Dopamine D3 Receptor Antagonist Reduces Opioid Addiction-Like Behaviors in Rats

From the blogpost site of the National Institute on Drug Abuse
Original Posting Date January  13, 2020

By Stacey C. Tobin, Ph.D., ELS, NIDA Notes Contributing Writer

This study reported:

  • The dopamine D3 receptor antagonist VK4-116 reduced oxycodone self-administration in rats, as well as drug-seeking behaviors after oxycodone reinstatement following withdrawal.
  • VK4-116 did not interfere with oxycodone’s pain-relieving effects.

Medications to prevent and treat opioid use disorder (OUD) as well as to prevent relapse are urgently needed. In animal studies, dopamine D3 receptors have emerged as potential therapeutic targets for reducing addiction-related behaviors. Dr. Zhi-Bing You and colleagues from NIDA’s Intramural Research Program (IRP) and Johns Hopkins University now show that a novel agent called VK4-116, which blocks dopamine D3 receptor activity, can reduce a variety of addiction-like behaviors related to oxycodone administration in rats. “We are very excited that our highly selective D3 receptor antagonist, VK4-116, was effective in a multitude of behavioral models associated with OUD, providing preclinical data to support further development toward the clinic,” says NIDA IRP’s Dr. Amy Hauck Newman, the study’s senior investigator.

Dr. You and colleagues trained rats to self-administer oxycodone by pressing a lever. The investigators then conducted several experiments modeling different aspects of addiction-like behaviors. In these tests, VK4-116 counteracted oxycodone’s effects. For example:

  • Pretreatment with VK4-116 reduced the number of oxycodone infusions the rats pressed the lever for, and this effect lasted for several days after treatment (see Figure 1A).
  • Once the rats self-administered oxycodone, VK4-116 pretreatment decreased lever responses for oxycodone (see Figure 1B).
  • Pretreatment with VK4-116 did not affect sucrose self-administration (see Figure 1C).
  • VK4-116–treated rats that were given a single injection of oxycodone to trigger reinstatement of drug use after extinction were less likely to seek out more drug (see Figure 2).

Dopamine D3 Receptor Antagonist Graphic Fig 1

Fig. 1

Dopamine D3 Receptor Antagonist Graphic Fig 2

Fig. 2

Additional experiments found that VK4-116 may also be useful in ameliorating naloxone-precipitated withdrawal symptoms in oxycodone-dependent animals. Naloxone, the drug used to counteract opioid overdose, will induce severe withdrawal symptoms in humans who are dependent on opioids. Oxycodone-dependent rats too will experience withdrawal when given naloxone and will avoid locations where they received that medication. This conditioned place aversion is thought to represent the aversive aspects of withdrawal. Dr. You and colleagues found that VK4-116 reduced the naloxone-triggered conditioned place aversion, suggesting that the compound may dampen withdrawal symptoms.

Oxycodone is a highly effective pain reliever, so the investigators also tested if VK4-116 interfered with analgesia. They found that pretreatment with VK4-116 did not reduce oxycodone’s analgesic effect and even enhanced it at the highest VK4-116 dose tested (see Figure 3).

Dopamine D3 Receptor Antagonist Graphic Fig 3

Fig. 3

Although all of these preclinical findings are promising, further evaluation will be needed to reveal their translational potential. Nevertheless, the research team hopes that D3 receptor antagonists may one day help prevent addiction in people prescribed opioid medications or that they could be combined with behavioral therapies to mitigate withdrawal and reduce relapse risk in those being treated for OUD. “Demonstrating that VK4-116 is safe for human use and that our preclinical models actually predict treatment potential in OUD patients is critical,” says Dr. Newman. “In the meantime, our lab will continue to develop the tools needed to further elucidate the role of the D3 receptor in OUD and pain management.”

This study was supported by NIDA-IRP grant DA000424.


You, Z.-B., Bi, G.-H., Galaj, E., et al. Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects. Neuropsychopharmacology. 44(8):1415-1424, 2019.

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