Incubation of Oxycodone Craving Following Adult-Onset and Adolescent-Onset Oxycodone Self-Administration in Male Rats

Abstract

Relapse is a major obstacle to curb the ongoing epidemic of prescription opioid abuse. We and others previously demonstrated that oxycodone seeking in adult rats progressively increases after abstinence from oxycodone self-administration (incubation of oxycodone craving). In humans, the onset of oxycodone use in adolescents may increase individuals’ vulnerability to later opioid addiction. However, little is known about incubation of oxycodone craving after adolescent-onset oxycodone self-administration in rats. In the first study, we trained single-housed adolescent (postnatal day 35 at start) and adult (postnatal day 77 at start) male Sprague–Dawley rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day for 10 days) and then tested oxycodone relapse on both abstinence day 1 and day 15. Given that social experience is critical for neurobehavioral development in adolescents, we performed the second study using group-housed adolescent and adult rats. In both studies, we observed no age differences in oxycodone self-administration and incubated oxycodone seeking on abstinence day 15. However, on abstinence day 1, we observed decreased oxycodone seeking in adolescents compared with adults. This pattern of data led to elevated incubation slopes in adolescent rats compared with adult rats. Finally, group-housed rats exhibited attenuated oxycodone seeking compared with single-housed rats on abstinence day 15, but not on day 1. Taken together, these data suggest that adolescents may be resistant to oxycodone relapse during early abstinence, but this resistance dissipates quickly during the transition between adolescent and young adulthood. In addition, group-housing plays a protective role against incubated oxycodone craving.

GluA2‐lacking AMPA receptors in the nucleus accumbens core and shell contribute to the incubation of oxycodone craving in male rats

“…This elevation in responding persisted on WD30 [Figure 2C; WD1 vs. WD30: F (1,28) = 40.40, Tukey's post hoc p = 0.012]. These findings are consistent with prior studies of the incubation of craving for oxycodone (e.g., previous works 12,14,30 ).…”

“…Recent studies have reported incubation of oxycodone craving 12,14,30,31 . The goals of the first experiment were to verify that incubation of craving occurs under our experimental conditions and to assess the duration of changes in drug‐seeking.…”

“…Rats were first trained to self‐administer saline or oxycodone (6 h/day × 10 days, 0.15 mg/kg/infusion) (Figure 1A). These experimental conditions were chosen based on previous studies showing incubation of craving with a 0.1‐ to 0.15‐mg/kg/infusion dose and 3‐ to 6‐h daily sessions 12,14,30,31 and because this dose has been shown to lead to an escalation of drug intake, a translationally relevant marker of addiction 32 . A two‐way ANOVA found significant main effects for oxycodone self‐administration day [ F (9,234) = 3.014, p = 0.002] and nose‐poke hole [ F (1,26) = 357.7, p < 0.0001], and a significant day × nose‐poke hole interaction [ F (9,234) = 9.042, p < 0.0001], indicating that oxycodone self‐administering animals learned to discriminate between active and inactive holes and formed a strong preference for the oxycodone‐associated hole (Figure 1B), unlike saline self‐administering controls, where we saw no main effect of nose‐poke hole [Figure 1C; F (1,15) = 4.445, p = 0.9983].…”

“…Recent studies have reported incubation of oxycodone craving. 12,14,30,31 The goals of the first experiment were to verify that incubation of craving occurs under our experimental conditions and to assess the duration of changes in drug-seeking. NAc tissue from these rats was then used to examine whether this incubation was accompanied by changes in AMPAR subunit surface expression (see next section).…”

“…Rats were first trained to self-administer saline or oxycodone (6 h/day  10 days, 0.15 mg/kg/infusion) (Figure 1A). These experimental conditions were chosen based on previous studies showing incubation of craving with a 0.1-to 0.15-mg/kg/infusion dose and 3to 6-h daily sessions 12,14,30,31 and because this dose has been shown to lead to an escalation of drug intake, a translationally relevant marker of addiction. 32…”