Economidou Daina, Mattioli Laura, Ubaldi Massimo, Lourdusamy Anbarasu, Soverchia Laura, Hardiman Gary, Campolongo Patrizia, Cuomo Vincenzo, Ciccocioppo Roberto
Department of Experimental Medicine and Public Health, University of Camerino, Via Scalzino 3, 62032 Camerino, Italy.
Toxicol Appl Pharmacol. 2007 Aug 15;223(1):73-85. doi: 10.1016/j.taap.2007.05.008. Epub 2007 May 24.
The present study evaluated the consequences of perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) treatment (5 mg/kg/day by gavage), either alone or combined with ethanol (3% v/v as the only fluid available), on ethanol self-administration and alcohol-seeking behavior in rat adult offspring. Furthermore, the effect of the selective cannabinoid CB(1) receptor antagonist, SR-141716A, on ethanol self-administration and on reinstatement of ethanol-seeking behavior induced either by stress or conditioned drug-paired cues was evaluated in adult offspring of rats exposed to the same perinatal treatment. Lastly, microarray experiments were conducted to evaluate if perinatal treatment with Delta(9)-tetrahydrocannabinol, ethanol or their combination causes long-term changes in brain gene expression profile in rats. The results of microarray data analysis showed that 139, 112 and 170 genes were differentially expressed in the EtOH, Delta(9)-THC, or EtOH+Delta(9)-THC group, respectively. No differences in alcohol self-administration and alcohol seeking were observed between rat groups. Intraperitoneal (IP) administration of SR-141716A (0.3-3.0 mg/kg) significantly reduced lever pressing for ethanol and blocked conditioned reinstatement of alcohol seeking. At the same doses SR-141716A failed to block foot-shock stress-induced reinstatement of alcohol seeking. The results reveal that perinatal exposure to Delta(9)-THC ethanol or their combination results in evident changes in gene expression patterns. However, these treatments do not significantly affect vulnerability to ethanol abuse in adult offspring. On the other hand, the results obtained with SR-141716A emphasize that endocannabinoid mechanisms play a major role in ethanol self-administration, as well as in the reinstatement of ethanol-seeking behavior induced by conditioned cues, supporting the idea that cannabinoid CB(1) receptor antagonists may represent interesting agents for the pharmacotherapy of alcoholism.
本研究评估了围产期给予δ-9-四氢大麻酚（δ-9-THC，灌胃给药，5毫克/千克/天）单独或与乙醇（3% v/v，作为唯一可获得的液体）联合使用，对成年大鼠后代乙醇自我给药及觅酒行为的影响。此外，在接受相同围产期处理的大鼠成年后代中，评估了选择性大麻素CB1受体拮抗剂SR-141716A对乙醇自我给药以及由应激或条件性药物配对线索诱导的觅酒行为恢复的影响。最后，进行了微阵列实验，以评估围产期给予δ-9-四氢大麻酚、乙醇或其组合是否会导致大鼠脑基因表达谱的长期变化。微阵列数据分析结果显示，乙醇组、δ-9-THC组或乙醇+δ-9-THC组分别有139、112和170个基因差异表达。各大鼠组之间在乙醇自我给药和觅酒方面未观察到差异。腹腔注射（IP）SR-141716A（0.3 - 3.0毫克/千克）显著减少了对乙醇的杠杆按压，并阻断了条件性觅酒行为的恢复。在相同剂量下，SR-141716A未能阻断足部电击应激诱导的觅酒行为恢复。结果表明，围产期暴露于δ-9-THC、乙醇或其组合会导致基因表达模式发生明显变化。然而，这些处理对成年后代乙醇滥用的易感性没有显著影响。另一方面，SR-141716A的实验结果强调，内源性大麻素机制在乙醇自我给药以及由条件性线索诱导的觅酒行为恢复中起主要作用，支持了大麻素CB1受体拮抗剂可能是酒精中毒药物治疗的有意义药物的观点。
