Addiction has been described as a disease of learning and memory, as the learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play a central role in human addictions. Our knowledge of specific environmental factors influencing drug-associated learning and memory is incomplete. A well-studied mechanism in other fields is prenatal infection, which stimulates maternal cytokines, soluble polypeptides mediating the innate inflammatory response. Consequences to the offspring of maternal cytokine elevation have been studied in an animal model termed 'prenatal immune activation' using the synthetic nucleic acid poly I:C, which stimulates maternal cytokine expression. Injecting poly I:C during pregnancy alters function in the offspring of neuronal systems involved in response to drugs of abuse. Estimates from studies of other disorders suggest as many as 1/3 of drug dependent patients may have had in utero exposure to conditions stimulating maternal cytokine expression. The objective of this application is to characterize the effect of poly I:C injection on acquisition, extinction, and reinstatement of conditioned place preference to amphetamine. We will also identify neurochemical indices of relevance to these behaviors. Our overarching hypothesis is that prenatal immune activation alters glutamate and dopamine transmission in prefrontal cortex and nucleus accumbens, elements of the final common pathway mediating drug relapse, thereby impairing extinction and facilitating reinstatement of conditioned preference for drugs of abuse. We will test this hypothesis in Specific Aim 1 by determining the consequence of prenatal immune activation on acquisition, extinction, and drug- and stress-induced reinstatement of conditioned place preference to amphetamine.
In Specific Aim 2, we will determine extracellular glutamate and dopamine in prefrontal cortex and nucleus accumbens preceding conditioning, and during drug-induced reinstatement following prenatal immune activation using microdialysis. Upon completion of these studies, we expect to demonstrate behavioral and neurochemical alterations following prenatal immune activation of direct relevance to the risk for drug relapse. Our expected findings may therefore suggest opportunities to detect a population at elevated risk for drug relapse, and simultaneously identify novel targets for intervention in this group.

Public Health Relevance

We propose to determine the effect of prenatal immune activation on learning and memory associated with drug use. We also expect to identify neurochemical mechanisms contributing to the observed behavioral effects. Our expected outcomes are important because they will elucidate the effect of a common environmental exposure; prenatal immune activation; on a key outcome measure of relevance to drug dependence: learning and memory associated with drug use. The expected findings may advance the understanding of prevention; treatment; and prognosis for drug dependence.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Sorensen, Roger
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Veterans Medical Research Fdn/San Diego
San Diego
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Cassella, Sarah N; Hemmerle, Ann M; Lundgren, Kerstin H et al. (2016) Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring. Schizophr Res 171:195-9
Hemmerle, Ann M; Ahlbrand, Rebecca; Bronson, Stefanie L et al. (2015) Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation. Schizophr Res 168:411-20