Richard L. Stiller

The Effect of Nicotine on Energy Expenditure during Light Physical Activity

The metabolic effects of nicotine have been implicated in the relation between smoking and lower body weight. This study examined whether the nicotine-induced increase in the metabolic rate observed at rest is also present during physical activity. We compared the energy expenditure of 10 male smokers receiving nicotine (15 micrograms per kilogram of body weight) with that of 10 male smokers receiving placebo on two occasions, each including a period of rest and a period of exercise on a modified bicycle ergometer at workloads designed to simulate and standardize light daily activity. All had abstained from cigarette smoking the night before the study. The excess energy expenditure attributable to nicotine was more than twice as great during exercise (difference between groups, 0.51 kJ per kilogram per hour, or 12.1 percent of the metabolic rate at rest; P less than 0.001) than during rest (0.23 kJ per kilogram per hour, or 5.3 percent of the metabolic rate at rest; P less than 0.05). In contrast, the expenditure was not affected by placebo during exercise or rest in the smokers or in a comparison group of 10 non-smokers, indicating that smoking status has no long-term metabolic effect in the absence of short-term nicotine intake. We conclude that the relatively small metabolic effect of nicotine when the subject is at rest is enhanced during light exercise. Our data also suggest that the weight gain that often follows smoking cessation may be influenced not only by nicotine intake but also by the level of physical activity a smoker typically engages in while smoking.

In Vitro Metabolism of Mivacurium Chloride (bw B1090u) and Succinylcholine

The in vitro rates of metabolism of mivacurium chloride and succinylcholine in pooled human plasma were compared. In addition, the rate of metabolism of mivacurium in buffered solutions of butyrylcholinesterase (E.C. 3.1.1.8) and acetylcholinesterase (E.C. 3.1.1.7) was determined. Succinylcholine concentrations were measured spectrophoto-metrically, and mivacurium concentrations were determined with a high-pressure liquid chromatographic assay. The hydrolysis of mivacurium in plasma followed first-order kinetics, and the rate of hydrolysis decreased as plasma was serially diluted. The Michaelis-Menten constant (Km) for mivacurium metabolism in plasma was 245/μmol/L, and the maximum velocity (Vmax) was 50 U/L; the Km for succinylcholine was 37 μmol/L, and Vmax was 74 U/L. At comparable multiples of the Km the hydrolysis rate of mivacurium was 70% of that of succinylcholine. Mivacurium was metabolized significantly in solutions containing butyrylcholinesterase, but only minimally in solutions containing acetylcholinesterase.

Nicotine discrimination in male and female smokers

Discriminative stimulus effects of nicotine were evaluated in humans using formal behavioral drug discrimination procedures. Male and female smokers (n=9 each) were trained on day 1 to reliably discriminate 0 versus 12 µg/kg nicotine administered by measured-dose nasal spray. All subjects were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 2, 4, 8, and 12 µg/kg (approximately 0–0.8 mg for typical subject) was then examined on day 2. Nicotine-appropriate responding was linearly related to dose, and subjects were able to distinguish the smallest dose (2 µg/kg) from placebo. Although there were no differences between males and females in behavioral discrimination, subjective effects were correlated with nicotine discrimination in females but not in males. These findings indicate that humans are able to discriminate among low doses of nicotine per se, that males and females may differ in the stimuli used to discriminate nicotine, and that drug discrimination procedures may be more sensitive than traditional subjective effects measures in distinguishing among low doses of nicotine.

Behavioral effects of a single neuroleptic treatment grow with the passage of time

The principal finding of this manuscript is that the incidence of catalepsy observed in the rat after a single administration of low, clinically relevant doses of the dopamine receptor antagonists and antipsychotic agents, haloperidol and fluphenazine hydrochloride, grows over time such that one re-exposure to the same compound up to 8 weeks later results in a marked enhancement (i.e. sensitization) of this response. This phenomenon appears to be independent of pharmacokinetic or conditioning factors as well as alterations in dopamine or dihydroxyphenylacetic acid. It suggests that the antidopaminergic influence of acute exposure to a neuroleptic not only persists but continues to sensitize for extraordinary periods of time even after the drug is no longer detectable in the system. Our findings may hold the key to understanding the apparent paradox that although neuroleptics presumably induce their therapeutic actions in disorders such as Tourette syndrome and schizophrenia as well as their parkinsonian effects by blocking dopamine receptors, this antagonism occurs immediately while behavioral changes often require weeks for maximal development.

Subjective and cardiovascular responses to nicotine combined with alcohol in male and female smokers

Nicotine and alcohol are often consumed concurrently by smokers. Each drug alone produces significant subjective and cardiovascular responses, but the effects of the two drugs in combination have rarely been examined. Smokers who were moderate alcohol drinkers (n = 18, 9 males and 9 females) participated in four sessions, involving acute administration of nicotine/placebo and alcohol/no alcohol. Subjects abstained overnight from tobacco and alcohol prior to each session. Nicotine (20 µg/kg per presentation) or placebo was administered by measured-dose nasal spray every 30 min for 2 h following consumption of diet tonic water with or without alcohol (0.5 g/kg). Subjective (visual analog scales, Profile of Mood States, Addiction Research Center Inventory) and cardiovascular (heart rate, systolic and diastolic blood pressure) responses were assessed after each nicotine/placebo administration. Nicotine increased head rush, dizzy, and most stimulant effects (i.e. jittery, tension, and arousal and decreased fatigue and relaxed), while alcohol increased intoxication, head rush, dizzy, and jittery, with no other stimulant effects. Nicotine and alcohol generally produced additive subjective and cardiovascular effects when consumed together, although nicotine attenuated sedating and intoxicating effects of alcohol alone. Furthermore, there were several interaction effects on subjective measures involving gender. Nicotine plus alcohol tended to attenuate some subjective effects due to one drug or the other alone in men but enhanced the effects of either alone in women. These findings indicate that nicotine and alcohol generally have additive subjective and cardiovascular effects, but that men and women differentially respond on some subjective measures to the combination of alcohol and nicotine.

Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior

The effects of short‐term nasal spray nicotine replacement in suppressing desire to smoke and ad libitum cigarette smoking behavior were evaluated in male and female smokers. In study I, 10 male and 10 female smokers received intermittent doses of 0, 7.5, 15, and 30 µg/kg nicotine by way of measured‐dose nasal spray, with each dose on a separate day. Self‐reported desire to smoke was significantly suppressed by each nicotine dose compared with placebo, but there were no significant differences among nicotine doses or between men and women. In study II, eight male and eight female smokers received 0, 15, and 30 µg/kg nicotine intermittently and were allowed to smoke their preferred brands of cigarettes ad libitum. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latency to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attributable to 15 µg/kg tended to be greater in men than in women. However, plasma nicotine concentrations were significantly higher after 15 and 30 µg/kg versus placebo, suggesting only partial compensation in smoking behavior with short‐term nasal nicotine replacement. These findings support the idea that short‐term nicotine replacement decreases smoking desire and behavior, but the findings indicate that smoking behavior is partly influenced by factors other than nicotine regulation.

The binding of ketamine to plasma proteins: Emphasis on human plasma

SummaryWe report for the first time that ketamine (K) is bound as much as 47% to human plasma. It was shown that binding of K to plasma and albumin is dependent on pH; binding is decreased at pH lower than 7.4 and increased at higher pH. This is in concordance with the pKa of K being 7.5; the partition coefficient between an organic phase and buffer was found to be sensitive to small pH changes. Binding of K is also influenced by albumin concentration and the affinity of K for human α1-acid glycoprotein (AAG) is much higher than for human albumin (HSA). The major metabolite nor-K does not appreciably displace K from binding sites on HSA. These findings may explain in part the variability of binding of K observed with different human samples. Human cord plasma exhibits a lower binding of K than adult plasma. This is probably the result of much lower AAG concentration in cord compared to adult plasma; cord and adult plasma albumin levels are known to be only slightly different. Since K has 2 optically active isomers, one of which is more potent than the other, experiments on the binding of racemic and the 2 isomers of K were performed; no differences in binding to AAG were found. We were, however, able to show that tris (butoxyethyl) phosphate (TBEP) can abolish binding of K to AAG. Thus the presence of TBEP would interfere in determining plasma levels and distribution of K. An example would be in the measurement of the partition of K between human red cells and plasma. We determined this ratio in human blood in the absence of TBEP and found it to be similar to that reported for dog red blood cells and plasma.

Acute effects of nicotine on hunger and caloric intake in smokers and nonsmokers

The inverse relationship between smoking and body weight may be due in part to nicotines effects on reducing hunger and eating. Male smokers and nonsmokers (n=10 each), abstinent overnight from smoking and food, participated in four sessions, involving consumption of a liquid caloric load or water followed by nicotine (15 µg/kg) or placebo via nasal spray every 20 min for 2 h. Hunger and satiety (“fullness”) ratings were obtained prior to each dose presentation. At the end of the two sessions involving the caloric load (simulating breakfast), subjects were also presented with typical lunch/snack food items varying in sweet taste and fat content for ad lib consumption. Results indicated that, for both smokers and nonsmokers, the hunger-reducing effects of nicotine occurred only following caloric load consumption, and there was no effect of nicotine on hunger after water consumption. Smokers unexpectedly reported greater satiation than nonsmokers following the caloric load regardless of nicotine or placebo condition. Nicotine also resulted in less caloric intake during the meal, and the decrease was not specific to consumption of sweet, high-fat foods. These results indicate that nicotine reduces appetite, possibly helping to explain the influence of smoking on body weight.

Conditioned tolerance to the anorectic and corticosterone-elevating effects of nicotine.

We have shown that tolerance to the behavioral effects of nicotine is partially dependent on conditioned environmental cues that predict drug delivery. The present research extends this finding to physiological effects of nicotine by assessing both the appetite-suppressing and adrenocortical-activating effects of nicotine, as measured by plasma corticosterone (CORT). In the first study, male rats on a 22-h food deprivation schedule were injected daily with 0.33 or 0.66 mg/kg (free base) of nicotine bitartrate or saline in a distinctive environment and tested for milk intake. Nicotine initially suppressed milk intake and tolerance developed over 10 days. Changing cues associated with drug administration partially reversed tolerance since injection of nicotine in a new environment reduced milk intake of tolerant animals. Similarly, animals who repeatedly received nicotine in one environment exhibited CORT levels lower than rats injected for the first time, and this tolerance also was partially reversed when administration occurred in the new environment. The second experiment indicated that the increased CORT of Experiment 1 was not a stress response associated with injecting animals in a different environment. These results indicate that tolerance to both behavioral and neuroendocrine effects of nicotine is influenced by conditioning.

Opioid neurotoxicity: fentanyl dose-response effects in rats.

Opioids, when administered in large doses, produce brain damage, primarily in the limbic system and association areas in rats.This investigation examined the relationship between opioid dose and severity and frequency of brain damage in rats. Forty male Sprague-Dawley rats were anesthetized with halothane/N2 O and underwent tracheal intubation, mechanical ventilation, arterial/venous cannulation, and insertion of a rectal temperature probe and biparietal electroencephalogram electrodes. After surgery, halothane was discontinued and O2/N2 O 30%/70% was administered for 1 h. Rats were then randomly assigned to one of eight groups. The control group received a loading dose (LD) of 4 mL/kg of 0.9% normal saline solution (NSS) and a maintenance dose (MD) of 4 mL [centered dot] kg-1 [centered dot] h-1 NSS. The other groups were given fentanyl lypophilized and reconstituted in NSS with the LD ranging from 50 to 3200 micro g/kg and the MD from 2 to 128 micro g [centered dot] kg-1 [centered dot] min-1. After 2 h of fentanyl or NSS infusion, all rats received 100% O2 and, when alert, their tracheas were extubated; after 7 days the rats underwent cerebral perfusion fixation, followed by light microscopic evaluation. Histopathologic lesions (primarily eosinophilic neuron degeneration) were subjectively graded by a pathologist unaware of the experimental treatment; the grades were based on the percentage of dead neurons. There were no lesions observed in the brain areas in any of the control or 200-8 (LD, micro g/kg; MD, micro g [centered dot] kg-1 [centered dot] min-1) groups. Eleven of 20 rats in the 400-16, 800-32, 1600-64, and 3200-18 groups showed evidence of brain damage primarily in limbic system structures and association areas (P < 0.05). Our data confirm that fentanyl produces limbic system brain damage in rats, and that the damage occurs over a broad range of doses. (Anesth Analg 1996;83:1298-306)