The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats

Abstract

The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence. We found that rats acquired oxycodone self-administration rapidly within a range of unit doses that was similar to that for heroin, confirming that oxycodone has significant abuse potential. Strikingly, pretreatment with either CAB2-015 or BAK4-54 (0.4-10 mg/kg, i.p.) dose-dependently decreased oxycodone self-administration, and shifted the oxycodone dose-response curve downward. Repeated pretreatment with CAB2-015 or BAK4-54 (0.4-4 mg/kg) facilitated extinction and inhibited oxycodone-induced reinstatement of drug-seeking behavior. In addition, pretreatment with CAB2-015 or BAK4-54 (4-10 mg/kg) also dose-dependently decreased oxycodone-enhanced locomotor activity, but only CAB2-015 decreased oral sucrose self-administration. These data suggest that D3R antagonists may be suitable alternatives or adjunctive to opioid-based medications currently used clinically in treating opioid addiction and that the D3R-selective ligands (CAB2-015 or BAK4-54) provide new lead molecules for development.

Keywords: BAK4-54; CAB2-015; Dopamine D3 receptor antagonist; Oxycodone; Prescription opioid; Self-administration.

Figure 1.

Comparison of the rewarding effects of oxycodone and heroin in rats. A: Time course of the acquisition of oxycodone self-administration maintained by different doses of oxycodone. B: Mean daily oxycodone intake (mg/kg) during the acquisition of oxycodone self-administration. C: Time course of the acquisition of heroin self-administration maintained by three different doses of heroin. D: Mean daily heroin intake (mg/kg) during the acquisition of heroin self-administration. N=6-7/group. Inactive LP – Inactive lever presses. *p<0.05, **p<0.01, compared to 100 μg/kg/infusion group.

Figure 2.

Effects of CAB2-015 or BAK4-54 on the maintenance of oxycodone (50 μg/kg/infusion) self-administration in rats. A: Systemic administration of CAB2-015 (0.4-10 mg/kg, i.p.; 15 min before session) dose-dependently decreased oxycodone self-administration as assessed by the total number oxycodone infusions (a), % change in oxycodone infusions (b), (or oxycodone intake (c).; B: Systemic administration of BAK4-54 (0.4-10 mg/kg, i.p.; 15 min before session) similarly inhibited oxycodone self-administration. *p<0.05, **p<0.01, compared to the vehicle pretreatment group. N=7-8/group.

Figure 3.

Effects of CAB2-015 or BAK4-54 on oxycodone self-administration dose-response curve in rats. A: Pretreatment with CAB2-015 (10 mg/kg, i.p.) or BAK4-54 (10 mg/kg, i.p.) significantly shifted the dose-response curve downward; B: Calculated oxycodone intake, indicating that CAB2-015 or BAK4-54 significantly shifted the dose-intake curves downward. *p<0.05, **p<0.01, compared to the vehicle group. N=7-8/group.

Figure 4.

Effects of CAB2-015 and BAK4-54 on drug-seeking behavior observed during extinction and oxycodone-induced reinstatement test. A: Active lever response observed during extinction, illustrating that repeated daily CAB2-015 pretreatment for 8 days significantly decreased oxycodone-seeking (see sessions 1-7) and oxycodone priming-induced reinstatement of drug-seeking behavior (session 8). B: Active lever response observed during extinction, illustrating that repeated daily BAK4-54 pretreatment for 8 days also significantly inhibited oxycodone-seeking (see sessions 1-7) and oxycodone priming-induced reinstatement of drug-seeking behavior (session 8). This inhibitory effect is long-lasting for at least 5 days (sessions 10-14). C/D: Normalized reinstatement response to oxycodone priming by subtraction of basal level of lever response (observed immediately before each oxycodone test session) from oxycodone-induced response on the test day, illustrating that both CAB2-015 and BAK4-54 significantly inhibited oxycodone-induced reinstatement of drug-seeking behavior. E/F: Inactive lever response, illustrating no significant difference between different treatment groups. *p<0.05, **p<0.01, compared to the vehicle group. N=6-7/group.

Figure 5.

Effects of CAB2-015 or BAK4-54 on basal or oxycodone-enhanced locomotor activity. A: Pretreatment with CAB2-015 (4-10 mg/kg, i.p., 15 min prior to oxycodone injection) dose-dependently inhibited oxycodone-enhanced locomotion. B: Pretreatment with BAK4-54 (4-10 mg/kg, i.p., 15 min prior to oxycodone injection) dose-dependently inhibited oxycodone-enhanced locomotion. C/D: CAB02-15 or BAK4-54 alone, at the same doses, had no effect on basal locomotor activity. *p<0.05, **p<0.01, compared to the vehicle group. N=8 in each group.

Figure 6.

Effects of CAB2-015 or BAK4-54 on oral sucrose self-administration. Pretreatment with CAB2-015, but not BAK4-54, dose-dependently inhibited oral sucrose self-administration behavior. N=12/group. *p<0.05, compared to the vehicle control group..