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.

Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

“…The acquisition in the males was consistent with that observed using similar procedures in a group of experimentally naïve adult males (Nguyen et al, 2019). Unfortunately the majority of rat oxycodone IVSA studies published so far have been in male rats (Austin Zamarripa et al, 2018;Blackwood et al, 2019;Bossert et al, 2018;Jordan et al, 2019;Leri and Burns, 2005;Mavrikaki et al, 2019;Nawarawong et al, 2018;Neelakantan et al, 2017;Nguyen et al, 2019;Nguyen, J. D. et al, 2018b;Pravetoni et al, 2014;Townsend et al, 2017;Wade et al, 2015;You et al, 2018;You et al, 2017); one exception was a study in pregnant rats (Vassoler et al, 2018). Interestingly, when female animals were evaluated on a fentanyl dose substitution under an FR procedure, the THC exposed rats self-administered more drug at the lowest dose (Figure 9).…”

Effects of the selective dopamine D3receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

“…Our results suggest that the robust attenuation of morphine-induced locomotion previously observed with nonselective D2-like receptor antagonism is primarily attributable to blockade of the D2R subtype. Moreover, our finding that pretreatment with the selective D3R antagonist PG01037 produces a significant, albeit weaker, attenuation of morphine-induced locomotion is in accord with a number of recent studies that also demonstrate modest reductions of the locomotor-activating effects of opioids following pretreatment with other highly-selective D3R antagonists (Kumar et al 2016;Lv et al 2019;You et al 2017). Based on these prior findings and our present results with PG01037 and L-741,626, we conclude that D3R antagonism and D2R antagonism exert qualitatively similar reductions of morphine-induced hyperlocomotion, however a pharmacological shift away from D3R selectivity towards either nonselective antagonism or selective D2R antagonism renders this modulation far more robust.…”

Role of mu, but not delta or kappa, opioid receptors in context‐induced reinstatement of oxycodone seeking

“…We received oxycodone hydrochloride (HCl) from NIDA pharmacy and dissolved it in sterile saline. We chose a unit dose of 0.1 and 0.05 mg/kg for self-administration training based on previous studies (Wade et al, 2015;Secci et al, 2016;You et al, 2017). In Exp.…”

“…However, in light of the current prescription opioid epidemic, we recently changed our focus to studying relapse to oxycodone, a prototypical prescription opioid drug that is widely used for pain management (Van Zee, 2009;Yaksh & Wallace, 2011). We also chose to study oxycodone because compared to heroin (Wise, 1989;Koob, 1992;Badiani et al, 2011;Bossert et al, 2013), there are very few published studies on oxycodone self-administration and relapse/reinstatement (Leri & Burns, 2005;Campbell et al, 2012;Pravetoni et al, 2014;Secci et al, 2016;Neelakantan et al, 2017;Townsend et al, 2017;You et al, 2017). Human and rodent binding studies show that oxycodone is a preferential mu opioid receptor (MOR) agonist (Lalovic et al, 2006;Peckham & Traynor, 2006) with lower affinity to MOR than morphine (Lalovic et al, 2006;Peckham & Traynor, 2006); there is also evidence that oxycodone binds to the kappa opioid receptor (KOR) (Nielsen et al, 2007).…”