997). In preliminary work (Cox et al., 2007; McMurray et al., 2006), we found less robust effects in oxytocin mRNA production following cocaine treatment, but after testing with a larger number of subjects and refined assessment tools, were able to increase the strength of our findings. The effect we report could potentially be in response to other reported cocaine-induced changes in oxytocin system dynamics, or may reflect oxytocin mRNA production increases following overnight exposure and interaction with pups. However, no maternal behavioral measures were assessed in these studies since that was not the focus of this work, and thus findings cannot be directly correlated with behavior.

The paraventricular nucleus is especially relevant not only for its magnocellular oxytocin producing neurons, but also for its parvocellular oxytocin neurons with central projections to distinct brain regions associated with maternal/social behavior (Bale et al., 2001; Ingram and Moos, 1992; Numan and Corodimas, 1985; Pedersen, 1997; Swanson and Sawchenko, 1983). Unfortunately, we could not clearly visualize a differentiation between the magnocellular and parvocellular neurons, which may have masked any parvocellular-specific effects. There were also very strong trends toward increased mRNA production in the supraoptic nucleus and had our sample size been slightly larger we may have found significant increases in both areas. The supraoptic and paraventricular nucleus differ in terms of cell composition and function. Unlike the paraventricular nucleus, the supraoptic nucleus contains primarily magnocellular neurons projecting to the posterior pituitary for the secretion of oxytocin into the peripheral nervous system (Swanson and Sawchenko, 1983). There is evidence for a parasympathetically driven “anti-stress” system, primarily mediated by oxytocin signaling (Uvnas-Moberg, 1997). If indeed peripheral oxytocin plays a role in the stress response, this nearly significant elevation in mRNA production in the supraoptic nucleus of cocaine-treated dams and their cocaine-exposed offspring may reflect subtle dysfunctions in the stress response of these animals (Huber et al., 2001; Molina et al., 1994; Wood et al., 1995).

Very few studies have examined the complex mechanisms of oxytocin synthesis following cocaine treatment, thus non-drug models are useful to examine possible target pathways for cocaine’s effects in the present study. As illustrated in Figure 5, the primary mechanism of oxytocin transcription regulation in a non-drug environment occurs through the steroid hormones estrogen and progesterone (Amico et al., 1995; Amico et al., 1997; Johnson, 1992; Kendrick and Keverne, 1992; Patchev et al., 1993; Rosenblatt et al., 1994; Thomas et al., 1995; Widmer et al., 2003; Zingg et al., 1995). Evidence exists supporting the differential modulatory roles of both estrogen and progesterone in cocaine’s behavioral effects, including its rewarding and locomotor effects (Niyomchai et al., 2005; Russo et al., 2003), although these effects were not examined in lactating dams. One publication has examined cocaine’s impact on estrogen (Mello et al., 2000), reporting only minor increases in estrogen levels following acute cocaine administration. As demonstrated by acute cocaine studies (Wu et al., 2006), cocaine can also directly influence progesterone levels, which may in turn alter oxytocin mRNA production, but little is known about the effects of chronic gestational cocaine in lactating animals on these steroid systems.

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Theoretical diagram of the major regulatory mechanisms of oxytocin mRNA transcription within the paraventricular and supraoptic nuclei. Plus and minus signs indicate direction of modulation of the respective systems, while size of sign and arrow indicates relative strength of modulation. Primary modulation occurs through estrogen and progesterone.

A third system of oxytocin mRNA regulation is mediated through the prolactin system (Bakowska and Morrell, 1997; Ghosh and Sladek, 1995a; Ghosh and Sladek, 1995b; Popeski et al., 2003). Decreased prolactin release has been shown to reduce oxytocin mRNA production (Grattan, 2001). During lactation, dopamine signaling, which is known to be altered by cocaine, has a direct inhibitory influence on prolactin levels (Byrnes and Bridges, 2007; Mello et al., 1994; Voogt, Lee, Yang, and Arbogast, 2001). Interestingly, acute dopamine D2 receptor activation can also reduce prolactin release, in turn reducing oxytocin mRNA production (Byrnes and Bridges, 2007; Popeski et al., 2003). Chronic cocaine administration has been associated with an overall decrease in the number of D2 receptors (Nader et al., 2006), which could then result in an overall increase in prolactin levels and thus contribute to the increase we saw in oxytocin mRNA; however, this has not been studied in a lactational model. Considering dopamine’s involvement in reward circuitry, it would be interesting to examine the oxytocin in regions associated with reward, such as the nucleus accumbens and amygdala, which are likely involved in maternal behavior. Oxytocin receptor activation may also further increase oxytocin release and possibly protein synthesis (Neumann et al., 1996), either directly through oxytocin receptor activation, or indirectly by increasing prolactin levels (Popeski et al., 2003; Samson et al., 1986) to stimulate oxytocin mRNA synthesis.

Cocaine is a potent reuptake inhibitor of dopaminergic, serotonergic, and less so of noradrenergic systems. In addition to the effects on dopamine receptors previously mentioned, the serotonin and norepinephrine systems have also been shown to increase oxytocin mRNA transcription in both the supraoptic and paraventricular nucleus, though the mechanism of these interactions has not been fully elucidated (Jorgensen et al., 2003; Vacher et al., 2002). Chronic cocaine administration through its multiple effects on these systems could result in alterations in neurotransmitter receptor levels and an overall change in the sensitivity of these systems.

In addition to blocking dopamine reuptake, cocaine also alters dopamine release and receptors (White, 1990). Manipulations of the dopamine system have been strongly associated with alterations in various aspects of maternal behavior and affect aspects of oxytocin. D2 receptor agonists particularly promote the release of peripheral oxytocin (Amico et al., 1992; Amico et al., 1993; Crowley et al., 1992; Parker and Crowley, 1992), while administration of dopamine antagonists results in a significant disruption in pup retrieval, nest building, and motor activity in general (Byrnes et al., 2002; Giordano et al., 1990; Keer and Stern, 1999; Silva et al., 2001; Silva et al., 2003; Stern and Keer, 1999).

Serotonin, though more strongly associated with aggression, also affects maternal behavior, and is therefore another candidate for oxytocin mRNA changes following cocaine treatment. Similar to cocaine treatment, serotonin reuptake inhibition has been associated with alterations in oxytocin receptor dynamics (Johns et al., 2004), and serotonin agonists alter peripheral oxytocin release, which is important for lactation (Bagdy et al., 1992; Bagdy and Kalogeras, 1993; Saydoff et al., 1991; Uvnas-Moberg et al., 1996). Serotonin’s role in oxytocin mRNA production is unclear, but the median raphe, a major production site for serotonin (Barofsky et al., 1983), projects to magnocellular neurons in the paraventricular and supraoptic nuclei (Sawchenko et al., 1983), and is known to affect oxytocin release under stressful conditions (Barofsky and Harney, 1978; Saphier, 1991), which could in turn alter oxytocin transcription.

In this study, we found no significant differences in receptor binding in dams following priming exposure to pups. This finding, in conjunction with preliminary reports examining cocaine treated-dams without a history of pup exposure, indicates that gestational cocaine does not alter receptor binding in the specific brain regions examined, regardless of the presence of pup stimuli. Receptor changes do not always occur in conjunction with level changes, and the results of studies such as this one are highly dependent on the time of sampling. It is clear that the oxytocin receptor system is complex and varies according to brain region and time of assessment (Meddle et al., 2007). Given reported alterations in receptor affinity in the later postpartum period following gestational cocaine treatment (Johns et al., 2004), it is also possible that receptor affinity changes occur earlier in the postpartum period, but the methods used in present study did not allow this determination.

With respect to prenatal cocaine exposure, little has been reported regarding the effects of cocaine on the oxytocin system other than slight level increases following pup stimulation (Johns et al., 2005). Given the previously reported behavioral alterations, some of which are very similar to treated dams, we expected differences in one or more aspects of the oxytocin system in prenatally exposed FGDs. However, we found only a strong trend for increased oxytocin mRNA in the supraoptic nucleus rather than the paraventricular nucleus of cocaine-exposed FGDs, similar to their biological dams. Since there was a relatively small number of offspring tested (8–9 per group), additional animals may have resulted in statistical significance given the strong trends in the supraoptic nucleus.

Since all offspring were fostered to untreated surrogate mothers, many confounds resulting from differential maternal care in these groups were controlled for, though fostering in itself has been shown to affect the stress response (Champagne and Meaney, 2001; Fish et al., 2004). Prenatal exposure to cocaine may alter the pup’s ability to elicit maternal care. Since the maternal behavior received by FGDs was not assessed in the current study, the impact of these factors on the effects we report here cannot be determined. There is a need for more definitive studies examining the impact of prenatal cocaine on the elicitation of maternal behavior. It would be interesting to repeat this study in animals lacking prenatal exposure to cocaine, but reared by cocaine-treated mothers. Such animals demonstrated alterations in central oxytocin levels (Johns et al., 2005), suggesting that additional aspects of oxytocin signaling may be disrupted.

Prenatal cocaine exposure disrupts many social/aggressive behaviors across development, and effects seem to manifest during stressful conditions (Johns et al., 1992b; Johns et al., 1992a; Johns and Noonan, 1995; Overstreet et al., 2000). If the stress response were a trigger for oxytocin mRNA changes, it would be extremely important to find a mechanism underlying abnormal stress responses in offspring prenatally exposed to cocaine. Since prenatal cocaine exposure alters multiple aspects of serotonin signaling, including receptors, affinity, release, etc. (Akbari et al., 1992; Cabrera et al., 1993; Henderson and McMillen, 1993; Johns et al., 2002; McReynolds and Meyer, 1998; Yan, 2002), it seems likely that the effects of cocaine on oxytocin transcription in the supraoptic nucleus could be related to serotonergic disruptions, since there was no effect of cocaine exposure on oxytocin receptor binding. These results suggest that prenatal cocaine exposure could influence oxytocin signaling during the later postpartum period through its effects on mRNA transcription, and add new and important data to the emerging picture on how cocaine influences oxytocin and perhaps maternal and social behavior through multiple generations. The potential role of stress response mechanisms highlights the exciting possibilities with respect to these systems.

Acknowledgments

We would like to acknowledge the support of Dr. Gary Duncan as well as Emily Fay for technical support and the National Institute on Drug Abuse for their financial support.

Support: NIH RO1-DA13283 awarded to J. Johns

Footnotes

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