Effect of Adolescent Stress on Adult Morphine-Induced Behavioral Sensitization is Dependent Upon Genetic Background

Abstract

Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence – a critical period of frontal lobe development–influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence (postnatal days, PND, 25-59) and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and miRNA gene expression in the prefrontal cortex. Male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals. No differences were observed in the acute locomotor response to morphine administration or morphine consumption in adult C57BL/6J mice. Stress did not influence morphine behaviors in BALB/cJ animals. C57BL/6J mice exposed to CVSS had a blunted corticosterone recovery following an acute stressor. Twelve miRNA were downregulated in the prefrontal cortex of C57BL/6J mice exposed to CVSS in adolescence, which suggests a biological mechanism through which stress may alter later morphine responses. The specificity of the effects for C57BL/6J versus BALB/cJ mice provides evidence of a gene by environmental interaction influencing opioid behaviors.