Tolliver B K, Newman A H, Katz J L, Ho L B, Fox L M, Hsu K, Berger S P
Department of Psychiatry, University of California at San Francisco San Francisco, USA.
J Pharmacol Exp Ther. 1999 Apr;289(1):110-22.
The current studies evaluated the novel diphenylmethoxytropane analog 4-chlorobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for their abilities to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, and elevate extracellular dopamine (DA) in the nucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally administered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4-Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discriminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. The time course of behavioral activation differed markedly between the two drugs, with much shorter onset and duration of locomotor stimulant effects for cocaine relative to 4-Cl-BZT. Similarly, i.p. cocaine (10 and 40 mg/kg) induced a pronounced, rapid, and short-lived increase in DA in the NAc, whereas i.p. 4-Cl-BZT was effective only at the higher dose and produced a more gradual, modest, and sustained (>/=2 h) elevation in accumbens DA. In contrast to i.p. administration, local infusion of 4-Cl-BZT (1-100 microM) into the NAc through the microdialysis probe elevated extracellular DA to a much greater extent than did local cocaine (nearly 2000% of baseline maximally for 4-Cl-BZT versus 400% of baseline for cocaine) and displayed a much longer duration of action than cocaine. However, when microinjected bilaterally into the NAc at 30 or 300 nmol/side, cocaine remained a more efficacious locomotor stimulant than 4-Cl-BZT. Finally, pretreatment with i.p. 4-Cl-BZT dose dependently enhanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmethoxytropane analog also facilitated the emergence of stereotyped behavior and convulsions induced by high-dose cocaine. The current results demonstrate that DA transporter ligands that do not share the neurochemical and behavioral profiles of cocaine nevertheless may enhance the effects of cocaine in vivo.
当前研究评估了新型二苯甲氧基托烷类似物4-氯苯扎托品（4-Cl-BZT）、可卡因以及这两种药物的组合，以研究它们刺激运动活性、产生可卡因样辨别刺激效应以及通过体内微透析测量升高伏隔核（NAc）细胞外多巴胺（DA）的能力。外周给药时，可卡因作为运动兴奋剂的效力约为4-Cl-BZT的两倍，且在比4-Cl-BZT更低的剂量下就具有行为活性。在训练用于区分腹腔注射10mg/kg可卡因和生理盐水的大鼠中，可卡因在产生辨别刺激效应方面也比4-Cl-BZT更有效。两种药物在行为激活的时间进程上有显著差异，相对于4-Cl-BZT，可卡因的运动兴奋效应起效时间更短、持续时间更短。同样，腹腔注射可卡因（10和40mg/kg）会使NAc中的DA显著、快速且短暂地增加，而腹腔注射4-Cl-BZT仅在较高剂量时有效，且使伏隔核DA产生更缓慢、适度且持续（≥2小时）的升高。与腹腔注射不同，通过微透析探针将4-Cl-BZT（1-100μM）局部注入NAc比局部注射可卡因能更大程度地升高细胞外DA（4-Cl-BZT最大可达基线的近2000%，而可卡因为基线的400%），并且作用持续时间比可卡因长得多。然而，当以30或300nmol/侧双侧微量注射到NAc中时，可卡因仍然是比4-Cl-BZT更有效的运动兴奋剂。最后，腹腔注射4-Cl-BZT预处理剂量依赖性地增强了运动兴奋、辨别刺激效应以及对随后低剂量腹腔注射可卡因激发的NAc DA反应。二苯甲氧基托烷类似物还促进了高剂量可卡因诱导的刻板行为和惊厥的出现。当前结果表明，不具有可卡因神经化学和行为特征的DA转运体配体在体内仍可能增强可卡因的作用。
