Research Of Effects Of Dopamine D3Receptor Antagonist On Opioid Addiction

Objective Drug addiction has become a serious public health problem which disturbs the national security, social development and population quality. This study was aim to research if D3R involves in opioid addiction and if specifically act on D3R can affect opioid addiction.Method Self-administration (SA)、conditioned place preference (CPP) and behavioral sensitization (BS) animal models were used to investigate if Y-QA14have addictive property and it’s effect of anti-opioid addiction.Result1. Y-QA14itself did not show any abuse liability:Y-QA14(6.25,12.5,25mg/kg, i.p.)failed in inducing conditioned place preference (CPP) in mice, suggesting that Y-QA14don’t have addictive property.Acute administration of Y-QA14(50mg/kg) inhibit spontaneous activity in all tested doses(3.125,6.25,12.5,25,50mg/kg; i.p.) in mice, suggesting that high dose of Y-QA14might act on other receptors. Systematic administration of Y-QA14(25and50mg/kg, i.p.) of10days didn’t affect spontaneous activity in mice.2. Y-QA14and Y-QA31inhibited opioid addiction:In self-administration animal model, Y-QA14(25mg/kg; i.p.) and Y-QA31(25mg/kg; i.p.) significantly inhibited FR2and PR procedure heroin (0.025mg/kg/injection, i.v.)-induced SA in rats. Y-QA14at50mg/kg (p.o.) also inhibited FR2procedure heroin (0.025mg/kg/injection, i.v.)-induced SA in rats. In CPP animal model, Y-QA14(6.25;12.5;25mg/kg; i.p.) decreased expression of morphine (10mg/kg, s.c.)-induce CPP in dose-dependent manner in rats. In behavioral sensitization (BS) animal model, it also inhibited acquisition of morphine (10mg/kg, s.c.)-induced BS in mice.Above results showed that Y-QA14specifically antagonized D3R, and inhibited reward effect of opioid.3. Y-QA14inhibited opioid-induced reinstatement.In SA animal model, Y-QA14at25mg/kg decreased reinstatement of heroin (0.25mg/kg, i.v.)-induced SA in rats.In CPP animal model, systematic administration of Y-QA14(6.25,12.5,25mg/kg, i.p.) in extinction training phase decreased reinstatement of morphine (5mg/kg, s.c.)-induced CPP in dose-dependent manner in rats, while systematic administration of Y-QA14(25mg/kg, i.p.) in withdrawal phase accelerated the extinguishing of CPP and have a tendency to decrease reinstatement of morphine (5mg/kg, s.c.)-induced CPP in mice. In BS animal model, chronic administration of Y-QA14in acquisition of morphine (10mg/kg, s.c.)-induced BS or administration of Y-QA14before reinstatement test inhibited morphine (5mg/kg, s.c.)-induced BS in mice.These researches demonstrated that low dose opioid-induce relapse of drug seeking can be prevented by specifically antagonizing D3R.Conclusion All together, this paper demonstrated that Y-QA14inhibited opioid addiction in whole process by specifically antagonizeing D3R, while didn’t show any abuse liability.