Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors.
Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors.
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DOI：
10.1017/s1461145712000661
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Skolnick P
中科院分区：
文献类型：
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作者：
Bergman J;Roof RA;Furman CA;Conroy JL;Mello NK;Sibley DR;Skolnick P
越来越多的证据表明，突触多巴胺水平的升高在可卡因的强化作用中起着关键作用，而可卡因的强化作用与其滥用倾向有关。这一证据导致了对多巴胺受体阻滞剂作为可卡因成瘾药物疗法的探索。虽然D1和D2受体拮抗剂都没有被证明是有效的，但作用于其他两个潜在靶点（D3和D4受体）的药物尚未在临床上探索用于该适应症。丁螺环酮是一种批准用于治疗焦虑症的5-HT 1A部分激动剂，据报道也以高亲和力与D3和D4受体结合。鉴于这种生物化学特征，本研究的目的是研究丁螺环酮对这些受体的功能作用，以及在非人灵长类动物中，丁螺环酮以行为选择性方式改变静脉注射可卡因的强化作用的能力。放射性配体结合研究证实，丁螺环酮与重组人D3和D4受体具有高亲和力（分别为~98和~29 nM）。活细胞功能测定还显示，丁螺环酮及其代谢产物在D3和D4受体上都起拮抗剂的作用。在行为研究中，对食物维持反应具有不一致影响的丁螺环酮剂量（0.1或0.3 mg/kg i.m.）在可卡因维持行为的剂量效应函数中产生了显著的下移，反映了每个受试者静脉注射一个或多个单位剂量可卡因的自我给药大幅减少。这些结果支持丁螺环酮作为可卡因成瘾管理的候选药物的进一步评价。
Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (~98 and ~29 nM respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose–effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction.