Sex Differences in the Rat Hippocampal Opioid System After Oxycodone Conditioned Place Preference

Abstract

Although opioid addiction has risen dramatically, the role of gender in addiction has been difficult to elucidate. We previously found sex-dependent differences in the hippocampal opioid system of Sprague-Dawley rats that may promote associative learning relevant to drug abuse. The present studies show that although female and male rats acquired conditioned place preference (CPP) to the mu-opioid receptor (MOR) agonist oxycodone (3mg/kg, I.P.), hippocampal opioid circuits were differentially altered. In CA3, Leu-Enkephalin-containing mossy fibers had elevated levels in oxycodone CPP (Oxy) males comparable to those in females and sprouted in Oxy-females, suggesting different mechanisms for enhancing opioid sensitivity. Electron microscopy revealed that in Oxy-males delta opioid receptors (DORs) redistributed to mossy fiber-CA3 synapses in a manner resembling females that we previously showed is important for opioid-mediated long-term potentiation. Moreover, in Oxy-females DORs redistributed to CA3 pyramidal cell spines suggesting the potential for enhanced plasticity processes. In Saline-injected (Sal) females, dentate hilar parvalbumin-containing basket interneuron dendrites had fewer MORs, however, plasmalemmal and total MORs increased in Oxy-females. In dentate hilar GABAergic dendrites that contain neuropeptide Y, Sal-females compared to Sal-males had higher plasmalemmal DORs, and near-plasmalemmal DORs increased in Oxy-females. This redistribution of MORs and DORs within hilar interneurons in Oxy-females would potentially enhance disinhibition of granule cells via two different circuits. Together, these results indicate that oxycodone CPP induces sex-dependent redistributions of opioid receptors in hippocampal circuits in a manner facilitating opioid-associative learning processes and may help explain the increased susceptibility of females to opioid addiction acquisition and relapse.

Chronic immobilization stress primes the hippocampal opioid system for oxycodone‐associated learning in female but not male rats

“…Rats were subjected to oxycodone CPP similar to that described in our recent study (Ryan et al, ). Behavioral experiments were staged over a period of 4 days, so that euthanasia for all rats would occur between 9:00 am and 1:00 pm at the termination of the CPP behavior.…”

“…A dose of 3 mg/kg i.p. oxycodone was administered because it has been shown to induce 90%–100% CPP in female and male rats in prior studies (Olmstead & Burns, ; Ryan et al, ). The dose and duration of oxycodone in the present study were much lower than those in oxycodone self‐administration studies in Sprague Dawley rats in which the females had normal estrous cycles (Mavrikaki, Pravetoni, Page, Potter, & Chartoff, ).…”

“…When subject to a conditioned place preference (CPP) paradigm to the MOR agonist oxycodone, our recent study showed that both unstressed females and males acquire oxycodone CPP and have sex‐specific alterations in the opioid system that would facilitate opioid‐associative learning processes especially in females [Figure ; Ryan et al ()]. In particular, DORs were redistributed within CA3b pyramidal cell dendrites and in mossy fiber‐CA3 synapses in both oxycodone‐injected (Oxy) females and males in a manner resembling that shown to be important for opioid‐mediated LTP in high estrogen females (Harte‐Hargrove et al, ; Ryan et al, ).…”

“…When subject to a conditioned place preference (CPP) paradigm to the MOR agonist oxycodone, our recent study showed that both unstressed females and males acquire oxycodone CPP and have sex‐specific alterations in the opioid system that would facilitate opioid‐associative learning processes especially in females [Figure ; Ryan et al ()]. In particular, DORs were redistributed within CA3b pyramidal cell dendrites and in mossy fiber‐CA3 synapses in both oxycodone‐injected (Oxy) females and males in a manner resembling that shown to be important for opioid‐mediated LTP in high estrogen females (Harte‐Hargrove et al, ; Ryan et al, ). However, unlike males, DORs and MORs redistributed in hilar interneurons in Oxy‐females in a manner that could enhance disinhibition of granule cells via two different circuits: (a) the number of DOR‐labeled cells increased in the hilus; and (b) plasmalemmal‐associated MORs and DORs increased in PARV‐labeled dendrites and GABAergic interneuron dendrites, respectively (Ryan et al, ).…”

“…Summary of sex differences in the opioid system following CIS and oxycodone CPP in the rat hippocampus. Our previous light and electron microscopic studies have revealed notable sex differences in mossy fiber LEnk levels and in the redistributions of DORs and MORs in pyramidal cells and GABAergic interneurons following CIS and oxycodone CPP (Mazid et al, ; McEwen & Milner, ; Ryan et al, ). *Females in diestrus; ^Females in estrus…”