Abstract
Opioid use disorder(OUD)has become a con-siderable global public health challenge;however,potential medications for the management of OUD that are effective,safe,and nonaddictive are not available.Accumulating pre-clinical evidence indicates that antagonists of the dopamine D3 receptor(D3R)have effects on addiction in different animal models.We have previously reported that YQA14,a D3R antagonist,exhibits very high affinity and selectiv-ity for D3Rs over D2Rs,and is able to inhibit cocaine-or methamphetamine-induced reinforcement and reinstatement in self-administration tests.In the present study,our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-admin-istered rats,also attenuated heroin-induced reinstatement of drug-seeking behavior.On the other hand,YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice.Moreover,we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibit-ing morphine-induced up-regulation of dopaminergic neu-ron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber pho-tometry recording system.These findings suggest that D3R might play a very important role in opioid addiction,and YQA14 may have pharmacotherapeutic potential in attenu-ating opioid-induced addictive behaviors dependent on the dopamine system.
基金项目
National Natural Science Foundation of China(81573405)
National Natural Science Foundation of China(U1502225)
Natural Science Foundation of Beijing(7212159)
National Key R&D Program of China(2016YFC0800907)
National Key R&D Program of China(2017YFC131040)
Medical Innovation Program(16CXZ033)
Beijing Nova Program(xx2014A014)
维普
万方数据