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

描述（由申请人提供）：中枢大麻素受体（CB 1）作为治疗靶点已经引起了人们的兴趣。激动剂激活的CB 1受体通过与G蛋白偶联向下游传播其信号。通常，这种偶联以高效率发生，导致高受体储备。老化和乙醇暴露都降低了大麻素受体与G蛋白偶联的效率，从而降低了受体储备。类似地，近交系C57 BL/6 J小鼠比近交系DBA/2 J小鼠具有更高的大麻素受体储备，表明对大麻素的品系依赖性应答。然而，大麻素受体储备的差异对大麻素行为反应的影响仍不清楚。本提案旨在研究CB 1激动剂δ-9-四氢大麻酚（THC）和CB 1反向激动剂/部分激动剂利莫那班（SR 141716 A）对大鼠和小鼠固定比例反应的影响。拟议的实验将表征由于年龄、乙醇暴露或基因型对这些药物（单独和组合）的行为反应的变化。年轻的大鼠，乙醇未处理的大鼠和C57 BL/6 J小鼠具有更有效的大麻素系统，导致更高的受体储备。THC的效力预计将在具有较高大麻素受体储备的受试者中增强。此外，在具有较高受体储备的受试者中，预期单独的利莫那班由于其对CB 1受体的内在活性而降低应答率，并且由于该活性而不能完全拮抗THC作用。相反，在老年大鼠、乙醇暴露大鼠和DBA/2 J小鼠中，假定具有较低的受体储备，预期利莫那班单独给药时没有活性，应该完全拮抗THC作用.除了促进申请人发展成为独立的研究人员外，本提案还将描述已知改变大麻素系统效率的条件下大麻素的行为药理学。这些研究将提供有价值的信息，将大麻素的细胞和行为效应联系起来。摘要：大麻被认为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、暴露于乙醇以及可能的遗传倾向如何改变对这些药物的行为反应。

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.