The highly selective dopamine D3R antagonist, RVK4-40, attenuates oxycodone reward and augments analgesia in rodents.

The highly selective dopamine D3R antagonist, RVK4-40, attenuates oxycodone reward and augments analgesia in rodents. Neuropharmacology. 2019 Apr 08;: Authors: Jordan CJ, Humburg B, Rice M, Bi GH, You ZB, Shaik AB, Cao J, Bonifazi A, Gadiano A, Rais R, Slusher B, Newman AH, Xi ZX Abstract Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of RVK4-40, a highly selective dopamine (DA) D3 receptor (D3R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of RVK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with RVK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D3 antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with RVK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, RVK4-40 produced...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research