Bradberry C W, Nobiletti J B, Elsworth J D, Murphy B, Jatlow P, Roth R H
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
J Neurochem. 1993 Apr;60(4):1429-35. doi: 10.1111/j.1471-4159.1993.tb03305.x.
Cocaethylene is a pharmacologically active metabolite resulting from concurrent cocaine and ethanol consumption. The effects of cocaine and cocaethylene on extracellular levels of dopamine in the nucleus accumbens, and serotonin in the striatum were characterized in vivo in the anesthetized rat. Both intravenous (3 mumol/kg) and intraperitoneal (44 mumol/kg) routes of administration were used. In addition to monitoring neurotransmitter levels, microdialysate levels of cocaine and cocaethylene were determined at 4-min intervals after intravenous administration, and at 20-min intervals after intraperitoneal administration. Extracellular levels of dopamine in the nucleus accumbens were increased to approximately 400% of preinjection value by both cocaine and cocaethylene when administered intravenously. Cocaine caused a significant increase of striatal serotonin to 200% preinjection value, whereas cocaethylene had no effect. Brain levels of cocaine and cocaethylene after intravenous administration did not differ. After intraperitoneal administration, extracellular levels of dopamine in the nucleus accumbens were increased to 400% of preinjection levels by cocaine, but were only increased to 200% of preinjection levels by cocaethylene, the difference being statistically significant. Serotonin levels were increased to 360% of preinjection levels by cocaine, but only to 175% of preinjection value by cocaethylene. Levels of cocaine attained in brain were significantly higher than those for cocaethylene, suggesting pharmacokinetic differences with the intraperitoneal route. These results confirm in vivo that cocaethylene is more selective in its actions than cocaine with respect to dopamine and serotonin uptake. In addition, route-dependent differences in attainment of brain drug levels have been observed that may impact on interpretations of the relative potency of the reinforcement value of these compounds.
可卡乙碱是同时摄入可卡因和乙醇后产生的一种具有药理活性的代谢产物。在麻醉大鼠体内，对可卡因和可卡乙碱对伏隔核中多巴胺细胞外水平以及纹状体中5-羟色胺的影响进行了表征。采用了静脉注射（3 μmol/kg）和腹腔注射（44 μmol/kg）两种给药途径。除了监测神经递质水平外，静脉注射后每隔4分钟、腹腔注射后每隔20分钟测定微透析液中可卡因和可卡乙碱的水平。静脉注射可卡因和可卡乙碱时，伏隔核中多巴胺的细胞外水平均升高至注射前值的约400%。可卡因使纹状体中5-羟色胺显著增加至注射前值的200%，而可卡乙碱没有影响。静脉注射后大脑中可卡因和可卡乙碱的水平没有差异。腹腔注射后，可卡因使伏隔核中多巴胺的细胞外水平升高至注射前水平的400%，而可卡乙碱仅升高至注射前水平的200%，差异具有统计学意义。5-羟色胺水平可卡因使其升高至注射前水平的360%，而可卡乙碱仅使其升高至注射前值的175%。大脑中达到的可卡因水平显著高于可卡乙碱，表明腹腔注射途径存在药代动力学差异。这些结果在体内证实，就多巴胺和5-羟色胺摄取而言，可卡乙碱的作用比可卡因更具选择性。此外，还观察到大脑药物水平达到过程中存在途径依赖性差异，这可能会影响对这些化合物强化价值相对效力的解释。
