Prolonged Withdrawal From Escalated Oxycodone Is Associated With Increased Expression of Glutamate Receptors in the Rat Hippocampus.

Aaron J Salisbury,Christopher A Blackwood,Jean Lud Cadet

doi:10.3389/fnins.2020.617973

Aaron J Salisbury, Christopher A Blackwood + Show 1 more

Open Access

https://doi.org/10.3389/fnins.2020.617973

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Abstract

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 h and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction analyses. Rats, given long-access (9 h per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 h per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6, and Grm8 subtypes of glutamate receptors after 31 days but not after 2 h of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

Highlights

The opioid epidemic that includes the abuse of oxycodone is associated with large numbers of overdose-related deaths (Wilson et al, 2020)
The hippocampus is essential for cognitive functions that can be disturbed in substance use disorders (SUDs), it has received much less attention than other brain regions such as the nucleus accumbens or dorsal striatum in studies involving animal models of SUDs
Rats that took fewer than 50 infusions per day were put in the longaccess low (LgA-L) group whereas the LgA-H consisted of rats that took more than 50 infusions per day

Summary

INTRODUCTION

The opioid epidemic that includes the abuse of oxycodone is associated with large numbers of overdose-related deaths (Wilson et al, 2020). There is evidence to show that the strength of hippocampal inputs into the nucleus accumbens can bidirectionally drive motivation for rewarding stimuli (LeGates et al, 2018) While these studies have shown a significant role for the hippocampus in mediating drug taking and reinstatement, there is not enough research that documents the effects of opioid drugs on gene expression in the hippocampus. In order to develop more effective opioid addiction treatments, it is necessary to identify molecular neuroadaptations that occur in the hippocampus during long-term exposure and withdrawal from these drugs To reach these aims, we have used a rat oxycodone self-administration (SA) model to probe the potential molecular changes that occur in that brain region. Some subunits of Group I and Group III metabotropic receptors were affected

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ETHICS STATEMENT