? ? Relatively little is known about the effects of exposure to environmental contaminants on substance abuse risk. The goal of this project is to determine if developmental exposure to polychlorinated biphenyls (PCBs) enhances the predisposition to develop drug addiction using a rodent model. Recent theories propose that drug addiction occurs due to increasing incentive salience for the drug and drug-associated cues as well as impaired inhibitory control at the cognitive level. Research in animal models suggests that reduced dopamine (DA) activity in the medial prefrontal cortex (mPFC) may mediate this process. PCB exposure reduces brain DA and impairs mPFC-mediated cognitive functions. Based on these findings it is hypothesized that PCB exposure during early development will result in reduced DA function in mPFC, produce inhibitory control deficits and enhance the incentive salience of psychostimulants. The objectives of the current proposal are to: (1) characterize inhibitory control deficits and determine psychostimulant sensitivity in rats developmentally exposed to an environmentally relevant PCB mixutre and (2) determine whether PCB induced changes in DA receptor expression in the mPFC mediate both the enhanced psychostimulant sensitivity and the inhibitory control deficits.
The specific aims of the mentored phase are to: (1) quantify differences in inhibitory control on a multiple fixed interval/extinction task, (2) measure changes in the expression of the dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), D1, D2, and D4 receptor subtypes in the mPFC of rats developmentally exposed to PCBs relative to controls, and (3) determine if perinatal PCB exposure is associated with enhanced sensitivity to the discriminative stimulus or motor-activating properties of psychostimulants.
The specific aims of the independent phase are to: (1) determine which DA receptor subtypes in the mPFC mediate the enhanced psychostimulant sensitivity and inhibitory control deficits in PCB-exposed animals, and (2) Determine whether developmental exposure to the polybrominated diphenyl ethers (PBDEs), ubiquitous environmental chemicals which are chemically similar to the PCBs, results in changes in DA receptor expression and enhanced psychostimulant sensitivity that parallel the effects produced by PCBs. The results will provide valuable information about substance abuse risk following developmental exposure to environmental contaminants that target the DA system. ? ? ? ?
| Poon, Emily; Monaikul, Supida; Kostyniak, Paul J et al. (2013) Developmental exposure to polychlorinated biphenyls reduces amphetamine behavioral sensitization in Long-Evans rats. Neurotoxicol Teratol 38:6-12 |
| Sable, Helen J K; Monaikul, Supida; Poon, Emily et al. (2011) Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs). Neurotoxicol Teratol 33:255-62 |
| Sable, Helen J K; Eubig, Paul A; Powers, Brian E et al. (2009) Developmental exposure to PCBs and/or MeHg: effects on a differential reinforcement of low rates (DRL) operant task before and after amphetamine drug challenge. Neurotoxicol Teratol 31:149-58 |
