Effect of chronic delivery of the NOP/MOR partial agonist AT-201 and NOP antagonist J-113397 on heroin relapse in a rat model of opioid maintenance

Abstract

Rationale: The opioid crisis persists despite availability of effective opioid agonist maintenance treatments (methadone and buprenorphine). Thus, there is a need to advance novel medications for the treatment of opioid use and relapse.

Objectives: We recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine and the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. In contrast, chronic delivery of the buprenorphine analog BU08028 had mixed effects on different heroin relapse-related measures. Here, we tested the effect of the mixed nociceptin (NOP) receptor/MOR partial agonist AT-201 and the NOP receptor antagonist J-113397 on different heroin relapse-related measures.

Methods: We trained male and female rats to self-administer heroin (6-h/d, 14-d) in context A and then implanted osmotic minipumps containing AT-201 (0, 3.8, or 12 mg/kg/d) or J-113397 (0, 12.6, or 40 mg/kg/d). Next, we tested the effect of chronic delivery of the compounds on (1) incubation of heroin seeking in a non-drug context B, (2) extinction responding reinforced by heroin-associated discrete cues in context B, (3) context A-induced reinstatement of heroin seeking, and (4) reacquisition of heroin self-administration in context A.

Results: In females, AT-201 modestly increased reacquisition of heroin self-administration and J-113397 modestly decreased incubation of heroin seeking. The compounds had no effect on the other relapse-related measures in females, and no effect on any of the measures in males.

Conclusion: The NOP/MOR partial agonist AT-201 and the NOP antagonist J-113397 did not mimic buprenorphine's inhibitory effects on relapse in a rat model of opioid maintenance treatment.

Keywords: Context-induced reinstatement; Extinction; Heroin self-administration; Incubation of craving; Opioid maintenance; Reacquisition.

Fig. 1

Effect of chronic delivery of AT-201 and J-113397 on food self-administration in male and female rats. A Timeline of Exp. 1. B AT-201: Number of pellets consumed and inactive and active lever presses after the rats were implanted with Alzet osmotic minipumps containing vehicle (n = 6, 4 males, 2 females) or 12 mg/kg/day AT-201 (n = 6, 3 males, 3 females). C J-113397: Number of pellets consumed and inactive and active lever presses after the rats were implanted with Alzet osmotic minipumps containing vehicle (n = 6, 2 males, 4 females) or 40 mg/kg/day J-113397 (n = 7, 3 males, 4 females). All data are mean ± SEM

Fig. 2

Heroin self-administration training in Context A. A Timeline of Exp. 2–3. B AT-201: Number of heroin infusions and lever presses during heroin self-administration in Context A (n = 53, 24 males, 29 females). C J-113397: Number of heroin infusions and lever presses during heroin self-administration in Context A (n = 54, 23 males, 31 females). All data are mean ± SEM

Fig. 3

Effect of chronic delivery of AT-201 and J-113397 on incubation of heroin seeking in Context B. A Timeline of Exp. 2–3. B AT-201: Number of active lever presses and inactive lever presses on abstinence day 1 (before minipump implantation) and on abstinence day 8 (after minipump implantation) in context B. Vehicle (n = 18, 8 males, 10 females), 3.8 mg/kg/day (n = 17, 8 males, 9 females), and 12 mg/kg/day AT-201 (n = 18, 8 males, 10 females). C J-113397: Number of active lever presses and inactive lever presses on abstinence day 1 (before minipump implantation) and on abstinence day 8 (after minipump implantation) in context B. Vehicle (n = 18, 8 males, 10 females), 12.6 mg/kg/day (n = 17, 7 males, 10 females), and 40 mg/kg/day J-113397 (n = 19, 8 males, 11 females). During the 30 min extinction sessions, active lever presses led to contingent presentations of the tone-light clue previously paired with heroin, but not heroin. All data are mean ± SEM. * Different from Day 1, p < 0.05

Fig. 4

Effect of chronic delivery of AT-201 and J-113397 on extinction responding in Context B. A Timeline of Exp. 2–3. B AT-201: Number of active and inactive lever presses and number of active lever presses during the seven 6-h extinction sessions in context B. Vehicle (n = 18, 8 males, 10 females), 3.8 mg/kg/day (n = 17, 8 males, 9 females), and 12 mg/kg/day AT-201 (n = 17, 7 males, 10 females). C J-113397: Number of active and inactive lever presses and number of active lever presses during the seven 6-h extinction sessions in context B. Vehicle (n = 18, 8 males, 10 females), 12.6 mg/kg/day (n = 17, 7 males, 10 females), and 40 mg/kg/day J-113397 (n = 19, 8 males, 11 females). During the 6-h extinction sessions, active lever presses led to contingent presentations of the tone-light clue previously paired with heroin, but not heroin. All data are mean ± SEM

Fig. 5

Effect of chronic delivery of AT-201and J-113397 on context-induced reinstatement in Context A. A Timeline of Exp. 2–3. B AT-201: Number of active lever presses during the 6-h reinstatement tests in contexts A & B and number of active lever presses during the six 1-h sessions in context A. Vehicle (n = 18, 8 males, 10 females), 3.8 mg/kg/day (n = 17, 8 males, 9 females), and 12 mg/kg/day AT-201 (n = 17, 7 males, 10 females C J-113397: Number of active lever presses during the 6-h reinstatement tests in contexts A & B and number of active lever presses during the six 1-h sessions in context A. Vehicle (n = 18, 8 males, 10 females), 12.6 mg/kg/day (n = 17, 7 males, 10 females), and 40 mg/kg/day J-113397 (n = 19, 8 males, 11 females). During the context-induce reinstatement tests, active lever presses led to contingent presentations of the tone-light clue previously paired with heroin, but not heroin. All data are mean ± SEM. * Different from context B, p < 0.05

Fig. 6

Effect of chronic delivery of AT-201 and J-113397 on reacquisition in Context A. A Timeline of Exp. 2–3. B AT-201: Number of heroin infusions (0.05 mg/kg/infusion) during the 6-h reacquisition test in context A and number of heroin infusions per hour. Vehicle (n = 18, 8 males, 10 females), 3.8 mg/kg/day (n = 17, 8 males, 9 females), and 12 mg/kg/day AT-201 (n = 18, 8 males, 10 females). C J-113397: Number of heroin infusions (0.05 mg/kg/infusion) during the 6-h reacquisition test in context A and number of heroin infusions per hour. Vehicle (n = 16, 8 males, 8 females), 12.6 mg/kg/day (n = 17, 7 males, 10 females), and 40 mg/kg/day J-113397 (n = 17, 8 males, 9 females). All data are mean ± SEM