De Vry J, Jentzsch K R
CNS Research, Bayer Health Care, Wuppertal, Germany.
Behav Pharmacol. 2003 Sep;14(5-6):471-6. doi: 10.1097/01.fbp.0000087739.21047.d8.
The present study estimated the apparent intrinsic activity of the cannabinoid CB1 receptor ligands CP 55,940, Delta9-tetrahydrocannabinol (Delta9-THC) and SR 141716A in a highly sensitive in vivo assay. Rats were trained to discriminate the cannabinoid CB1 receptor agonist CP 55,940 (either 0.03 or 0.014 mg/kg, i.p., t=30 min) from vehicle, in a two-lever food-reinforced procedure, and were subsequently tested with the three compounds. Although reduction of the training dose did not affect the maximum level of generalization or antagonism (>80% generalization for CP 55,940 and Delta9-THC; 0% generalization and >80% antagonism for SR 141716A), the potency of the compounds was differentially affected. Thus, the generalization curves obtained with CP 55,940 and Delta9-THC were shifted three- and sixfold to the left; whereas no potency difference was obtained for the antagonism of CP 55,940 by SR 141716A. The data are consistent with the hypothesis that the level of intrinsic activity of CP 55,940 is higher than that of Delta9-THC, and that SR 141716A may have a very low level of intrinsic activity. It is concluded that variation of the training dose increases the sensitivity of the in vivo intrinsic activity estimation of cannabinoid CB1 receptor ligands.
本研究在一项高灵敏度的体内试验中评估了大麻素CB1受体配体CP 55,940、Δ9-四氢大麻酚（Δ9-THC）和SR 141716A的表观内在活性。在一项双杠杆食物强化程序中，训练大鼠区分大麻素CB1受体激动剂CP 55,940（腹腔注射，剂量为0.03或0.014 mg/kg，t = 30分钟）与溶剂，随后用这三种化合物进行测试。虽然降低训练剂量并未影响最大泛化或拮抗水平（CP 55,940和Δ9-THC的泛化率>80%；SR 141716A的泛化率为0%，拮抗率>80%），但这些化合物的效价受到了不同程度的影响。因此，用CP 55,940和Δ9-THC获得的泛化曲线分别向左移动了三倍和六倍；而SR 141716A对CP 55,940的拮抗作用未观察到效价差异。这些数据与以下假设一致：CP 55,940的内在活性水平高于Δ9-THC，且SR 141716A可能具有非常低的内在活性水平。得出的结论是，改变训练剂量可提高大麻素CB1受体配体内在活性体内评估的灵敏度。
