Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol[(+)-PD 128,907]
Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol[(+)-PD 128,907]
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DOI：
10.1124/jpet.103.059980
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发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Gasior, M
中科院分区：
文献类型：
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作者：
Witkin, JM;Dijkstra, D;Gasior, M
可卡因滥用是一个公共卫生问题，癫痫发作和死亡是过量的后果之一。在本研究中，多巴胺D-3/D-2受体激动剂剂量依赖性，完全防止可卡因的惊厥和致死作用。优选D-3的激动剂R-（+）-反式-3，4a，10 b-四氢-4-丙基-2H，5 H-[1]苯并吡喃并[4，3-B]-1，4-恶嗪-9-醇）[（+）-PD 128，907]、（+）-7-羟基-二丙基氨基四氢化萘和混合D-3/D-2激动剂喹吡罗和喹咯烷均对小鼠中的可卡因毒性有效。这些化合物的抗惊厥作用发生在低于产生运动障碍的剂量下，如在倒置屏幕测试中所评估的。（+）-PD 128，907还可防止选择性多巴胺摄取抑制剂1-[2-[双（4-氟苯基）甲氧基]乙基]-4-[3-苯基-丙基]哌嗪（GBR 12909）的惊厥作用。（+）-PD 128，907（3 mg/kg）对这些多巴胺能化合物的作用的可能选择性通过其对通过其他神经机制起作用的许多惊厥剂[戊四氮、（+）-荷包牡丹碱和印防己毒素、4-氨基吡啶和叔丁基双环磷硫代膦酸盐、N-甲基-D-天冬氨酸盐、红藻氨酸盐、毛果芸香碱、尼古丁、士的宁、氨茶碱、阈值电击和6-Hz电刺激]。直接和相关的证据表明，这些作用是由D-3受体介导的。D-3受体拮抗剂[3-{4[1-（4-{2[4-（3-二乙基氨基-丙氧基）-苯基]苯并咪唑-1-基}-丁基）-1H-苯并咪唑-2-基]-苯氧基}丙基）-二乙基-胺; PD 58491]而非D-2受体拮抗剂[3[[4-（4-氯苯基）-4羟基哌啶-1-基]甲基-1H-吲哚; L-741，626]的保护作用具有立体特异性且可逆。抗惊厥效力与D-3受体功能试验中的效力呈正相关，但与D-2受体功能无关。总之，这些发现表明，（+）-PD 128，907对可卡因惊厥和致死性的预防可能是由于D-3受体介导的事件。
Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D-3/D-2 receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D-3-preferring agonists R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol) [(+)-PD 128,907], (+)-7-hydroxy-dipropylaminotetralin, and the mixed D-3/D-2 agonists quinpirole and quinelorane were all effective against cocaine toxicity in mice. The anticonvulsant effects of these compounds occurred at doses below those that produced motor impairment as assessed in the inverted screen test. Protection against the convulsant effects of the selective dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenyl- propyl] piperazine (GBR 12909) was also conferred by (+)-PD 128,907. The possible selectivity of the effects of (+)-PD 128,907 (3 mg/kg) for these dopaminergic compounds was demonstrated by its general lack of protective efficacy against a host of convulsants acting through other neural mechanisms [pentylenetetrazol, (+)-bicuculline, and picrotoxin, 4-aminopyridine, and t-butylbiclyclophosphoorothionate, N-methyl-D-aspartate, kainate, pilocarpine, nicotine, strychnine, aminophylline, threshold electric shock, and 6-Hz electrical stimulation]. Direct and correlational evidence suggests that these effects were mediated by D-3 receptors. Protection was stereospecific and reversible by an antagonist of D-3 receptors [3-{4[1-(4-{2[4-(3-diethyamino-propoxy)-phenyl]benzoimidazol-1-yl}-butyl)-1H-benzoimidazol-2-yl]-phenoxy}propyl)-diethyl-amine; PD 58491] but not D-2 receptors [3[[4-(4-chlorophenyl)-4hydroxypipeidin-1-yl]methyl-1H-indole; L-741,626]. Anticonvulsant potencies were positively associated with potencies in a functional assay of D-3 but not D-2 receptor function. Together, these findings suggest that the prevention of cocaine convulsions and lethality by (+)-PD 128,907 may be due to D-3 receptor-mediated events.