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Effects of prenatal alcohol exposure on interactions between stress and dopamine systems : a potential pathway to increased vulnerability to substance use disorders Uban, Kristina Andrea

Abstract

Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of substance use disorders (SUDs). Dopaminergic systems provide a key neurobiological substrate for SUDs. The hypothalamic-pituitary-adrenal (HPA) axis and dopamine systems have overlapping neurocircuitries, with stress altering dopamine pathways implicated in drug-related reinforcement and motivation, and conversely drug exposure activating stress systems, enhancing sensitivity to subsequent stressors. PAE alters both HPA and dopaminergic regulation, resulting in increased HPA tone and an overall reduction in tonic dopamine activity. Thus, alterations in HPA-dopamine interactions in PAE subjects may provide a neurobiological mechanism underlying enhanced vulnerability to SUDs. Adult Sprague- Dawley offspring from PAE, pair-fed, and ad libitum-fed control groups were examined. In Chapter 2, the effects of PAE and stress on basal regulation of stress and dopamine systems are discussed. Subjects were subjected to either chronic variable stress (CVS) or no stress conditions, and corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and dopamine receptor expression, were measured under basal conditions. In the hippocampus, glucocorticoid receptor (MR) mRNA levels were lower in PAE than control females under non- CVS conditions, while CVS resulted in broader upregulation of MR in PAE compared to control males. A decrease in dopamine receptors was observed following CVS exposure in control but not in PAE subjects. Overall, PAE enhanced sensitivity to CVS and attenuated the effects of chronic stress on basal dopamine receptor expression, and did so in a sexually-dimorphic manner. In Chapter 3, repeated exposure to d-amphetamine (AMPH) induced behavioral sensitization in PAE but not control subjects, and this behavioral measure is positively correlated with vulnerability to SUDs. The current study also assessed cross-sensitization between AMPH and stress, and indeed PAE facilitated cross-sensitization between AMPH and stress, and did so in a sexually dimorphic manner. PAE altered AMPH-stress interactions, and did so in a manner consistent with increased neurobiological vulnerability to SUDs. Together, the present results enhance our understanding of PAE effects on the cross-talk between dopamine and stress systems, and provide insight into underlying mechanisms influencing the increased prevalence of SUDs among individuals with an FASD.

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