Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%-10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D₃ receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D₃ receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D₃ receptor antagonism may be a viable therapeutic approach for the treatment of OUD.

In contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca²⁺ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals.