• James D Ryan, Yan Zhou, Natalina H Contoreggi, Farah K Bshesh, Jason D Gray, Joshua F Kogan, Konrad T Ben, Bruce S McEwen, Jeanne Kreek Mary M The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, United States., and Teresa A Milner.
• Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065, United States; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Ave, New York, NY 10021, United States. Electronic address: jdr2003@med.cornell.edu.
• Neuroscience. 2018 Nov 21; 393: 236-257.

AbstractAlthough 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 (3 mg/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.Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

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