Sex and Chronic Stress Alter the Distribution of Corticotropin‐Releasing Factor Receptor in Rat Hippocampus Following Oxycodone Conditioned Place Preference

Corticotropin-releasing factor receptor 1 (CRFR1) plays a role in stress-induced hippocampal plasticity that can affect learning and memory processes including those important for addiction. Our prior work revealed sex differences in the distribution of CRFR1 within CA3 pyramidal cells and hilar interneurons in rats that could differentially affect associative learning processes in females and males, especially in response to chronic immobilization stress (CIS). Here, we examine the effect of oxycodone (Oxy) conditioned place preference (CPP) in unstressed and CIS adult female and male rats on the subcellular distribution of CRFR1 in CA3 pyramidal cells and dentate gyrus (DG) hilar interneurons using immuno-electron microscopy. After Oxy CPP, males compared to females had greater plasmalemmal-associated CRFR1 in CA3 pyramidal cell and DG interneuron dendrites, consistent with a greater binding capacity for corticotropin-releasing factor (CRF) in males. CIS alone resulted in increases in corticotropin-releasing hormone receptor 1 (Crhr1) mRNA in the pyramidal cell layer and stratum oriens of CA3 in males. Following CIS and Oxy CPP behavior, only females acquired CPP. Oxy CIS females compared to Oxy CIS males had more total CRFR1 in DG interneuron dendrites. Moreover, CRFR1 trafficked from the cytoplasm toward the plasmalemma in DG interneuron dendrites in CIS Oxy females, indicating a potential greater binding capacity for CIS Oxy females in this neuronal population. These findings along with prior studies suggest that changes in CRFR1 and opioid receptor trafficking in CIS females contribute to mechanisms that are associated with the development of Oxy CPP in CIS females, but not males.