Self administration of oxycodone by adolescent and adult mice affects striatal neurotransmitter receptor gene expression

Abstract

Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n=12) and of adult mice (11 weeks old, n=11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice.

Keywords: ANOVA; GRP; Grpr; MOP-r; Maoa; Npy5r; adolescent; adult; analysis of variance; dorsal striatum; gastrin-releasing peptide; gastrin-releasing peptide receptor; monoamine oxidase A; mu opioid receptors; neuropeptide Y receptor 5; neurotransmitter receptor gene expression; oxycodone; self administration.

Figure 1

The number of self-administered infusions of oxycodone (0.25 mg/kg per infusion) by both adolescent and adult mice is shown in A. Adults self administered more infusions of oxycodone than adolescents. The number of nose pokes at the active hole during 20-s time out period is shown in B.

Figure 2

Alteration in monoamine oxidase A (Maoa) mRNA levels in the dorsal striatum following 14-day oxycodone or yoked-saline self administration in the adolescent and adult mice. There were lower levels of Maoa mRNA in the adolescent than in the adult mice. The levels of Maoa mRNA were higher in mice that had self administered oxycodone compared with those of the yoked saline controls.

Figure 3

(A) The effect of Age on neuropeptide Y receptor Y5 (Npy5r) mRNA expression in the dorsal striatum. The levels of Npy5r mRNA in the adolescent mice were significantly lower those of the adult mice. (B) A significant Age × Drug Condition Interaction in the expression of gastrin-releasing peptide receptor (Grpr) mRNA levels. The interaction effect was seen as a decrease in means from adolescent to adult mice in yoked saline control mice and increase in means from adolescent to adult in mice that had self administered oxycodone.

Figure 4

The correlation between the amount of oxycodone self administered with oxycodone-induced increases in Mao mRNA level. There is a significant positive correction between the total amount (mg) of oxycodone self-administered across the 14 sessions with the levels of Mao mRNA, r=0.855, p<0.0005 across all mice in the two age groups (A). A significant positive correlation between the total amounts (mg) of oxycodone and Mao mRNA levels was also found, r=0.826, p<0.05 in adolescent mice (B). There was also a significant positive correlation between the amount (mg) of oxycodone self administered in the last session and Mao mRNA levels across all mice, r=0.745, p<0.0054 (C).