Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats.
Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats.
复制标题
通过大鼠渐进比例和可变成本可变回报固定比例可卡因自我给药评估，SB-277011A 的选择性多巴胺 D3 受体拮抗作用减弱了可卡因强化。
DOI：
10.1111/j.1460-9568.2005.04159.x
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Gardner,EliotL
中科院分区：
文献类型：
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作者：
Xi,Zheng-Xiong;Gilbert,JeremyG;Pak,ArleneC;AshbyJr,CharlesR;Heidbreder,ChristianA;Gardner,EliotL
在大鼠中，急性给予SB-277011A，一种高选择性的多巴胺(DA)D3受体拮抗剂，可阻断可卡因增强的大脑刺激奖励、可卡因寻找行为和可卡因寻找行为的恢复。在这里，我们调查了SB-277011A是否减弱可卡因强化，这是在可变成本可变收益固定比率(FR)和累进比率(PR)强化计划下通过可卡因自我给药评估的。急性IP。注射SB-277011A(3-24 mg/kg)不能显著改变单次注射可卡因(0.75 mg/kg/次)。而急性给药SB-277011A(24 mg/kg，i.p.)(A)自我注射可卡因的单位剂量从0.75 mg/kg降至0.125-0.5FRg/kg，以及(B)加强可卡因的工作需求从第一季度第一季度增加到第十季度。在PR(每次连续注射可卡因的杠杆按压次数增加)可卡因强化下，急性给予SB-277011A(6-24 mg/kg ip)。以剂量依赖的方式降低可卡因自身给药的PR转折点。2 4 mg/kg SB-2 77011A对可卡因(0.2 5~1.0 mg/kg)剂量-反应转折点曲线的降低与可卡因增强效应的降低是一致的。当用SB-277011A替代可卡因时，单独的SB-277011A无法维持自我给药行为。与混合多巴胺D2/D3受体拮抗剂氟哌啶醇(1 mg/kg)相比，SB-277011A(3、12或24 mg/kg)不能抑制小鼠的运动活动，不能损害饲养行为，不能产生惊厥，不能影响转杆运动能力。这些结果表明，SB-277011A除了在高剂量可卡因和对可卡因的低工作需要量外，对急性可卡因诱导的增强有明显的抑制作用。如果这些结果外推到人类，SB-277011A或类似的选择性DA D3受体拮抗剂可能在治疗可卡因成瘾方面有用。
In rats, acute administration of SB‐277011A, a highly selective dopamine (DA) D3receptor antagonist, blocks cocaine‐enhanced brain stimulation reward, cocaine‐seeking behaviour and reinstatement of cocaine‐seeking behaviour. Here, we investigated whether SB‐277011A attenuates cocaine reinforcement as assessed by cocaine self‐administration under variable‐cost–variable‐payoff fixed‐ratio (FR) and progressive‐ratio (PR) reinforcement schedules. Acute i.p. administration of SB‐277011A (3–24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self‐administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB‐277011A (24 mg/kg, i.p.) progressively attenuated cocaine self‐administration when: (a) the unit dose of self‐administered cocaine was lowered from 0.75 to 0.125–0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB‐277011A (6–24 mg/kg i.p.) lowered the PR break point for cocaine self‐administration in a dose‐dependent manner. The reduction in the cocaine (0.25–1.0 mg/kg) dose–response break‐point curve produced by 24 mg/kg SB‐277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB‐277011A alone did not sustain self‐administration behaviour. In contrast with the mixed DA D2/D3receptor antagonist haloperidol (1 mg/kg), SB‐277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB‐277011A significantly inhibits acute cocaine‐induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB‐277011A or similar selective DA D3receptor antagonists may be useful in the treatment of cocaine addiction.