Nicotine discrimination and self-administration in humans as a function of smoking status

Nicotine’s discriminative stimulus effects may be critical to understanding reinforcement of tobacco smoking. It is not known whether regular nicotine exposure produces tolerance or sensitivity to these effects. In this study, male and female smokers (n = 11) and never-smokers (n = 10) were trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) on day 1. On day 2, both groups were tested on generalization of this discrimination across intermittent presentations of 0, 3, 6, 12, and 20 μg/kg nicotine in random order. Quantitative and quantal behavioral discrimination tasks, used in previous research, were employed. On day 3, subjects were instructed to self-administer sprays from the 20 μg/kg nicotine versus 0 bottles in a concurrent-choice procedure. All but one subject (female smoker) learned reliably to discriminate 20 μg/kg nicotine from placebo (≥ 80% correct) on day 1. Nicotine-appropriate responding on day 2 was attenuated in smokers versus never-smokers at 20 μg/kg on the quantitative task and at 12 μg/kg on the quantal task, suggesting tolerance. There was no difference in responding at other doses. Smokers also showed attenuated responses on the subjective measure of “head rush”, which was associated with discrimination responding in both groups. Nicotine self-administration was significantly greater in smokers versus never-smokers, who self-administered nicotine below chance levels, and was inversely related to discrimination behavior in never-smokers but unrelated in smokers. Women smokers showed less change in nicotine-appropriate responding across generalization doses, reported less confidence in discriminating training doses during acquisition on day 1, and tended to self-administer less nicotine on day 3. These results indicate that smokers may become tolerant to the discriminative stimulus effects of nicotine, perhaps promoting increased use. Received: 1 October 1996/Final version: 28 January 1997     

Nicotine reinforcement in rats with histories of cocaine self-administration

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8±4.5/h to 5.4±1.1/h but returned to pre-saline levels when it was reintroduced (12.0±5.5/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.     

Randomised controlled trial of ondansetron in smoking cessation

A double-blind, placebo controlled trial was undertaken to examine the effect of the 5-HT₃ antagonist, ondansetron .25 mg bd on cigarette withdrawal symptoms and on proportion of individuals maintaining continuous abstinence for 4 weeks in a smoking treatment programme. A total of 111 smokers were allocated to active or placebo conditions and began taking their study medication 2 weeks before the quit date. They attended the smokers clinic for weekly group treatment sessions. The results showed no evidence for less severe withdrawal symptoms or improved abstinence rates in the active medication group. They suggest that inhibiting 5-HT₃ activity is not an effective method of controlling nicotine withdrawal or helping smokers to stop.     

Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine

Habitual smokers frequently report that when they are stressed smoking helps them to relax. One potential explanation for the reported stress ameliorating effect of smoking is that cigarette consumption (nicotine self-administration) may decrease the sympathetic autonomic nervous system activity which is associated with the stress response. In the present study, rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administation on plasma corticosterone, catecholamine (epinephrine, norepinephrine and dopamine) and glucose responses to physical restraint stress. Nicotine (0.025, 0.05 or 0.10 mg nicotine base/kg body weight) was administered for 10 days prior to the stress test to allow for the development of habituation/tolerance to its acute toxic effects. Independent administration of nicotine, or the application of the physical restraint stressor, resulted in increases in the plasma concentrations of corticosterone, epinephrine, norepinephrine, and glucose. Nicotine administration during restraint stress enhanced the increase in plasma corticosterone and epinephrine, as compared to the responses induced by either factor alone. The results suggest that the stress ameliorating effect of continued cigarette smoking, as reported by habitual smokers, is not due to a reduction in the activity of the peripheral sympathetic autonomic nervous system.     

Stereospecific monoclonal antibodies to nicotine and cotinine and their use in enzyme-linked immunosorbent assays

Stereospecific monoclonal antibodies (McAb) have been prepared against the tobacco alkaloid (S)-(-)-nicotine and its major metabolite (S)-(-)-cotinine. Nine anti-nicotine and 4 anti-cotinine hybridomas, selected by a screening procedure that utilized immunoprecipitation of the ³H-labeled natural isomers of nicotine or cotinine, were grown in the ascites fluid of pristane-primed syngeneic BALB/c mice. Antibodies in concentrations up to 7.5 mg/ml ascites and with binding affinities that generally exceeded 10⁸ M⁻¹ were obtained. Enzyme-linked immunosorbent assays (ELISAs) were developed in which nicotine or cotinine derivatives bound covalently to poly- -lysine werecoated onto wells of polyvinyl chloride microtiter plates. Coated wells were incubated sequentially with McAb in the presence or absence of inhibitor, rabbit anti-mouse immunoglobulin, then horseradish peroxidase-labeled protein A (HRP-SpA) before addition of substrate. The antibodies are highly specific and show minimal cross-reactivity with several nicotine metabolites and other structurally related compounds. In the respective assays, only 0.25 ng (S)-(-)-nicotine and 0.12 ng (S)-(-)-cotinine are required to give 50% inhibition of antibody binding, and as little as 0.05 ng nicotine and 0.02 ng cotinine give 15% inhibition. These assays are 5–10 times more sensitive than analogous ELISAs developed with rabbit antisera and HRP-SpA or conventional radioimmunoassays (RIAs) that utilize the rabbit antisera and ³H-labeled ligands. There was good correlation between the levels of nicotine (r = 0.967) found in saliva samples from smokers and non-smokers assayed by McAb-based ELISAs and conventional RIAs.     

尼古丁依赖的功能影像学研究进展

在过去10年中,随着功能脑影像学技术在物质滥用领域的发展,越来越多的研究者运用这些技术以探讨尼古丁成瘾的神经生物学机制。本文主要总结了尼古丁急、慢性暴露下对脑功能影响的神经脑影像学研究进展,证实了尼古丁依赖与中脑边缘犒赏系统、调节注意、记忆、运动以及联想相关脑环路之间的相关性。这些研究发现将为揭示尼古丁依赖的神经生物学机制提供更多的证据支持,进一步促进今后戒烟治疗的发展。     

儿童退缩和同伴关系的相关

目的：用元分析方法对近20年关于儿童退缩和同伴关系相关的研究结果进行总结。方法：用多水平分析技术对儿童退缩和同伴接受的相关、退缩和同伴拒绝相关的研究结果进行总结分析。结果：儿童退缩和同伴接受之间有显著的负相关关系，退缩和同伴拒绝之间有低度的非负相关关系，各研究结果之间的变异显著。结论：退缩导致儿童不良的同伴关系。     

A role for the basal ganglia in nicotinic modulation of the blink reflex

Summary In humans and rats we found that nicotine transiently modifies the blink reflex. For blinks elicited by stimulation of the supraorbital branch of the trigeminal nerve, nicotine decreased the magnitude of the orbicularis oculi electromyogram (OOemg) and increased the latency of only the long-latency (R2) component. For blinks elicited by electrical stimulation of the cornea, nicotine decreased the magnitude and increased the latency of the single component of OOemg response. Since nicotine modified only one component of the supraorbitally elicited blink reflex, nicotine must act primarily on the central nervous system rather than at the muscle. The effects of nicotine could be caused by direct action on lower brainstem interneurons or indirectly by modulating descending systems impinging on blink interneurons. Since precollicular decerebration eliminated nicotine's effects on the blink reflex, nicotine must act through descending systems. Three lines of evidence suggest that nicotine affects the blink reflex through the basal ganglia by causing dopamine release in the striatum. First, stimulation of the substantia nigra mimicked the effects of nicotine on the blink reflex. Second, haloperidol, a dopamine (D₂) receptor antagonist, blocked the effect of nicotine on the blink reflex. Third, apomorphine, a D₂ receptor agonist, mimicked the effects of nicotine on the blink reflex.     

Recent developments in molecular action of antihormones

 Antihormones are by definition antagonists of steroid hormone action. They interact with the ligand binding domains of steroid hormone receptors and competitively inhibit the action of the receptors by mechanisms that are not quite understood. In certain cases antihormones also exhibit agonistic activity especially in connection with certain naturally occurring receptor mutants. These observations together with findings of indiscriminate interaction of antihormones with several classes of steroid receptors have necessitated a search of more effective and reliable antihormones. Recent advances in the resolution of the crystal structure of the ligand binding domains of certain members of the steroid receptor family and identification of non-liganded activation of steroid receptors have produced considerable information that can be harnessed into a fruitful search for a new generation of antihormones. Received: 19 June 1997 / Accepted: 10 October 1997     

Differential involvement of GABA system in mediating behavioral and neurochemical effect of acupuncture in ethanol-withdrawn rats

In our previous study we demonstrated that acupuncture at Shenmen (HT7) points suppressed a decrease of accumbal dopamine (DA) release in ethanol-withdrawn rats. Furthermore, here we found that it inhibited behavioral withdrawal signs of ethanol. In an effort to better understand the mechanisms underlying this inhibition, the potential role of GABA receptor system in acupuncture was investigated. Male Sprague–Dawley rats were treated with 3 g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 48 or 72 h of ethanol withdrawal, acupuncture was applied at bilateral HT7 for 1 min. The selective GABA_A antagonist bicuculline and the selective GABA_B antagonist SCH 50911 were injected intraperitoneally 20 min before acupuncture, respectively. Importantly, suppressive effects of acupuncture on DA deficiency were completely abolished by SCH 50911, but not by bicuculline, whereas ameliorating effects of acupuncture on ethanol withdrawal syndrome were completely blocked either by SCH 50911 or bicuculline. These results suggest that acupuncture at specific acupoint HT7 may normalize the DA release in the mesolimbic system and attenuate withdrawal syndrome through the GABA_B receptor system in ethanol-withdrawn rats.