Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts 02478, USA.
J Pharmacol Exp Ther. 2010 Jun;333(3):834-43. doi: 10.1124/jpet.110.165746. Epub 2010 Feb 26.
The present studies were conducted to investigate the relationship between discriminative stimulus effects of indirectly acting monoaminergic psychostimulants and their ability to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcb) shell. First, the behavioral effects of methamphetamine (MA), cocaine (COC), 1-[2-[bis(4-fluorophenyl-)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), d-amphetamine, and methylphenidate were established in rats trained to discriminate intraperitoneal injections of 0.3 mg/kg MA from saline. In other studies, in vivo microdialysis was used to determine the effects of MA, COC, and GBR 12909 on extracellular DA levels in the NAcb shell. Results show that all drugs produced dose-related and full substitution for the discriminative stimulus effects of 0.3 mg/kg MA. In microdialysis studies, cumulatively administered MA (0.3-3 mg/kg), COC (3-56 mg/kg), and GBR 12909 (3-30 mg/kg) produced dose-dependent increases in DA efflux in the NAcb shell to maxima of approximately 1200 to 1300% of control values. The increase in DA levels produced by MA and COC was rapid and short-lived, whereas the effect of GBR 12909 was slower and longer lasting. Dose-related increases in MA lever selection produced by MA, COC, and GBR 12909 corresponded with graded increases in DA levels in the NAcb shell. Doses of MA, COC, and GBR 12909 that produced full substitution increased DA levels to approximately 200 to 400% of control values. Finally, cumulatively administered MA produced comparable changes in DA levels in both naive and 0.3 mg/kg MA-trained rats. These latter results suggest that sensitization of DA release does not play a prominent role in the discriminative stimulus effects of psychomotor stimulants.
本研究旨在探讨间接作用的单胺能精神兴奋剂的辨别刺激效应与其增加伏隔核壳部细胞外多巴胺（DA）水平的能力之间的关系。首先，在经过训练能够辨别 0.3mg/kg 甲基苯丙胺（MA）与生理盐水的腹腔注射的大鼠中，确立了 MA、可卡因（COC）、1-[2-[双（4-氟苯基）甲氧基]乙基]-4-[3-苯基丙基]哌嗪（GBR 12909）、d-苯丙胺和哌醋甲酯的行为效应。在其他研究中，采用体内微透析技术测定 MA、COC 和 GBR 12909 对伏隔核壳部细胞外 DA 水平的影响。结果表明，所有药物均产生剂量相关且完全替代 0.3mg/kg MA 的辨别刺激效应。在微透析研究中，逐渐给予 MA（0.3-3mg/kg）、COC（3-56mg/kg）和 GBR 12909（3-30mg/kg）可导致伏隔核壳部的 DA 外流量呈剂量依赖性增加，最大可达对照值的 1200-1300%左右。MA 和 COC 引起的 DA 水平升高迅速且短暂，而 GBR 12909 的作用较慢且持续时间较长。MA、COC 和 GBR 12909 引起的与剂量相关的 MA 操纵杆选择增加与伏隔核壳部 DA 水平的分级增加相对应。产生完全替代作用的 MA、COC 和 GBR 12909 剂量可将 DA 水平提高到对照值的 200-400%左右。最后，逐渐给予 MA 可在未经处理和 0.3mg/kg MA 训练的大鼠中引起相似的 DA 水平变化。这些结果表明，DA 释放的敏化作用在精神兴奋剂的辨别刺激效应中没有起重要作用。
