Muñiz Javier A, Gomez Gimena, González Betina, Rivero-Echeto María Celeste, Cadet Jean Lud, García-Rill Edgar, Urbano Francisco J, Bisagno Veronica
Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Fisiología, Biología Molecular y Celular "Dr. Hector Maldonado" (DFBMC), Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Junín 956, piso 5, Ciudad Autónoma de Buenos Aires, C1113, Buenos Aires, Argentina.
Neurotox Res. 2016 May;29(4):525-38. doi: 10.1007/s12640-016-9601-0. Epub 2016 Feb 8.
Caffeine is the world's most popular psychoactive drug and is also an active adulterant found in many drugs of abuse, including seized cocaine samples. Despite several studies which examine the effects of caffeine or cocaine administered as single agents, little data are available for these agents when given in combination. The purpose of the present study was to determine if combined intake of both psychostimulants can lead to maladaptive changes in striatal function. Mice were injected with a binge regimen (intermittent treatment for 13 days) of caffeine (3 × 5 mg/kg), cocaine (3 × 10 mg/kg), or combined administration. We found that chronic caffeine potentiated locomotion induced by cocaine and that both caffeine-treated groups showed sensitization. Striatal tissue was obtained 24 h and 7 days after last injection (withdrawal) for immunohistochemistry and mRNA expression. Our results show that combined intake of both psychostimulants can increase GFAP immunoreactivity in the striatum at both times post treatment. Gene expression analysis, targeted at dopamine, adenosine, and glutamate receptor subunit genes, revealed significant transcript down-regulation in the dorsal striatum of AMPA, NMDA, D1 and D2 receptor subunit mRNA expression in the group that received combined treatment, but not after individual administration. At withdrawal, we found increased D1 receptor mRNA expression along with increased A1, AMPA, NMDA, and metabotropic subunit expression. A2A mRNA showed decreased expression after both times in all experimental groups. Our study provides evidence that there are striatal alterations mediated by combined caffeine and cocaine administration, and highlights negative outcomes of chronic intake of both psychostimulants.
咖啡因是世界上最受欢迎的精神活性药物，也是在许多滥用药物中发现的活性掺杂物，包括查获的可卡因样本。尽管有几项研究考察了单独使用咖啡因或可卡因的效果，但关于这两种药物联合使用的数据却很少。本研究的目的是确定两种精神兴奋剂联合摄入是否会导致纹状体功能的适应不良变化。给小鼠注射咖啡因（3×5毫克/千克）、可卡因（3×10毫克/千克）的暴饮方案（间歇性治疗13天）或联合给药。我们发现，慢性咖啡因增强了可卡因诱导的运动，且两个咖啡因治疗组均表现出敏化作用。在最后一次注射（戒断）后24小时和7天获取纹状体组织用于免疫组织化学和mRNA表达分析。我们的结果表明，两种精神兴奋剂联合摄入在治疗后的两个时间点均可增加纹状体中的GFAP免疫反应性。针对多巴胺、腺苷和谷氨酸受体亚基基因的基因表达分析显示，联合治疗组背侧纹状体中AMPA、NMDA、D1和D2受体亚基mRNA表达显著下调，而单独给药后则无此现象。在戒断时，我们发现D1受体mRNA表达增加，同时A1、AMPA、NMDA和代谢型亚基表达增加。在所有实验组的两个时间点后，A2A mRNA表达均降低。我们的研究提供了证据，表明咖啡因和可卡因联合给药会介导纹状体改变，并突出了两种精神兴奋剂长期摄入的负面后果。
