Sex Differences in Neuroplasticity- and Stress-Related Gene Expression and Protein Levels in the Rat Hippocampus Following Oxycodone Conditioned Place Preference.

Prescription opioid abuse is a serious public health issue. Recently, we showed that female and male Sprague–Dawley rats acquire conditioned place preference (CPP) to the mu opioid receptor agonist oxycodone. Anatomical analysis of the hippocampus from these rats unveiled sex differences in the opioid system in a way that would support excitation and opiate associative learning processes especially in females. In this study, we examined the expression and protein densities of opioid, plasticity, stress and related kinase and signaling molecules in the hippocampus of female and male rats following oxycodone CPP. Oxycodone CPP females have: a) increases in ARC (activity regulated cytoskeletal-associated protein)-immunoreactivity (ir) in CA3 pyramidal cells; b) decreases in Npy (neuropeptide Y) gene expression in the medial hippocampus but higher numbers of NPY-containing hilar interneurons compared to males; c) increases in Crhr2 (corticotropin releasing factor receptor 2) expression in CA2/3; d) increases in Akt1 (AKT serine/threonine kinase 1) expression in medial hippocampus; and e) decreases in phosphorylated MAPK (mitogen activated protein kinase)-ir in CA1 and dentate gyrus. Oxycodone CPP males have: a) increases in Bdnf (brain derived-neurotrophic factor) expression, which is known to be produced in granule cells, relative to females; b) elevated Mapk1 expression and pMAPK-ir in the dentate hilus which harbors newly generated granule cells; and c) increases in CRHR1-ir in CA3 pyramidal cell soma. These sex-specific changes in plasticity, stress and kinase markers in hippocampal circuitry parallel previously observed sex differences in the opioid system after oxycodone CPP. Unlabelled Image • Hippocampal gene expression and protein levels vary depending on sex after oxycodone (Oxy) conditioned place preference (CPP) • After Oxy CPP, Npy mRNA expression decreases but a subset of NPY-labeled cells increases in the dentate gyrus (DG) in females • In CA3, plasticity and stress markers differentially increase in Oxy CPP females (ARC, Crhr2) and males (Arc , CRHR1) • After Oxy CPP, signaling kinases (Akt1 , pAKT, pMAPK) change in opposite directions in females and males in CA1 and DG • Differences in signaling, kinase, and stress markers suggest sex-specific hippocampal pathways for opioid-associated learning [ABSTRACT FROM AUTHOR]