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Age, ethanol, and strain effects on the behavioral pharmacology of cannabinoids

年龄、乙醇和应变对大麻素行为药理学的影响

基本信息

批准号：
7432571
负责人：
BRETT C GINSBURG
金额：
$ 7.15万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Central cannabinoid receptors (CB1) have gained interest as a therapeutic target. Agonist activated CB1 receptors propagate their signals downstream via coupling with G-proteins. Normally, this coupling occurs at a high efficiency, resulting in a high receptor reserve. Both aging and ethanol exposure reduce the efficiency of cannabinoid receptor coupling with G-proteins, and thus receptor reserve. Similarly, inbred C57BL/6J mice have higher cannabinoid receptor reserve than inbred DBA/2J mice, suggesting strain- dependent responses to cannabinoids. However, the impact of differences in cannabinoid receptor reserve on behavioral responses to cannabinoids remains unclear. The present proposal is designed to examine the effects of the CB1 agonist delta-9-tetrahydrocannabinol (THC) and the CB1 inverse agonist/partial agonist rimonabant (SR141716A) on fixed-ratio responding in rats and mice. Proposed experiments will characterize changes in the behavioral response to these drugs (alone and in combination) due to aging, ethanol exposure, or genotype. Young rats, ethanol-naive rats, and C57BL/6J mice have more efficient cannabinoid systems, resulting in higher receptor reserve. The potency of THC is expected to be enhanced in subjects with higher cannabinoid receptor reserve. Further, in subjects with a higher receptor reserve, rimonabant alone is expected to reduce response rate due to its intrinsic activity at CB1 receptors, and will be unable to completely antagonize THC effects due to this activity. Conversely, in older rats, ethanol- exposed rats, and DBA/2J mice, presumed to have a lower receptor reserve, rimonabant is expected to have no activity when administered alone and should completely antagonize THC effects. In addition to fostering the development of the applicant into an independent researcher, the present proposal will characterize the behavioral pharmacology of cannabinoids under conditions known to alter cannabinoid system efficiency. These studies will provide valuable information linking cellular and behavioral effects of cannabinoids. LAY SUMMARY: Cannabis is thought to produce euphoric and therapeutic effects through the cannabinoid receptors in the brain. Drugs that act at these receptors are important because they are involved in cannabis abuse and may be valuable medications. This project will help us understand how aging, exposure to ethanol, and perhaps genetic disposition change the behavioral response to these drugs.

描述（由申请人提供）：中枢大麻素受体（CB1）作为一种治疗靶点已经引起了人们的兴趣。激动剂激活的CB1受体通过与g蛋白偶联向下游传播其信号。通常情况下，这种耦合以高效率发生，导致高受体储备。衰老和乙醇暴露都会降低大麻素受体与g蛋白偶联的效率，从而降低受体储备。同样，近亲繁殖的C57BL/6J小鼠比近亲繁殖的DBA/2J小鼠具有更高的大麻素受体储备，表明对大麻素的反应依赖于菌株。然而，大麻素受体储备差异对大麻素行为反应的影响尚不清楚。本研究旨在研究CB1激动剂δ -9-四氢大麻酚（THC）和CB1逆激动剂/部分激动剂利莫那班（SR141716A）对大鼠和小鼠固定比率反应的影响。拟议的实验将描述由于年龄、乙醇暴露或基因型对这些药物（单独或联合）的行为反应的变化。幼龄大鼠、乙醇初始大鼠和C57BL/6J小鼠具有更有效的大麻素系统，导致更高的受体储备。四氢大麻酚的效力有望在具有较高大麻素受体储备的受试者中增强。此外，在受体储备较高的受试者中，由于利莫那班对CB1受体的内在活性，预计单独使用利莫那班会降低反应率，并且由于这种活性，将无法完全拮抗四氢大麻酚的作用。相反，在年龄较大的大鼠、乙醇暴露大鼠和DBA/2J小鼠中，假设受体储备较低，利莫那班单独给药时预计没有活性，应该完全拮抗四氢大麻酚的作用。除了促进申请人发展成为独立研究人员外，本提案还将描述大麻素在已知改变大麻素系统效率的条件下的行为药理学。这些研究将为大麻素对细胞和行为的影响提供有价值的信息。概要：大麻被认为是通过大脑中的大麻素受体产生欣快和治疗效果。作用于这些受体的药物很重要，因为它们与大麻滥用有关，可能是有价值的药物。这个项目将帮助我们了解衰老、酒精暴露，或许还有基因倾向是如何改变对这些药物的行为反应的。