Reavill C, Walther B, Stolerman I P, Testa B
Department of Psychiatry, Institute of Psychiatry De Crespigny Park, London, U.K.
Neuropharmacology. 1990 Jul;29(7):619-24. doi: 10.1016/0028-3908(90)90022-j.
Previous work has suggested that cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.
先前的研究表明，尽管金雀花碱和洛贝林具有一些类似尼古丁的外周效应，并能有效抑制氚化尼古丁与大鼠脑的结合，但它们产生类似尼古丁行为效应的效力较低。在一种以食物强化的双杆操作性条件反射程序中，训练大鼠区分尼古丁和生理盐水。已证实金雀花碱具有类似尼古丁的辨别效应，但效力远低于尼古丁本身。即使在大大降低总体反应率的剂量下，洛贝林也未能产生类似尼古丁的辨别效应。两种药物均未减弱对尼古丁的辨别反应。通过高效液相色谱法（HPLC）测定了与行为实验中所用大鼠性别、品系和年龄相同的大鼠血浆和脑中药物的浓度。脑与血浆浓度比的排序为洛贝林大于尼古丁大于金雀花碱，这与通过反相高效液相色谱法测定的它们的亲脂性成正比。根据脑中的浓度以及对高亲和力尼古丁结合位点的已知亲和力，体内试验应显示金雀花碱的效力略高于尼古丁，而洛贝林在所使用的剂量下具有尼古丁效应。这些预测并未得到证实，因此，金雀花碱和洛贝林的行为效应与其在氚化尼古丁结合位点的效应无法关联。由于药代动力学因素无法解释这种差异，因此需要一种药效学解释。
