Baumann M H, Char G U, De Costa B R, Rice K C, Rothman R B
Clinical Psychopharmacology Section, National Institute of Drug Abuse/National Institutes of Health, Baltimore, Maryland.
J Pharmacol Exp Ther. 1994 Dec;271(3):1216-22.
Previous studies have shown that the dopamine (DA) reuptake inhibitor 1-(2-[bis(4-fluorophenyl)-[methoxy]ethyl)-4-(3-phenylpropyl) piperazine (GBR12909) antagonizes the increase in extracellular DA evoked by local perfusion of cocaine into the striatum. In the present work, in vivo microdialysis methods were used to examine the effects of i.v. cocaine, GBR12909 and combinations of the two drugs on DA overflow in the nucleus accumbens of awake rats. Both cocaine and GBR12909 (0.3, 1.0 and 3.0 mg/kg) caused dose-related elevations in extracellular DA when given alone. However, the temporal profile of DA overflow was different with each drug. Cocaine caused a rapid and short-lived increase in DA, whereas GBR12909 caused a slow and sustained elevation of transmitter. In drug combination studies, the rise in extracellular DA after a modest dose of cocaine (1.0 mg/kg) was significantly reduced from 250% to 175% of baseline by pretreatment with a subthreshold dose of GBR12909 (0.3 mg/kg). A high dose of cocaine (3.0 mg/kg) increased dialysate DA by 600%; this rise in DA was decreased to 450% and 325% of baseline by pretreatment with 0.3 and 1.0 mg/kg of GBR12909, respectively. The neurochemical effect of the combination of GBR12909 plus cocaine was clearly not additive. GBR12909 also blocked the DA-releasing action of amphetamine (1.0 mg/kg). Our findings show that GBR12909 antagonizes the rise in extracellular DA produced by systemic cocaine and these results provide further evidence that DA reuptake inhibitors may be useful pharmacological adjuncts in the treatment of cocaine addiction and withdrawal in human patients.
先前的研究表明，多巴胺（DA）再摄取抑制剂1-(2-[双(4-氟苯基)-[甲氧基]乙基]-4-(3-苯基丙基)哌嗪（GBR12909）可拮抗通过向纹状体局部灌注可卡因所诱发的细胞外DA的增加。在本研究中，采用体内微透析方法来检测静脉注射可卡因、GBR12909以及这两种药物联合使用对清醒大鼠伏隔核中DA溢出的影响。单独给予可卡因和GBR12909（0.3、1.0和3.0mg/kg）时，二者均引起细胞外DA呈剂量依赖性升高。然而，每种药物引起DA溢出的时间模式有所不同。可卡因引起DA快速且短暂的增加，而GBR12909引起递质缓慢且持续的升高。在联合用药研究中，用阈下剂量的GBR12909（0.3mg/kg）预处理后，中等剂量可卡因（1.0mg/kg）给药后细胞外DA的升高从基线的250%显著降低至175%。高剂量可卡因（3.0mg/kg）使透析液中DA增加600%；分别用0.3和1.0mg/kg的GBR12909预处理后，DA的这种升高分别降至基线的450%和325%。GBR12909与可卡因联合使用的神经化学效应显然并非相加性的。GBR12909还阻断了苯丙胺（1.0mg/kg）释放DA的作用。我们的研究结果表明，GBR12909可拮抗全身给予可卡因所产生的细胞外DA的升高，这些结果进一步证明DA再摄取抑制剂可能是治疗人类患者可卡因成瘾和戒断的有用药理学辅助药物。
