Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys
Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys
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DOI：
10.1124/jpet.110.167619
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发表时间：
2010-08-10
影响因子：
3.5
通讯作者：
Spealman, Roger D.
中科院分区：
文献类型：
--
作者：
Achat-Mendes, Cindy;Grundt, Peter;Spealman, Roger D.
多巴胺（DA）D3和D2受体机制与可卡因滥用相关的行为效应有关，但这两种受体亚型的相对贡献仅部分表征。本研究通过测定D3-偏好性拮抗剂PG 01037 [N-{4-[4-（2-氨基乙基）-2-氧代（二、3-二氯苯基）-哌嗪-1-基]-反式-丁-2-烯基}-4-吡啶-2-基-苯甲酰胺HCl]和D2-偏好拮抗剂L-741626 [3-[4-[3-（2-氯苯基）-哌嗪-1-基]-反式-丁-2-烯基]-4-吡啶-2-基-苯甲酰胺HCl]。（4-氯苯基）-4-羟基哌啶-1-基]甲基-1H-吲哚]减弱可卡因对松鼠猴的几种行为效应。定量观察研究确定了每种拮抗剂的剂量，这些剂量不会产生不良反应，并用于随后的比较。此外，D3偏好激动剂PD 128907 [（R-（+）-反式-3，4a，10 b-四氢-4-丙基-2H，5H [1]苯并吡喃并[4，3-B]-1，4-恶嗪-9-醇）]和D2偏好激动剂sumanirole [（R）-5，6-二氢-5-[（甲氨基）-4H-咪唑并[4，5，1-ij]喹啉-2（1H）-酮（Z）-2-丁烯二酸酯]复制可卡因的辨别刺激（DS）和启动效应。在训练区分可卡因车辆的猴子，两个DA拮抗剂衰减和DA激动剂部分再现可卡因的DS效果。PG 01037还选择性减弱PD 128907的可卡因样DS效应，而L-741626减弱两种激动剂的可卡因样DS效应。在自我给药研究中，L-741626非选择性地减少可卡因和食物维持的反应，而PG 01037对这两种增强剂均无效。在涉及恢复熄灭可卡因寻求的研究中，两种拮抗剂减弱可卡因诱导的恢复反应，两种激动剂诱导至少部分恢复可卡因寻求。L-741626也减弱了舒马尼罗诱导的，但不是PD 128907诱导的，反应的恢复，而PG 01037对任一DA激动剂无效。这些结果与D3和D2受体机制在可卡因的DS效应和可卡因诱导的药物寻求恢复中的作用一致，但没有提供证据证明D3受体在可卡因的直接强化效应中的主要作用。
Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazinl-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4hydroxypiperidin- 1-yl] methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a, 10b-tetrahydro-4-propyl-2H, 5H[ 1] benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaine's discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine-and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine.