Self administration of oxycodone alters synaptic plasticity gene expression in the hippocampus differentially in male adolescent and adult mice

Abstract

Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available “synaptic plasticity” PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age × Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice.

Adolescent oxycodone self administration alters subsequent oxycodone-induced conditioned place preference and anti-nociceptive effect in C57BL/6J mice in adulthood

“…This is consistent with differential adaptations in the expression of specific genes in adolescent versus adult mice that had self-administered oxycodone (Mayer-Blackwell et al, 2014; Zhang et al, 2014, 2015). Studies in adult mice have shown that the magnitude of antinociceptive tolerance is directly related to the level exposure to chronic MOP-r agonists (Kumar et al, 2008).…”

“…Of note, our CPP and antinociception measurements occurred after a 14-day drug free period, considerably longer than most studies of MOP-r agonist tolerance, to allow for the transition from adolescence to adulthood. We speculate that changes in synaptic plasticity in pathways that are involved in pain and reward may occur in the mice that had self administered oxycodone in adolescent more than in the adult mice (Zhang et al, 2014; 2015, Dong et al, 2007). We cannot exclude that the differential profile observed between adult and adolescent exposure to oxycodone herein are due in part to pharmacokinetic differences across these age periods.…”

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

“…In addition, OXY has reinforcing effects as measured by self-administration and condition place preference studies in rodents (Beardsley et al, 2004; Zhang Y. et al, 2009; Rutten et al, 2011; Bryant et al, 2014; Zhang et al, 2015). The mesocorticolimbic dopaminergic system is a key pathway involved in drug reinforcement (Koob, 1992) and as such, we anticipated OXY would affect activity in this neural circuit.…”

Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study

“…We identified 61 genes that were downregulated and 18 genes that were upregulated in several brain regions in male adult and adolescent mice. Those studies focused on genes involved in neurotransmission or synaptic plasticity (Mayer-Blackwell et al 2014; Zhang et al 2015; Zhang et al 2014). …”