Collins A C, Bhat R V, Pauly J R, Marks M J
Institute for Behavioral Genetics, School of Pharmacy, University of Colorado, Boulder 80309.
Ciba Found Symp. 1990;152:68-82; discussion 82-6. doi: 10.1002/9780470513965.ch5.
Although numerous studies have demonstrated that chronic nicotine treatment often results in tolerance to this drug, the mechanisms that underlie this tolerance are not well defined. Recent evidence suggests that chronic nicotine treatment results in an up-regulation of brain nicotinic receptors, but the majority of these receptors may be desensitized or inactivated, thereby explaining tolerance. There is evidence that while all mouse strains show increased receptor numbers following chronic nicotine treatment, some mouse strains develop maximal changes in [3H] nicotine binding before any tolerance is detected. Other strains show a high correlation between increase in receptor number and tolerance. Studies with several other nicotinic agonists indicate that up-regulation of nicotine receptors can occur without changes in drug sensitivity. Similarly, chronic antagonists treatment can also elicit changes in receptors without affecting sensitivity to nicotine. Some of these discrepancies may be due to genetically influenced interactions between the adrenal steroid, corticosterone (CCS), and the nicotinic receptors. The addition of CCS in vitro inhibits binding to nicotinic receptors, and chronic CCS treatment results in decreases in the number of brain nicotinic receptors measured by [125I] bungarotoxin binding. Either of these biochemical measures may explain why altering CCS concentrations in vivo results in altered sensitivity to nicotine. It may be that both changes in the number of receptors and altered steroid interactions with the nicotinic receptors explain tolerance to nicotine.
尽管众多研究表明，长期尼古丁治疗常常会导致对该药物产生耐受性，但这种耐受性背后的机制尚未明确。最近的证据表明，长期尼古丁治疗会导致脑烟碱受体上调，但这些受体中的大多数可能会脱敏或失活，从而解释了耐受性的产生。有证据表明，虽然所有小鼠品系在长期尼古丁治疗后都会出现受体数量增加的情况，但一些小鼠品系在检测到任何耐受性之前，[3H]尼古丁结合就已发生最大变化。其他品系则显示受体数量增加与耐受性之间存在高度相关性。对其他几种烟碱激动剂的研究表明，烟碱受体上调可能在药物敏感性无变化的情况下发生。同样，长期给予拮抗剂治疗也可引起受体变化，而不影响对尼古丁的敏感性。其中一些差异可能归因于肾上腺类固醇皮质酮（CCS）与烟碱受体之间受遗传影响的相互作用。体外添加CCS会抑制与烟碱受体的结合，长期给予CCS治疗会导致用[125I]银环蛇毒素结合法测得的脑烟碱受体数量减少。这两种生化指标中的任何一种都可能解释为什么体内改变CCS浓度会导致对尼古丁的敏感性改变。也许受体数量的变化以及类固醇与烟碱受体相互作用的改变共同解释了对尼古丁的耐受性。
