Assessing the effects of adolescent PCB exposure on executive functions in humans and animals

Converging evidence from studies in animal models and humans suggests that early developmental exposure to polychlorinated biphenyls (PCBs), a class of persistent organic pollutants, leads to deficits in cognitive functions such as cognitive flexibility and inhibitory control. These cognitive processes are mediated to a large extent by the prefrontal cortex (PFC). The dopamine (DA) system is a neurochemical system thought to play a critical role in modulating these cognitive functions, and the cognitive deficits seen with early PCB exposure may be mediated by DA dysfunction. Previous PCB studies have focused on the perinatal period as a critical period of exposure, and little or no research has examined the effects of exposure during another critical period of brain development – adolescence. During this period, the PFC and DA innervation of the PFC are undergoing marked maturation. Thus, executive functions mediated by the PFC, including cognitive flexibility and response inhibition, may be especially sensitive to disruption during adolescence. The goal of this research was to investigate the effects of adolescent PCB exposure on cognitive flexibility and response inhibition using parallel human and animal studies. In the animal study, the goal was to examine the long-term effects of adolescent PCB exposure on cognitive flexibility, using an operant set-shifting task, and response inhibition, using a differential reinforcement of low rates of responding (DRL) task. An additional goal was to determine whether exposure during this period would lead to long-lasting changes in dopamine transporter (DAT) expression that could underlie changes in cognitive performance that were observed. One male and one female pup from each of 14 litters were assigned to each of three treatment groups, 0, 3 or 6 mg/kg/day PCBs. Rats were orally dosed daily from postnatal day (PND) 27-50 to capture the whole period of adolescence in rats, and cognitive testing began at PND 90. In the set-shifting task, we saw a sex-specific effect of PCBs on the reversal phase with PCB-exposed males performing better in this phase, possibly due to these rats employing a simpler, more “habit-based” response strategy rather than learning the actual response reversal relevant to the task. In the DRL task, we found no effect of PCB-exposure. The PCB-related effects in performance on these two cognitive tasks were not as robust as hypothesized, and, perhaps not-surprisingly then, there were no significant differences in DAT expression in the orbital frontal cortex - which is important for reversal learning - or the striatum. To explore effects of PCB exposure in human adolescents, data were collected from 115 12-18 year old children of sport anglers in Green Bay, Wisconsin, where this population is exposed to PCBs through consumption of fish from contaminated waters. PCB concentrations were measured in the childrens’ serum and assessed in relation to performance on computerized tasks of cognitive flexibility, using the CANTAB Intradimensional/Extradimensional (ID/ED) set-shifting task, and response inhibition, using the Integrated Visual and Auditory (IVA) Continuous Performance Task. Behaviors associated with ADHD were assessed using the Conner-Wells’ Behavior Rating Scale Parent Report. PCB exposure was not associated with scores on the Conners’ scales, but higher PCB exposure was associated with more total trials to complete the ID/ED test in males. Higher PCB exposure, however, was not associated with a difference in performance on the response inhibition measure in boys or in girls. In summary, the results of these studies suggest there are subtle sex-specific disruptions in cognitive flexibility associated with PCB exposure during adolescence in both male rats and humans

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6. mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0. mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25. mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125. mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting that the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest that developmental PCB exposure can alter the interoceptive cues of psychostimulants. © 2010 Elsevier Inc

Developmental exposure to polychlorinated biphenyls reduces amphetamine behavioral sensitization in Long-Evans rats

PCBs have long been known to affect dopamine (DA) function in the brain. The current study used an amphetamine behavioral sensitization paradigm in rats developmentally exposed to PCBs. Long-Evans rats were given perinatal exposure to 0, 3, or 6. mg/kg/day PCBs and behavioral sensitization to d-amphetamine (AMPH) was assessed in one adult male and female/litter. Non-exposed (control) males showed increasing locomotor activity to repeated injections of 0.5. mg/kg AMPH, typical of behavioral sensitization. PCB-exposed males showed greater activation to the initial acute AMPH injection, but sensitization occurred later and was blunted relative to controls. Sensitization in control females took longer to develop than in the males, but no exposure-related differences were observed. Analysis of whole brain and serum AMPH content following a final IP injection of 0.5. mg/kg revealed no differences among the exposure groups. Overall, these results indicated developmental PCB exposure can alter the motor-stimulating effects of repeated AMPH injections. Males developmentally exposed to PCBs appeared to be pre-sensitized to AMPH, but quickly showed behavioral tolerance to the same drug dose. Results also revealed the behavioral effect was not due to exposure-induced alterations in AMPH metabolism following PCB exposure. © 2013 Elsevier Inc