Subjective and behavioural effects of nicotine in humans: some sources of individual variation.

Despite its addictiveness, the subjective effects of nicotine in "smoking doses" are of low intensity compared with those of other addictive drugs. Although mildly pleasurable to many regular users, it causes no striking euphoriant effects and its effects on mood, performance and the level of arousal are relatively small. This chapter does not attempt to list or review the numerous effects of nicotine, but focuses instead on some of the multiple sources of individual variation. The subjective and behavioral effects of nicotine in humans differ markedly, not only between individuals but also within individuals, according to the stage of their smoking career, their level of dependence and the time since their last few doses. Some of the influences and mechanisms discussed include innate and acquired factors, pharmacokinetic factors, acute and chronic tolerance, learning and conditioning. It is not clear to what extent the effects of nicotine are primary, or how much they reflect reversal or relief of acquired withdrawal effects. Only one study has found a "rebound" element in the effects of withdrawal and although chronic exposure to nicotine induces an increase in the number of nicotinic receptors, chronic tolerance to nicotine has not been demonstrated in humans. Acute tolerance (tachyphylaxis) develops rapidly to many of the effects of nicotine and is completely reversible after nicotine depletion. Other effects of nicotine are less sensitive to acute tolerance. It is suggested that it is the effects of nicotine at postsynaptic receptors that are most susceptible to acute tolerance and that those mediated by its action at presynaptic receptors are less sensitive to it. Due to accumulation of nicotine and other pharmacokinetic factors, for most of the day and much of the night, regular smokers have high levels of acute tolerance to nicotine. In other words, there is a chronic partial blockade of its agonist effects at postsynaptic receptors. This explains why nicotinic receptors are upregulated rather than downregulated and why heavy smokers experience no subjective effects from a cigarette smoked during the course of a normal smoking day. When the effects of acute tolerance are unmasked after abstinence for 24 h, it is the more addicted heavy smokers who experienced more severe withdrawal effects who also have stronger subjective and heart rate effects following the first post-abstinence cigarette. Their greater sensitivity to nicotine after abstinence may reflect their higher density of unoccupied nicotinic receptors. On the other hand, those who have higher innate sensitivity may be more likely to take up smoking and to become more dependent if they