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首页> 外文期刊>The European Journal of Neuroscience >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.
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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.

机译：SB-277011A对多巴胺D3受体的选择性拮抗作用减弱了可卡因的增强作用，这种增强作用是通过大鼠的逐步配比和可变成本-可变-回报固定比例可卡因自我给药评估的。

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In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor 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 D(2)/D(3) receptor 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 D(3) receptor antagonists may be useful in the treatment of cocaine addiction.
机译：在大鼠中，SB-277011A（一种高度选择性的多巴胺（DA）D（3）受体拮抗剂）的急性给药可阻断可卡因增强的脑刺激奖赏，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是否减弱了可卡因的强化作用，这是根据可变成本-可变收益固定比率（FR）和渐进比率（PR）强化方案下的可卡因自我管理评估的。急性腹泻SB-277011A（3-24 mg / kg）的给药并没有显着改变可卡因（0.75 mg / kg /滴注）在FR1（一次按压一次可卡因滴注）条件下加强的自我给药。但是，在以下情况下，SB-277011A（24 mg / kg，ip）的急性给药会逐渐减弱可卡因的自我给药：（a）将可卡因的单位剂量从0.75降低至0.125-0.5 mg / kg，并且（b ）可卡因强化的工作需求从FR1增加到FR10。在PR（每次连续可卡因输注时增加杠杆按压次数）可卡因的加强下，SB-277011A（6-24 mg / kg i.p.）的急性给药以剂量依赖的方式降低了可卡因自我给药的PR断裂点。 24 mg / kg SB-277011A产生的可卡因剂量响应断裂点曲线降低（0.25-1.0 mg / kg）与可卡因增强功效的降低是一致的。当代替可卡因时，仅SB-277011A不能维持自我管理的行为。与混合的DA D（2）/ D（3）受体拮抗剂氟哌啶醇（1 mg / kg）相比，SB-277011A（3、12或24 mg / kg）不能阻止运动能力，不能损害饲养行为，无法产生僵直症，也不会损害旋转脚踏车的性能。这些结果表明，SB-277011A显着抑制了可卡因引起的急性增强作用，除非在可卡因剂量较高且对可卡因的工作要求较低的情况下。如果这些结果推断给人类，则SB-277011A或类似的选择性DA D（3）受体拮抗剂可能可用于治疗可卡因成瘾。

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