Selective dopamine D3 receptor antagonist YQA14 inhibits morphine-induced behavioral sensitization in wild type, but not in dopamine D3 receptor knockout mice

Abstract

Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25-25 mg/kg every day ip) prior to morphine (10 mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25-25 mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R) mice in the expression phase. In addition, D3R mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.

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.…”

“…A similar pattern of results has also been reported in a comparison between the nonselective D2-like receptor antagonist haloperidol and the modestly-selective D3R antagonist, U99194A (Manzanedo et al, 1999). More recent studies utilizing D3R antagonists that exhibit high D3R vs. D2R selectivity such as VK4-116, BAK4-54, CAB2-015, and YQA14 also demonstrate significant but modest reductions in the locomotor-activating effects of opioids (Kumar et al, 2016;Lv et al, 2019;You et al, 2017). Based on these prior findings and our present results with PG01037, we conclude that D3R antagonism reliably attenuates the locomotor-activating effects of opioids regardless of the specific compound used, suggesting a D3R receptor antagonist class effect.…”

“…The D3R has emerged as an appealing target in this regard for reasons that have been reviewed extensively elsewhere (Galaj et al, 2020;Heidbreder and Newman, 2010;Sokoloff and Le Foll, 2017). Of most relevance to the present report is preclinical evidence that selective D3R antagonism attenuates opioid self-administration under various schedules of reinforcement as well as opioid-seeking behaviors, without producing adverse side effects associated with nonselective D2-like receptor antagonists (Boateng et al, 2015;de Guglielmo et al, 2019;Galaj et al, 2015;Hu et al, 2013;Jordan et al, 2019a;Lv et al, 2019;You et al, 2019). Moreover, two recently-developed D3R antagonists have been reported to potentiate the desirable analgesic properties of opioids (Jordan et al, 2019a;You et al, 2019).…”

“…The D3R has emerged as an appealing pharmacological target in this regard as reviewed elsewhere [30][31][32]. Of most relevance to this report is preclinical evidence that selective D3R antagonism attenuates opioid-induced hyperactivity, opioid self-administration, and opioidseeking behavior, without producing adverse motoric effects associated with nonselective D2like receptor antagonism [33][34][35][36][37][38][39]. Furthermore, two newly-developed and highly-selective D3R antagonists, R-VK4-40 and VK4-116, were recently reported to enhance the analgesic effects of oxycodone while simultaneously reducing its abuse-related effects, lending additional support to the potential use of D3R antagonists as treatments for OUD and also possibly as add-on medications to be administered concurrently with opioid analgesics [37,38].…”

“…Second, postmortem studies in humans and animals have revealed that chronic exposure to drugs of abuse including opioids increases D3R mRNA expression within components of the mesolimbic DA system including the VTA and NAc (Le Foll et al 2003;Liang et al 2011;Spangler et al 2003;Staley and Mash 1996). Finally, accumulating preclinical evidence suggests that pretreatment with selective D3R antagonists attenuates ongoing opioid self-administration under various schedules of reinforcement as well as opioid-seeking behaviors in the general absence of adverse side effects associated with nonselective D2-like receptor antagonists (Boateng et al 2015;Galaj et al 2015;Hu et al 2013;Jordan et al 2019;Lv et al 2019;. Despite these promising findings, the underlying neuropharmacological mechanisms by which D3R antagonism alters the neurochemical and/or behavioral effects of opioids remain largely unresolved.…”