Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects

Abstract

Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.

Fig. 1

Effects of VK4-116 on oxycodone- or sucrose-taking and oxycodone-seeking behavior in rats. a, b pretreatment with VK4-116 (5 or 15 mg/kg, i.p. for 5 consecutive days) dose-dependently inhibited the acquisition of oxycodone self-administration as assessed by oxycodone infusions (a) and active lever presses (b) (n = 8). c, d Pretreatments with VK4-116 (5–25 mg/kg, i.p.) also dose-dependently reduced oxycodone self-administration during the maintenance of self-administration (c) and oxycodone seeking when oxycodone was replaced by saline during self-administration (d) (n = 6–7). e–g VK4-116 treatment had no effect on oral sucrose self-administration as assessed by the total number of sucrose deliveries (e), the time spent to maximal delivery (f), and the rate of sucrose deliveries (per h) (g) (n = 7). *p < 0.05, **p < 0.01, compared to vehicle group. ^#p < 0.05, compared to baseline

Fig. 2

Oxycodone self-administration under progressive-ratio and multiple-dose conditions. a Break-point levels for oxycodone self-administration under PR reinforcement in the presence or absence of VK4-116. b Oxycodone dose–response self-administration function illustrating the total numbers of oxycodone infusions across five doses during daily 3-h sessions. c Cumulative oxycodone intake at each dose. *p < 0.05, **p < 0.01, ***p < 0.001 compared to vehicle group. ^##p < 0.01, compared to baseline

Fig. 3

Effects of VK4-116 pretreatment (5–15 mg/kg, i.p.) on reinstatement of oxycodone seeking behavior induced by a priming injection of oxycodone (1 mg/kg, i.p.). Data represent mean (±S.E.M) for N = 7–8 in each group. **p < 0.01 compared to the vehicle group

Fig. 4

Effects of VK4-116 on the antinociceptive effects of oxycodone in rats. a VK4-116 pretreatment produced an upward or left shift in the dose–response curve of oxycodone-induced analgesia in the hot plate test. Data represent mean (±S.E.M) for n = 8–9 in each group. b Time courses of 2.0 mg/kg oxycodone-induced analgesia as assessed by the hot plate test in the absence or presence of VK4-116 pretreatment. Oxycodone dose-dependently increased MPE% and pretreatment with VK4-116, at the 25 mg/kg dose, significantly potentiated oxycodone’s analgesic effect at the 1 and 2 mg/kg doses. Data represent mean (±SEM) for n = 8–9 in each group. **p < 0.01 compared to the vehicle control group

Fig. 5

Effects of VK4-116 pretreatment on naloxone-precipitated conditioned place aversion (CPA) in rats. a Schematic drawing showing the general procedure for naloxone (Nalx)-precipitated CPA; b VK4-116 administered 1 h prior to Nalx conditioning significantly attenuated Nalx-precipitated CPA in oxycodone-treated rats tested 24 h after the last conditioning session (right panel). VK4-116 or Nalx alone had no effect in saline-treated rats (left panel). ^#p < 0.05, ^## p < 0.01, compared to saline-treated group; *p < 0.05, **p < 0.01, compared to vehicle + Nalx group. Data represent means (±SEM) for n = 8 in each group

Fig. 6

Species-specific phase I metabolic stability of VK4-116 in liver microsomes from rat, rhesus monkey, and human. VK4-116 was generally stable in all thee species following incubation in liver microsomes fortified with NADPH. The general rank order for different species was rat > human > rhesus monkey. In all three species, the compound remained completely stable, >95% remaining, in microsomes lacking NADPH (negative control, data not shown), suggesting that VK4-116 undergoes specific CYP-dependent metabolism. Data are presented as means ± SEM (n = 3/compound/time point). Buprenorphine was used as a positive control, with <10% remaining at 60 min (data not shown).