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

Randesi, Matthew; Contoreggi, Natalina H.; Zhou, Yan; Rubin, Batsheva R.; Bellamy, Julia R.; Yu, Fangmin; Gray, Jason D.; McEwen, Bruce S.; Milner, Teresa A.; Kreek, Mary Jeanne

doi:10.1016/j.neuroscience.2019.04.047

Cited by 22 publications

(27 citation statements)

References 97 publications

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“…Rats were injected with Oxy (3 mg/kg, I.P.) or saline (Sal) using the same 14‐day timeline as our prior Oxy CPP behavioral paradigm (Randesi et al., 2019; Reich et al, 2019; Ryan et al., 2018), but without being placed in the behavioral apparatus. Specifically, rats were kept in their home cages throughout the experimental period and injected between 9 and 9:30 AM .…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies demonstrated that both female and male Sprague Dawley rats acquired conditioning place preference (CPP) to the mu opioid receptor (MOR) agonist Oxy and that this results in sex‐specific alterations in the hippocampal opioid system (Bellamy et al., 2019; Randesi et al., 2019; Ryan et al., 2018). Notably, following Oxy CPP delta opioid receptors (DOR) redistributed within mossy fiber–CA3 synapses in females and males in a manner similar to that shown to be important for opioid‐mediated LTP in high estrogen females (Harte‐Hargrove et al., 2015; Ryan et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

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Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Ashirova

Contoreggi

Johnson

et al. 2020

Synapse

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Oxycodone (Oxy) conditioned place preference (CPP) in Sprague Dawley rats results in sex‐specific alterations in hippocampal opioid circuits in a manner that facilitates opioid‐associative learning processes, particularly in females. Here, we examined if Oxy (3 mg/kg, I.P.) or saline (Sal) injections not paired with behavioral testing similarly affect the hippocampal opioid system. Sal‐injected females compared to Sal‐injected males had: (1) higher densities of cytoplasmic delta opioid receptors (DOR) in GABAergic hilar dendrites suggesting higher baseline reserve DOR pools and (2) elevated phosphorylated DOR levels, but lower phosphorylated mu opioid receptor (MOR) levels in CA3a suggesting that the baseline pools of activated opioid receptors vary in females and males. In contrast to CPP studies, Oxy‐injections in the absence of behavioral tests resulted in few changes in the hippocampal opioid system in either females or males. Specifically, Oxy‐injected males compared to Sal‐injected males had fewer DORs near the plasma membrane of CA3 pyramidal cell dendrites and in CA3 dendritic spines contacted by mossy fibers, and lower pMOR levels in CA3a. Oxy‐injected females compared to Sal‐injected females had higher total DORs in GABAergic dendrites and lower total MORs in parvalbumin‐containing dendrites. Thus, unlike Oxy CPP, Oxy‐injections redistributed opioid receptors in hippocampal neurons in a manner that would either decrease (males) or not alter (females) excitability and plasticity processes. These results indicate that the majority of changes within hippocampal opioid circuits that would promote opioid‐associative learning processes in both females and males do not occur with Oxy administration alone, and instead must be paired with CPP.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Ashirova

Contoreggi

Johnson

et al. 2020

Synapse

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“…Strikingly, ultrastructural analysis of the hippocampus from these rats revealed that MORs and delta opioid receptors (DORs) within hilar interneurons and in CA3 and CA1 pyramidal cells redistribute in a manner that would enhance opioid‐mediated learning, particularly in females (McEwen & Milner, 2017; Rubin et al, 2020; Ryan et al, 2018). Moreover, we demonstrated that these changes in opioid trafficking following Oxy CPP are paralleled by sex‐specific increases in the expression of plasticity genes and proteins in select hippocampal cell types and regions (Randesi et al, 2019).…”

Section: Introductionmentioning

confidence: 94%

“…In contrast, CIS in males had limited redistribution of opioid receptors within pyramidal cells and interneurons and thus reduces the ability of the opioid system to support opioid‐mediated learning processes (Reich et al, 2019; Rubin et al, 2020). Moreover, these sex‐specific changes in opioid‐receptor trafficking are accompanied by a down‐regulation of opioid, stress, plasticity and kinase/signaling genes in the hippocampus of CIS males (Randesi et al, 2018; Randesi et al, 2019). Notably, we have found that following CIS, Oxy CPP is attenuated in male, but not female, rats (Reich et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Chronic stress differentially altersmRNAexpression of opioid peptides and receptors in the dorsal hippocampus of female and male rats

et al. 2021

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Chronic immobilization stress (CIS) results in sex‐dependent changes in opioid peptide levels and receptor subcellular distributions within the rat dorsal hippocampus, which are paralleled with an inability for males to acquire conditioned place preference (CPP) to oxycodone. Here, RNAScope in situ hybridization was used to determine the expression of hippocampal opioid peptides and receptors in unstressed (US) and CIS estrus female and male adult (∼2.5 months old ) Sprague Dawley rats. In all groups, dentate granule cells expressed PENK and PDYN; additionally, numerous interneurons expressed PENK. OPRD1 and OPRM1 were primarily expressed in interneurons, and to a lesser extent, in pyramidal and granule cells. OPRK1‐was expressed in sparsely distributed interneurons. There were few baseline sex differences: US females compared to US males had more PENK‐expressing and fewer OPRD1‐expressing granule cells and more OPRM1‐expressing CA3b interneurons. Several expression differences emerged after CIS. Both CIS females and males compared to their US counterparts had elevated: (1) PENK‐expressing dentate granule cells and interneurons in CA1 and CA2/3a; (2) OPRD1 probe number and cell expression in CA1, CA2/3a and CA3b and the dentate gyrus; and (3) OPRK1‐expressing interneurons in the dentate hilus. Also, CIS males compared to US males had elevated: (1) PDYN expression in granule cells; (2) OPRD1 probe and interneuron expression in CA2/3a; (3) OPRM1 in granule cells; and (4) OPRK1 interneuron expression in CA2/3a. The sex‐specific changes in hippocampal opioid gene expression may impact network properties and synaptic plasticity processes that may contribute to the attenuation of oxycodone CPP in CIS males.

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“…These results are surprising and yet, in light of the paucity of previous studies using both males and females, it is difficult to determine how unexpected they are. Although sparse, there have been reports of sex interactions with ARC expression (Henderson et al, 2017;Randesi et al, 2018;Randesi et al, 2019). Nonetheless, in each of those cases, the sex difference in ARC expression was one of degree, rather than kind.…”

Section: Sex Differences In Arc Expressionmentioning

confidence: 99%

The medial entorhinal cortex mediates basolateral amygdala effects on spatial memory and downstream activity-regulated cytoskeletal-associated protein expression

Wahlstrom

Alvarez-Dieppa

McIntyre

et al. 2020

Neuropsychopharmacol.

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

Cited by 22 publications

References 97 publications

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Chronic stress differentially altersmRNAexpression of opioid peptides and receptors in the dorsal hippocampus of female and male rats

The medial entorhinal cortex mediates basolateral amygdala effects on spatial memory and downstream activity-regulated cytoskeletal-associated protein expression

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