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Official websites use. Share sensitive information only on official, secure websites. Corresponding author: Helen J. Sable, Ph. Polychlorinated biphenyls PCBs are ubiquitous environmental toxicants known to adversely impact human health. Ortho-substituted PCBs affect the nervous system, including the brain dopaminergic system. The reinforcing effects of psychostimulants are typically modulated via the dopaminergic system, so this study used a preclinical i. SA for the psychostimulant cocaine. Rats were trained to lever press for a food reinforcer in an operant chamber under a fixed-ratio 5 FR5 schedule and later underwent jugular catheterization. Active lever presses and infusions were higher in males during response acquisition and maintenance. The same sex effect was observed during later sessions which evaluated responding for cocaine doses ranging from PCB-exposed males not females exhibited an increase in cocaine infusions with a similar trend in active lever presses during acquisition, but no PCB-related differences were observed during maintenance, examination of the cocaine dose-response relationship, or progressive ratio sessions. Overall, these results indicated perinatal PCB exposure enhanced early cocaine drug-seeking in this preclinical model of developmental contaminant exposure particularly the males , but no differences were seen during later cocaine SA sessions. As such, additional questions regarding substance abuse proclivity may be warranted in epidemiological studies evaluating environmental contaminant exposures. Keywords: behavioral neurotoxicology, psychostimulant abuse, fetal basis of adult disease. Polychlorinated biphenyls PCBs are ubiquitous environmental toxicants that adversely impact human health. This is alarming given the emerging and converging evidence suggesting environmental contaminants may be playing a role in the increasing number of developmental and neurological disorders observed in the United States population over the last 30 years CDC, ; Schieve et al. While previous research has been able to show that developmental contaminant exposure impacts executive functions associated with addictive behavior including inhibitory control, cognitive flexibility, and working memory Boucher et al. Developmental PCB exposure in rats has been shown to produce alterations in the dopamine system that persist into adulthood. The reinforcing effects of psychostimulants are typically modulated at least in part via the dopaminergic system, so this study used a preclinical i. SA for the psychostimulant cocaine later in life. We have previously demonstrated that rats perinatally exposed to PCBs exhibit alterations in behavior following experimenter -administered cocaine and amphetamine. Compared to non-exposed controls, rats perinatally exposed to PCBs exhibited greater locomotor activation an initial injection of amphetamine 0. With cocaine However, unlike the attenuation seen for amphetamine, behavioral sensitization for cocaine occurred earlier in PCB-exposed animals, but the overall degree of locomotor sensitization looked similar across exposure groups unpublished results. The difference in behavioral sensitization for PCB-exposed rats following repeated psychostimulant injections appear to be tied to differences in dopamine neurotransmission. While control animals exhibited a significant increase in stimulated dopamine release following repeated injections of the same dose of cocaine an effect tied to dopamine sensitization , stimulated peak dopamine release in the PCB-exposed rats was attenuated following repeated cocaine administration. Overall, these studies indicate perinatal PCB exposure modifies dopamine synaptic transmission in a manner that may alter the reinforcing effects of psychostimulants. However, these studies demonstrate differences in the interoceptive and locomotor-activating effects of experimenter-administered psychostimulants in perinatally PCB-exposed animals, but did not measure psychostimulant reinforcement per se. Thus, this project looked at the effects of perinatal PCB exposure on adult cocaine i. SA in order to determine if PCB-related dopamine dysfunction led to a greater propensity to self-administer cocaine. It was hypothesized that PCB-exposed rats would a reach the pre-set criterion marking the acquisition of cocaine SA in fewer sessions, b self-administer more cocaine and press the lever more during maintenance SA sessions, c show a greater sensitivity to cocaine i. All rats were given water ad libitum and fed a diet of Harlan Teklad X. This standard feed is a high-protein, low phytoestrogen diet which helped maintain overall rodent health and ensured that pregnant females were able to support their litters. Upon arrival, each female was weighed and given an undosed vanilla wafer cookie to acclimate it to eating this novel food item. The female rats were then divided into one of the three PCB dose groups which were counterbalanced for body weight. Dosing procedures were identical to those used by Sable et al. The dosing solutions were pipetted onto a vanilla wafer cookie at a volume of 0. The females were exposed to PCB laced cookies starting 28 days prior to breeding and continuing throughout gestation and lactation until postnatal day 21 when weaning of offspring occurred. Subtle reductions in birth weight and postnatal growth as well as deficits in inhibitory control have also been reported in children born to PCB-exposed mothers Fein et al. For breeding, the females were paired with an unexposed Long-Evans male rat Harlan barrier A. Breeding pairs remained together for eight days, with the female being removed for PCB dosing daily as previously described. After breeding, the females continued to be dosed throughout gestation roughly twenty-one days and lactation twenty-one days. Thus, the offspring of each dam were exposed to PCBs during both gestation and lactation. These outcomes were similar to those previously reported that used the same PCB mixture Kostyniak et al. In each litter, one female and one male were tested for cocaine i. SA as described below such that the number of males and females tested within each PCB exposure group was equal. As attrition is often inherent in i. The offspring were kept on a hr light and hr dark cycle on at , off at Behavioral testing was conducted in 10 automated operant testing chambers Med Associates; St. Albans, VT. These chambers were both sound attenuated and well ventilated with a fan. On one wall of the chamber, there was a food magazine tray positioned in the middle with two retractable response levers symmetrically aligned on each side of the tray. Each response lever had a cue light above it and was 7 cm from the floor and 5. A house light was situated on the wall opposite of the levers. Upon completion of fixed-ratio training, rats underwent catheterization surgery at approximately PND — The rats had a jacket with a port SAI Infusion Technologies, CA where the catheter exited dorsally between the shoulder blades, allowing access to the vein for drug infusions. Lastly, rats were given an additional subcutaneous injection of Rimadyl 2. Each animal was given approximately three days for recovery and then returned to behavioral testing. Furthermore, a daily regimen of the same doses of Baytril and heparin, indicated above, were administered through the catheter port to prevent infection and maintain catheter patency, respectively. Cocaine hydrochloride Sigma, St. Louis, MO was dissolved in 0. The SA testing examining the dose-effect relationship used concentrations of cocaine that were An experimental timeline is presented in Fig. The food restriction was used to ensure the motivation to work for a food reinforcer. This food restriction also helped maintain a relatively consistent body weight of each animal and ensured a comfortable fit of the rat SA jacket throughout the duration of the study. All offspring were weighed and fed at approximately the same time each day, during the lights-on phase of the cycle. At around days old, the rats began testing in the operant chambers. Operant testing occurred seven days a week, one session per day in the order described below. Each dosed cookie was orally consumed by the dam. At approximately days of age, jugular catheterization surgery occurred and around PND , i. To train the rats to press the lever, autoshaping was followed immediately by fixed ratio training procedures that have been described in detail elsewhere Sable et al. Rats remained on autoshaping until lever presses occurred within the 60 min session and no free 45 mg reward pellets Bio-Serve; Frenchtown, New Jersey were dispensed. Each FR session ended after the rat had earned food reinforcers. After three days of recovery from surgery, the animal resumed the previously described FR5 schedule for 3—4 days to ensure full recuperation had taken place and that the animal was adequately lever pressing. Once responding on FR5 had been re-established, the food reinforcer was removed and the rat began i. SA response acquisition for an infusion of cocaine as the reinforcer. The response requirement to earn a cocaine infusion was on the FR5 schedule on the active lever. Previous research has demonstrated that other rat strains acquire and maintain cocaine i. SA at this dose Kosten et al. Sessions lasted two hr or until a maximum of infusions were delivered. When the criterion for acquisition was met, each rodent then moved to maintenance responding which was evaluated over another two weeks of testing. The parameters for maintenance were exactly the same as those used in response acquisition discussed above. Following maintenance, a different dose of cocaine Other than the changes in cocaine dose, the SA testing parameters examining the dose-effect relationship were identical to those used during acquisition and maintenance. After the dose-response paradigm, progressive ratio testing began and lasted for 4 sessions one session per day. During each PR session, deliver of the cocaine reinforcer was the same as during acquisition and maintenance. During each PR session, an increasing number of lever presses were required for each successive drug infusion. Specifically, the number of responses needed to earn a drug infusion was: 1, 2, 4, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, , , , , , , , , , , , , , , and for each successive drug infusion such that the response requirement to earn an infusion increased at an exponential rate minus five. This schedule has been reported to be appropriate for studies examining cocaine i. Each PR session ended after 20 min elapsed between active lever presses. All catheterized rats were checked for patency daily and again at necropsy. After euthanasia an immediate incision was made to expose the catheter implantation site and methylene blue dye was pushed through the port into the catheter line to visually confirm vascular patency. For acquisition, sessions to criterion was the total number of sessions conducted until the criterion for acquisition was met. On the other hand, active and inactive lever presses and the number of infusions for acquisition were averaged only across the three consecutive sessions that demonstrated the acquisition criterion had been met. Similar analyses with the additional independent variable session for maintenance and progressive ratio or dose for dose-response was also included as a repeated-measures factor where appropriate. In the case of any missing data, mean substitution was employed. To ensure that this did not dramatically alter the experimental results, any dependent variable that required mean substitution was analyzed both with the substituted mean and also by dropping the entire litter both male and female from the analysis. No changes in the pattern of results were observed, so instances of mean substitution were retained for the analyses reported below. A MANOVA was run on the dependent variables sessions to criterion, active lever presses, inactive lever presses, and infusions measured during acquisition. Given the observed sex difference, additional one-way ANOVAs for each dependent variable were done to determine if the significant effect of PCB dose was present when separated by sex. These results are presented below. As can be seen in Figure 2A , the number of active lever presses was higher in males but not females that were exposed to PCBs. For both of these measures, there appeared to be more variability in the PCB-exposed males, with a distinct increase in the upper end of the distribution. One male and one female offspring from each litter were tested during adulthood. No difference was found on the number of active lever presses that occurred during acquisition in the female offspring. Error bars represent standard error of the mean. B A significant effect of PCB dose on the number of cocaine infusions earned occurred in the males but not in the females. PCB exposure appeared to increase variation in the males, be extending the upper end of the distribution. See Figure 2B. A MANOVA was run on the dependent variables active lever presses, inactive lever presses, infusions, active lever response duration, inactive lever response duration, and overall response rate measured during the 14 days of maintenance responding. As such, no obvious PCB-related differences were observed across the maintenance sessions in the males or females. The number of active lever presses and infusions see Figure 3 were higher in males than in females. However, within each sex, these measures were similar among the three PCB exposure groups across all days of testing. Males received more cocaine infusions i. However, there were no obvious PCB-related differences in either the males or females see insets. A MANOVA was run on the dependent variables active lever presses, inactive lever presses, infusions, active lever response duration, inactive lever response duration, and session duration measured across the six different cocaine doses examined. As such, no obvious PCB-related differences in the males or females were observed among the dependent variables analyzed across the sessions evaluating the dose-effect relationship. The number of infusions including the total amount of cocaine administered are presented in Figure 4. Active lever presses and infusions were higher in males than in females. These measures decreased in both sexes with increasing cocaine dose. Within each sex, these measures were similar among the three PCB exposure groups across all cocaine doses. Males had a higher number of infusions i. However, there were no PCB-related differences in either the males or females across any of the cocaine doses examined or on the total amount of cocaine self-administered during the dose-effect phase see insets. A MANOVA was run on the dependent variables breakpoint, active lever presses, inactive lever presses, infusions, active lever response duration, inactive lever response duration, and session duration measured across the three days of progressive ratio testing. As such, no obvious PCB-related differences were observed across the three progressive ratio sessions in the males or females among the dependent variables analyzed. The breakpoint and infusions are presented in Figure 5A and 5B , respectively. The breakpoint and active lever presses were higher in females than in males, while the reverse was true for infusions. These measures changed across testing day with the three measures being slightly higher on day 2 compared to the other two days. Within each sex, the breakpoint and number of infusions delivered were similar among the three PCB exposure groups across all three sessions. A Females had a higher breakpoint than males, but there were no PCB-related differences in either the males or females. B Males earned a higher number of reinforcers than females, but there were no PCB-related differences in either the males or females. PCB-exposed male, but not female, offspring had a significantly higher number of cocaine infusions with a similar trend on active lever presses during the acquisition phase. This effect was driven primarily by an increase in variability in the PCB-exposed males, particularly at the upper end of the distribution. There was no difference in the number of sessions required to meet the criterion for acquisition. Recall that sessions to criterion for acquisition was a measure of behavioral in stability across groups, while number of infusions was a measure of intake across groups. The PCB group differences seen in the males during acquisition did not carry over into the maintenance phase. Rather, with more chronic cocaine exposure, the PCB-exposed and non-exposed rats of both sexes demonstrated similar behaviors during the maintenance phase. Likewise, no PCB-related effects were observed during examination of the dose-effect relationship or during progressive ratio testing which occurred later. Taken together these results seem to suggest that developmental PCB exposure has relatively little effect on cocaine SA. However, we are cautious about making such an assertion as one possible explanation for the lack of effect during later i. SA testing phases i. In addition, we have shown adult rats perinatally exposed to PCBs exhibit an attenuation in stimulated peak dopamine release in the nucleus accumbens core following repeated cocaine administration, an effect likely tied to the depletion of presynaptic dopamine stores Fielding et al. Therefore, the impact of PCB exposure could be difficult to evaluate with prolonged cocaine exposure since a reduction in dopamine neurotransmission might be exhibited after many cocaine SA sessions, making it difficult to tease out PCB-associated effects. In this study, rats were continuously tested for cocaine SA seven days per week from the beginning of acquisition throughout maintenance and examination of the dose-effect relationship, and concluding only after three days of progressive ratio testing. Going forward, one approach that might be more effective would be to include periods of forced abstinence within the testing paradigm. Notably, this study did not evaluate the impact of PCB exposure on relapse responding. Evaluating the impact of PCB exposure on i. SA after several periods of forced deprivation i. It is interesting to note that we have previously demonstrated rats perinatally exposed to PCBs were more resistant to extinction on an inhibitory control task for a food reinforcer Sable et al. A second approach would be to evaluate cocaine i. SA starting at adolescence not during adulthood as was done in this study in animals that have undergone the same environmental contaminant exposure model. It has been well established that drug use is frequently initiated during adolescence Johnston et al. Furthermore, adolescent male rats have been shown to more readily self-administer cocaine even at lower doses and escalate their cocaine intake compared to adults Wong et al. Thus, it would be interesting to evaluate whether the dopamine dysfunction associated with environmental contaminant exposure would have a more profound impact on cocaine SA during this more sensitive developmental window. Of course it is also entirely possible that the detrimental effects of perinatal PCB exposure are limited to only i. SA cocaine response acquisition and not SA sessions that occur later and are sex-specific. There is a number of papers that propose that the frontal cortex is involved in initial learning or response acquisition while the striatum has been argued to be involved in maintaining well-established i. As such, the result of this study could be speaking to regional specificity regarding the effects of developmental PCB exposure in the brain, with the frontal cortex but not the striatum being affected. Indeed, we have demonstrated that the same PCB exposure paradigm as the one used in this study impaired performance on executive function tasks requiring frontal cortex modulation for their successful execution Sable et al. Recall that there was a significant effect of PCB exposure on the number of cocaine infusions during the acquisition phase only in the males, suggesting dopamine dysfunction is more profound in the PCB-exposed males. This sex effect was also observed by Poon et al. Interestingly, cocaine behavioral sensitization unpublished results and stimulated dopamine release Fielding et al. PCBs are an endocrine-disrupting compound, which means they can alter normal endocrine functions including the normal function of thyroid and steroid hormones. Male offspring seem to be particularly sensitive to perinatal ortho- substituted PCB exposure Cocchi et al. The exact mechanism is not clear, but PCBs have been shown to lower aromatase activity Hany et al. This theory is intriguing because an alteration in aromatase activity during early development has been shown to affect dopamine concentrations in the prefrontal cortex Lauber et al. As previously mentioned, differences in cocaine unpublished results and amphetamine Poon et al. Likewise, other studies using animal models have reported that developmental exposure to lead Clifford et al. Thus, there is converging research to demonstrate that exposure to monoamine-disrupting chemicals during early development can promote drug-seeking later in life. Evaluation of the impact of perinatal environmental contaminant exposure on substance use and abuse later in life is extremely difficult to examine in prospective longitudinal birth cohorts due to challenges associated with the cost of such studies, participant retention, interpretation of results because participants have often been exposed to multiple contaminants , and the validity of self-reported or historical drug use data. As such, preclinical models like the one used here are needed to accurately evaluate the impact of early developmental contaminant exposure on drug-seeking as well as any other negative behavioral consequences. In summary, the results of this project using an animal model supported a link between developmental contaminant exposure in PCB-exposed males and enhanced acquisition of cocaine i. Such results suggest that individuals perinatally exposed to PCBs may exhibit a greater propensity for drug abuse than individuals without a history of contaminant exposure. Future research using this preclinical environmental exposure model while looking at different SA parameters and in different age groups will be necessary to explore this issue further. Likewise, it will be important to consider this issue and attempt to accurately assess similar outcomes in ongoing and future epidemiological studies of individuals developmentally exposed to monoamine-disrupting environmental contaminants. Data collected in this study using a preclinical model of developmental contaminant exposure indicated that perinatal exposure to the legacy contaminant polychlorinated biphenyls PCBs increased the acquisition of cocaine intravenous self-administration in male but not female offspring. These results suggest that developmental exposure to environmental contaminants may sex-specifically increase the propensity for drug-seeking. The latter does not necessarily imply endorsement by the University of the research conclusions. All authors contributed in a significant way to the manuscript and all authors have read and approved the final manuscript. As a library, NLM provides access to scientific literature. Exp Clin Psychopharmacol. Published in final edited form as: Exp Clin Psychopharmacol. Find articles by Mellessa M Miller. Find articles by Abby E Meyer. Find articles by Jenna L N Sprowles. Find articles by Helen J K Sable. Issue date Apr. PMC Copyright notice. The publisher's version of this article is available at Exp Clin Psychopharmacol. Open in a new tab. All authors have no conflicts of interest to report. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. 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