Amphetamine sensitization and cross-sensitization with acute restraint stress: impact of prenatal alcohol exposure in male and female rats
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Individuals with fetal alcohol spectrum disorder (FASD) are at increased risk for substance use disorders (SUD). In typically developing individuals, susceptibility to SUD is associated with alterations in dopamine and hypothalamic-pituitary-adrenal (HPA) systems, and their interactions. Prenatal alcohol exposure (PAE) alters dopamine and HPA systems, yet effects of PAE on dopamine-HPA interactions are unknown. Amphetamine-stress cross-sensitization paradigms were utilized to investigate sensitivity of dopamine and stress (HPA) systems, and their interactions following PAE.
Adult Sprague-Dawley offspring from PAE, pair-fed, and ad libitum-fed control groups were assigned to amphetamine-(1–2 mg/kg) or saline-treated conditions, with injections every other day for 15 days. Fourteen days later, all animals received an amphetamine challenge (1 mg/kg) and 5 days later, hormones were measured under basal or acute stress conditions. Amphetamine sensitization (augmented locomotion, days 1–29) and cross-sensitization with acute restraint stress (increased stress hormones, day 34) were assessed.
PAE rats exhibited a lower threshold for amphetamine sensitization compared to controls, suggesting enhanced sensitivity of dopaminergic systems to stimulant-induced changes. Cross-sensitization between amphetamine (dopamine) and stress (HPA hormone) systems was evident in PAE, but not in control rats. PAE males exhibited increased dopamine receptor expression (medial prefrontal cortex (mPFC)) compared to controls.
PAE alters induction and expression of sensitization/cross-sensitization, as reflected in locomotor, neural, and endocrine changes, in a manner consistent with increased sensitivity of dopamine and stress systems. These results provide insight into possible mechanisms that could underlie increased prevalence of SUD, as well as the impact of widely prescribed stimulant medications among adolescents with FASD.
KeywordsPrenatal alcohol Amphetamine Stress Dopamine Addiction Sex differences Sensitization Prefrontal cortex Nucleus accumbens Striatum
We would like to thank Linda Ellis who developed the IHC protocol for DA-R expression, Wayne Yu for technical support with RIAs, Nikki Kitay, Farinaz Poursoltani, and Andrew Choe for their valuable assistance with data collection and brain slicing, Stephanie Lieblich for her technical support with IHC, and Dr. Douglas Allan and Luba Veverytsa at the Facility for Synaptic Imaging at the University of British Columbia for training and access to their confocal microscope for imaging of dopamine receptors. This research was funded by grants from the Canadian Foundation for Fetal Alcohol Research (CFFAR) to JW and LAMG, and NIH/NIAAA R37 AA007789 to JW. LAMG is also supported by grants from CIHR, NSERC and Alzheimer’s Society for Canada. KAU was funded by IMPART (CIHR STIHR Training Program) and grant support.
No financial support from any individual or corporate body has been received for compensation of work; therefore, the authors declare no potential conflict of interest.
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