Relatively little is known about the effects of exposure to environmental contaminants on substance abuse risk. Tiie goal of this project is to determine if developmental exposure to polychlorinated biphenyls (RGBs) 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-associatedUues 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, including inhibitory control. Preliminary results from our laboratory suggest that developmental PCB exposure pre-sensitizes rats to the locomotor activating effects of amphetamine (AMPH), and produces functional tolerance with repeated administration. Based on these findings and previous research examining the effects of PCB exposure on DA function, 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 PCBinduced changes in DA receptor expression in the mPFC mediate both the enhanced psychostimulant sensitivity and the inhibitory control deficits.
The specific aims are to: (1) Determine which DA receptor subtypes in the mPFC contribute to enhanced psychostimulant sensitivity in PCB-exposed animals, (2) Determine which DA receptor subtypes in the mPFC are involved in the inhibitory control deficits seen in PCB-exposed animals, and (3) Determine whether developmental exposure to polybrominated diphenyl ethers (PBDEs) results in changes in DA receptor expression and enhanced behavioral sensitization following psychostimulant exposure 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.
This grant will provide important information about how perinatal exposure to ubiquitous environmental contaminants including PCBs and PBDEs may influence the likelihood of developing substance abuse.
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|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|