Miller Dennis K, Rodvelt Kelli R, Constales Consuela, Putnam William C
Department of Psychological Sciences and Interdepartmental Neuroscience Program, University of Missouri, Columbia, MO 65202, USA.
Life Sci. 2007 Jun 13;81(1):63-71. doi: 10.1016/j.lfs.2007.04.024. Epub 2007 May 1.
The CB(1) cannabinoid receptor antagonist SR-141716A (Rimonabant) markedly diminishes the behavioral effects of opiates and nicotine and has been an important tool to ascertain the role of cannabinoid receptors in drug addiction. The present goal was to determine the less-explored interaction of SR-141716A and d-amphetamine in neurochemical and behavioral assays. Additionally, the effect of the substituents and substitution patterns on the phenyl ring located at the 5 position of SR-141716A (4-chlorophenyl), and of the CB(1)/CB(2) cannabinoid receptor agonist WIN-55,212-2, was determined. SR-141716A, AM-251 (4-iodophenyl) and NIDA-41020 (4-methoxyphenyl) did not alter amphetamine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine. MRI-8273-30-1 (4-fluorophenyl; 0.1-10 microM) attenuated amphetamine (3 microM)-evoked [(3)H]overflow, and MRI-8273-59 (3,4-dichlorphenyl; 0.01-10 microM) augmented amphetamine (0.3-3 microM)-evoked [(3)H]overflow. WIN-55,212-2 was without effect. In a locomotor activity experiment, SR-141716A and MRI-8273-30-1 did not alter amphetamine-induced hyperactivity. However, MRI-8273-59 (1-3 mg/kg) dose-dependently attenuated amphetamine (1 mg/kg)-induced hyperactivity. The present results suggest that SR-141716A is less efficacious to alter amphetamine effects than its reported efficacy to diminish the effects of opiates and nicotine. Modification of the 5-phenyl position of SR-141716A affords compounds that do interact with amphetamine in vitro and in vivo.
CB(1)大麻素受体拮抗剂SR-141716A（利莫那班）能显著减弱阿片类药物和尼古丁的行为效应，并且一直是确定大麻素受体在药物成瘾中作用的重要工具。目前的目标是在神经化学和行为学实验中确定SR-141716A与右旋苯丙胺之间较少被探索的相互作用。此外，还确定了位于SR-141716A（4-氯苯基）5位的苯环上取代基和取代模式的影响，以及CB(1)/CB(2)大麻素受体激动剂WIN-55,212-2的影响。SR-141716A、AM-251（4-碘苯基）和NIDA-41020（4-甲氧基苯基）不会改变预先用[(3)H]多巴胺加载的大鼠纹状体切片中苯丙胺诱发的[(3)H]溢出。MRI-8273-30-1（4-氟苯基；0.1-10微摩尔）减弱了苯丙胺（3微摩尔）诱发的[(3)H]溢出，而MRI-8273-59（3,4-二氯苯基；0.01-10微摩尔）增强了苯丙胺（0.3-3微摩尔）诱发的[(3)H]溢出。WIN-55,212-2没有效果。在一项运动活性实验中，SR-141716A和MRI-8273-30-1不会改变苯丙胺诱导的多动。然而，MRI-8273-59（1-3毫克/千克）剂量依赖性地减弱了苯丙胺（1毫克/千克）诱导的多动。目前的结果表明，SR-141716A改变苯丙胺效应的效力低于其减弱阿片类药物和尼古丁效应的报道效力。对SR-141716A的5-苯基位置进行修饰可得到在体外和体内确实与苯丙胺相互作用的化合物。
