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Abstract
Opioid use disorder (OUD) is characterized by compulsive drug taking despite adverse life consequences. Here, we sought to identify neurobiological consequences associated with the behavioral effects of contingent footshocks administered after escalation of oxycodone self-administration. To reach these goals, Sprague-Dawley rats were trained to self-administer oxycodone for 4 weeks and were then exposed to contingent electric footshocks. This paradigm helped to dichotomize rats into two distinct behavioral phenotypes: (1) those that reduce lever pressing (shock-sensitive) and (2) others that continue lever pressing (shock-resistant) for oxycodone during contingent punishment. The rats were euthanized at 2-h after the last oxycodone plus footshock session. The dorsal striata and prefrontal cortices were dissected for use in western blot and RT-qPCR analyses. All oxycodone self-administration rats showed significant decreased expression of Mu and Kappa opioid receptor proteins only in the dorsal striatum. However, expression of Delta opioid receptor protein was decreased in both brain regions. RT-qPCR analyses documented significant decreases in the expression of c-fos, fosB, fra2, junB, egr1, and egr2 mRNAs in the dorsal striatum (but not in PFC) of the shock-sensitive rats. In the PFC, junD expression was reduced in both phenotypes. However, egr3 mRNA expression was increased in the PFC of only shock-resistant rats. These results reveal that, similar to psychostimulants and alcohol, footshocks can dichotomize rats that escalated their intake of oxycodone into two distinct behavioral phenotypes. These animals also show significant differences in the mRNA expression of immediate early genes, mainly, in the dorsal striatum. The increases in PFC egr3 expression in the shock-resistant rats suggest that Egr3 might be involved in the persistence of oxycodone-associated memory under aversive conditions. This punishment-driven model may help to identify neurobiological substrates of persistent oxycodone taking and abstinence in the presence of adverse consequences.
Highlights
Opioid use disorders (OUDs) continue to constitute a public health crisis (Cicero et al, 2005; Skolnick, 2017)
Regression analysis revealed that the levels of mRNA expression were significantly related to the amount of total oxycodone taken during the experiment (Figure 3B)
The changes in the expression of opioid receptors were similar in both resistant and sensitive rats, we found significant differences in the mRNA expression of several immediate early genes (IEGs) including fosB, fra2, and egr2 that showed decreased expression in the dorsal striatum, but not the prefrontal cortex (PFC), of sensitive rats compared to control and resistant rats
Summary
Opioid use disorders (OUDs) continue to constitute a public health crisis (Cicero et al, 2005; Skolnick, 2017). Some groups have tried to remedy this conundrum by adding contingent punishment during the performance of selfadministration of alcohol, cocaine, and methamphetamine by rodents (Chen et al, 2013; Vanderschuren et al, 2017; Marchant et al, 2018; Cadet et al, 2019) In these models, footshocks are used to segregate rats that continue to self-administer drugs [shock-resistant (SR), addicted] from those that significantly reduce or stop [shock-sensitive (SS), non-addicted users] their intake in the presence of punishment (Chen et al, 2013; Vanderschuren et al, 2017; Marchant et al, 2018; Cadet et al, 2019). It remains to be determined if punishment could help to dichotomize rats that escalated their oxycodone intake into SR and SS rats as reported for other drugs (Chen et al, 2013; Marchant et al, 2018; Cadet et al, 2019)
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