Plasma Nicotine Levels Research Articles

Adolescent nicotine exposure produces immediate and long-term changes in CNS noradrenergic and dopaminergic function

Animal studies have only recently begun to address whether nicotine evokes unique or persistent effects on brain structure or function during adolescence, the period in which smokers typically begin their habit. In the current study, we examined the impact of adolescent nicotine treatment on catecholaminergic synaptic function in rats infused with nicotine on postnatal days 30–47.5, using a paradigm that reproduces the plasma levels of nicotine found in smokers. We assessed norepinephrine and dopamine content, turnover (an index of neural activity), and the response to an acute challenge dose of nicotine. In the midbrain, the region most closely associated with addiction, both norepinephrine and dopamine turnover were activated during the infusion period, an effect not seen in any other region for norepinephrine, and only in the striatum for dopamine. In the immediate post-infusion period (PN50–60), there was a decrement in midbrain catecholamine turnover restricted to males, whereas there was a later-emerging (PN80) activation of these pathways. Again, this pattern was not observed in any other region: the cerebral cortex showed post-treatment increases in turnover without gender selectivity, the striatum showed late-emerging deficits in dopamine turnover and the hippocampus displayed a profound deficit in noradrenergic activity that was limited to females. We also assessed the catecholaminergic response to an acute challenge with nicotine (0.3 mg/kg s.c.). The midbrain once more displayed unique properties; there was initial suppression of responses followed by post-treatment rebound elevations that were more prominent in males and eventual deficits that, in the case of dopamine, were selective for males. With the exception of the cerebellum, other regions showed the initial loss of response during the infusion period but no persistent changes in responsiveness. The current results indicate that adolescent nicotine produces immediate and long-term changes in CNS catecholaminergic systems, with regional targeting and gender selectivity corresponding to the changes seen previously in nicotinic receptor upregulation or indices of cell damage. These effects may underlie long-term behavioral changes associated with adolescent nicotine exposure.

Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokers

Eleven healthy tobacco smoking adult male volunteers of mixed race were tobacco abstinent overnight for this study. In each subject, positron emission tomographic images of regional cerebral metabolism of glucose with [ 18F]fluorodeoxyglucose were obtained in two conditions in the morning on different days: about 3 min after approximately 1–2 mg of nasal nicotine spray and after an equivalent volume of an active placebo spray of oleoresin of pepper in a random counterbalanced design. A Siemens/CTI 931/08-12 scanner with the capability of 15 horizontal brain slices was used. The images were further converted into a standard uniform brain format in which the mean data of all 11 subjects were obtained. Images were analysed in stereotactic coordinates using pixel-wise t statistics and a smoothed Gaussian model. Peak plasma nicotine levels varied three-fold and the areas under the curve 0–30 min varied seven-fold among the individual subjects. Nicotine caused a small overall reduction in global cerebral metabolism of glucose but, when the data were normalized, several brain regions showed relative increases in activity. Cerebral structures specifically activated by nicotine (nicotine minus pepper, Z score >4.0) included: left inferior frontal gyrus, left posterior cingulate gyrus and right thalamus. The visual cortex, including the right and left cuneus and left lateral occipito-temporal gyrus fusiformis, also showed an increase in regional cerebral metabolism of glucose with Z scores >3.6. Structures with a decrease in regional cerebral metabolism of glucose (pepper minus nicotine) were the left insula and right inferior occipital gyrus, with Z scores >3.5. Especially important is the fact that the thalamus is activated by nicotine. This is consistent with the high density of nicotinic cholinoceptors in that brain region. However, not all brain regions affected by nicotine are known to have many nicotinic cholinoceptors. The results are discussed in relation to the cognitive effects of nicotine.

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding.

Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.

Naltrexone Alteration of Acute Smoking Response in Nicotine-Dependent Subjects

There are mixed results on the effects of opioid antagonists on acute nicotine response in humans. The present study examined the effects of a single dose of 50 mg oral naltrexone relative to placebo on smoking response in 22 chronic smokers during short-term nicotine abstinence, after acute smoking and subsequent smoking deprivation, and on smoking behavior in a choice paradigm. The results showed that naltrexone significantly reduced immediate postcigarette ratings of smoking craving and desire to smoke and increased light-headedness, dizziness, and head rush ( ps < 0.05). Reductions in craving and smoking desire persisted during a subsequent 1 h nonsmoking interval. Naltrexone also was found to significantly reduce the total number of cigarettes smoked in the choice interval, which was supported by objective measures of both reduced CO and plasma nicotine levels ( ps < 0.01). Exploratory analyses on potential individual difference factors revealed that smokers with the highest levels of craving during abstinence showed the most pronounced naltrexone attenuation of smoking response. The results support the continued exploration of naltrexone as an adjunct to smoking cessation, especially in identified smoker subgroups most sensitive to the effects of opioid antagonism.

Nicotine Blood Levels and Subjective Craving for Cigarettes

This study examined cigarette craving and blood nicotine levels in 11 male heavy smokers who were observed during 16 h of tobacco abstinence. Subjects rated their urge to smoke on a new brief 10-item questionnaire, Urge to Smoke (UTS), Schuh and Stitzer's four-item Visual Analog Scale (SSI), and a Strength of Urge to Smoke (SUTS) item. Testing occurred: 1) after 16 h (1700 h the night before to 0900 h the next morning) of abstinence from smoking; 2) after an ad lib smoking period following the 16 h abstinence; 3) every hour during 6 hours of abstinence; 4) and finally, after the 6 h abstinence, another ad lib smoking period. Thus, subjects smoked twice in each session. Blood plasma nicotine levels were measured before, after, and every 2 h during the 6-h abstinence period for a total of six measures. Blood pressure and heart rate were measured prior to each blood draw. There was a significant negative correlation between blood nicotine levels and craving for cigarettes on all craving questionnaires ( rs = −0.55 to −0.78; ps < 0.002). Carbon monoxide was shown to correlate highly with nicotine blood levels ( rs = 0.83 to 0.98 across subjects; ps < 0.001). Results are consistent with the hypothesis that “urge to smoke” reflects nicotine seeking in continuing smokers.

A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrophysiological study

Increased neurotransmission within the mesolimbic dopamine system is considered an essential component for the rewarding and dependence producing properties of nicotine. Nicotinic acetylcholine receptors on dopamine containing neurons in the ventral tegmental area are thought to be a prime target for nicotine’s stimulatory effects. However, there is no evidence regarding the actions of nicotine on ventral tegmental GABAergic interneurons which play an important modulatory role in mesolimbic dopamine neuronal excitability. In the present study we sought to characterize the effects of nicotine on the activity of both dopamine and non-dopamine neurons in the juvenile rat ventral tegmentum. Extracellular recording techniques in rat brain slices and two methods of drug perfusion were used. Nicotine was found to markedly increase the firing rate of both groups, although the dopamine neuronal response pattern was considerably different and more vigorous than that in the non-dopamine neurons. The nicotine-induced excitations were also reversed by mecamylamine. Furthermore, desensitization to nicotine’s stimulatory effects occurred in both neuronal populations, although non-dopamine neurons appeared to desensitize to a greater degree. In fact, the desensitization accompanying sequential uninterrupted applications of nicotine appears to occur at concentrations below that described to produce receptor activation. The low nM concentrations of nicotine used in the present study are comparable to plasma levels of nicotine found after smoking a cigarette or even with passive inhalation of tobacco smoke. Thus, the present results not only confirm that nicotine stimulates the firing rate of ventral tegmental area dopamine neurons, but also that GABAergic neurons may be an important target for nicotine’s central nervous system effects. The less robust response in the non-dopamine presumptive GABAergic population and their more pronounced desensitization could lead to disinhibition of dopamine neurons thereby facilitating a more sustained increase in the response of mesolimbic dopamine neurons to nicotine.

Prolonged delivery of nicotine in rats via nasal administration of proliposomes

In order to achieve a prolonged delivery of nicotine to the systemic circulation, proliposomes containing nicotine base (NB–proliposomes) or nicotine hydrogen tartarate salt (NS–proliposomes) and a mixture of powdered nicotine hydrogen tartarate salt and sorbitol (1:9 mixture, MP) were administered intranasally to rats at a nicotine dose of 1 mg/kg. Proliposomes, lipid–sorbitol mixtures that form liposomes upon contact with water, were prepared according to previously established methods, and the mixture (MP) was prepared by mixing NS powder with sorbitol particles (105–350 μm in size). Nasal absorption of nicotine from these formulations was very rapid (i.e. less than 10 min was required to reach plasma peaks) and showed substantially sustained plasma nicotine levels compared to saline solutions of NB and NS, and previously reported nasal nicotine sprays. The AUC values from the proliposomes and MP were comparable to those from the saline solutions of NB and NS. However, the mean residence time (MRT) and plasma half-life (T1/2β) of nicotine in the present study were much larger than those from the saline solutions. Thus, a prolonged delivery of nicotine to systemic circulation via the application of proliposomes or MP intranasally appears feasible. NB–proliposomes exhibited the best characteristics in terms of the area under the plasma concentration (AUC), MRT and T1/2β of nicotine, which was followed by NS–proliposomes and MP. Retarded conversion of proliposomes and MP to liposomal emulsions and solution in the nasal cavity seems responsible, in part, for the sustained plasma nicotine concentrations, since the emulsions and solution yielded very short MRT and T1/2β of nicotine. In addition, reduced metabolism to cotinine from the proliposomes and MP was apparently responsible for the sustained plasma nicotine levels. These dosage forms of nicotine appear to circumvent some of the shortcomings of transdermal patches (i.e. long Tmax) and nasal sprays (i.e. short T1/2β and physicochemical instability).

The effect of smoking on energy expenditure and plasma catecholamine and nicotine levels during light physical activity.

A number of studies have found that cigarette smoking causes an acute increase in resting energy expenditure, but the effect on energy expenditure during light physical activity is less clear. Since both smoking and activity have been shown to increase plasma catecholamines, these could produce additive effects on energy expenditure when smoking during light physical activity. In this study, the impact of cigarette smoking on energy expenditure, cardiovascular function, plasma nicotine and plasma catecholamine levels was determined in adult male subjects at rest and while engaged in light physical activity. Smoking at rest resulted in a 3.6% increase in energy expenditure above the resting baseline; whereas the increase in energy expenditure caused by smoking during light physical activity (compared with the light physical activity baseline) was 6.3%. This increase during light physical activity was significantly greater than the increase observed at rest (p < 0.025). As expected, plasma nicotine increased with smoking during both rest and light physical activity. An increase in plasma nicotine was associated with smoking during light physical activity. When this increase was adjusted as a covariate, the difference in smoking-related energy expenditure between light physical activity and rest disappeared, suggesting nicotine accounts for the effect. Plasma epinephrine and norepinephrine levels increased with smoking and showed a significantly greater increase during light physical activity compared to rest. Cigarette smoking caused a significantly greater increase in heart rate during light physical activity than it did while at rest, but there was no significant effect of smoking on mean blood pressure. It was concluded that there is enhanced energy expenditure associated with cigarette smoking during light physical activity when compared with smoking at rest which could be due in part to smoking-induced increases in circulating plasma catecholamines and perhaps nicotine.

Adolescent nicotine exposure causes persistent upregulation of nicotinic cholinergic receptors in rat brain regions

Whereas numerous studies have explored the consequences of fetal or adult nicotine exposure, little or no basic research has been conducted for nicotine exposure during adolescence, the developmental period in which regular cigarette use typically begins. We administered nicotine to adolescent rats on postnatal days 30–47 via continuous infusion with implanted osmotic minipumps, using a dose rate (3–6 mg kg −1 day −1) set to achieve plasma nicotine levels found in smokers; results were compared to exposure of adult rats. During and after exposure, we assessed nicotinic cholinergic receptor binding in the midbrain, cerebral cortex, and hippocampus, using [ 3 H ]cytisine. Robust receptor upregulation was observed with both adolescent and adult nicotine exposure but there were major differences in the regional specificity and persistence of effect. In adolescents, upregulation was uniform across all regions during the infusion period, whereas in adults, there was a distinct regional hierarchy: midbrain<cerebral cortex<hippocampus; accordingly, receptors in the adolescent midbrain were upregulated far more than with adult exposure. In addition, adolescent nicotine treatment produced long-lasting effects on the receptors, with significant increases still apparent in male rats 1 month after the termination of drug exposure. We also obtained evidence for hippocampal cell damage in adolescent female rats exposed to nicotine, characterized by increases in total membrane protein concentration indicative of a decrease in overall cell size. Adolescent nicotine exposure thus elicits region- and gender-selective effects that differ substantially from those in adults, effects that may contribute to increased addictive properties and lasting deficits in behavioral performance.

Arterial/venous plasma nicotine concentrations following nicotine nasal spray.

Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1-2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r = 0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations.

Nicotine treatment for ulcerative colitis.

Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases of unknown aetiology which, although similar in various aspects, exhibit some contrasting features. A typical example is their relationship with cigarette smoking. While smoking appears to exert deleterious effects in Crohn’s disease [1, 2], there is overwhelming epidemiological evidence that smoking protects against ulcerative colitis, the risk of developing the disease being significantly lower in smokers than in non-smokers or former smokers [2, 3]. The fact that patients with ulcerative colitis who resume or start smoking often experience clinical improvement [4] prompted attempts to verify the hypothesis that nicotine might be the active component of smoking responsible for the beneficial effects on the course of the disease. Preliminary, uncontrolled observations employing nicotine gum, a pharmaceutical form generally poorly tolerated, yielded encouraging but inconclusive results [5]. The introduction of transdermal nicotine in the market made it possible to assess the potential therapeutic role of nicotine in a more extensive way.

Efficacy of providing nicotine in a liquid diet to rats.

To determine if rats would consume nicotine at psychoactive levels, a nutritionally balanced diet with 0, 20, 60, or 200 mg of nicotine tartrate per kg of diet was provided. Diet consumption and body weight differences were recorded for 14 days after which, following 16 hr of withdrawal, animals were given access to a two-bottle choice of the previously presented diet and a nicotine-free diet. Spontaneous horizontal motor activity was recorded 8, 16, and 24 hr after withdrawal. By Day 14, all animals showed a significant increase in diet consumption and significant weight gain compared to Day 1. Animals consumed an average of 2.1, 6.8, or 19.5 mg/kg/day of nicotine on the low, medium, and high-nicotine diets, respectively. However, animals receiving the high-nicotine diet consumed less diet and gained less weight than the control, low, and medium nicotine groups. During only the first 4 hr of the two-bottle choice (16-20 hr postwithdrawal), the high-nicotine group consumed significantly higher amounts of nicotine base than the other groups, but also consumed more of the control diet during the first 2 hr. In a replicate experiment, animals receiving the medium-nicotine diet showed an increased consumption of the nicotine diet and increased preference for nicotine following a 14-day exposure compared to the control-fed animals and compared to a baseline preference test. Also, this group showed differences in locomotor activity consistent with other studies using an injection regimen or subcutaneuos pumps to induce dependence. Finally, animals in all three groups exhibited high plasma nicotine and cotinine (a major nicotine metabolite) levels. Because animals in all groups tolerated the diet well, gained weight, selected the nicotine diet in a choice test, and showed withdrawal symptoms, we conclude that the liquid diet proved to be a satisfactory method of inducing nicotine dependence in rats.

Efficacy of Providing Nicotine in a Liquid Diet to Rats

To determine if rats would consume nicotine at psychoactive levels, a nutritionally balanced diet with 0, 20, 60, or 200 mg of nicotine tartrate per kg of diet was provided. Diet consumption and body weight differences were recorded for 14 days after which, following 16 hr of withdrawal, animals were given access to a two-bottle choice of the previously presented diet and a nicotine-free diet. Spontaneous horizontal motor activity was recorded 8, 16, and 24 hr after withdrawal. By Day 14, all animals showed a significant increase in diet consumption and significant weight gain compared to Day 1. Animals consumed an average of 2.1, 6.8, or 19.5 mg/kg/day of nicotine on the low, medium, and high-nicotine diets, respectively. However, animals receiving the high-nicotine diet consumed less diet and gained less weight than the control, low, and medium nicotine groups. During only the first 4 hr of the two-bottle choice (16–20 hr postwithdrawal), the high-nicotine group consumed significantly higher amounts of nicotine base than the other groups, but also consumed more of the control diet during the first 2 hr. In a replicate experiment, animals receiving the medium-nicotine diet showed an increased consumption of the nicotine diet and increased preference for nicotine following a 14-day exposure compared to the controlfed animals and compared to a baseline preference test. Also, this group showed differences in locomotor activity consistent with other studies using an injection regimen or subcutaneuos pumps to induce dependence. Finally, animals in all three groups exhibited high plasma nicotine and cotinine (a major nicotine metabolite) levels. Because animals in all groups tolerated the diet well, gained weight, selected the nicotine diet in a choice test, and showed withdrawal symptoms, we conclude that the liquid diet proved to be a satisfactory method of inducing nicotine dependence in rats.

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats.

The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015. 0.03 and 0.06 mg/kg per infusion). The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50-200 ng/ml) were approximately 2-fold higher than nicotine levels (40-120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence.

Acute effect of nicotine patch on gastric emptying of liquid and solid contents in healthy subjects.

The effect of nicotine on gastric emptying remains controversial. Gastric emptying is delayed in chronic smokers after smoking high-dose nicotine cigarettes, but it is unchanged after chewing nicotine gums. No information is available on the effect of transdermal nicotine patches on the gastric emptying of solid and liquid contents in healthy nonsmokers. Our objective was to prospectively evaluate the effect of the nicotine patch on gastric emptying of liquid and solid contents in healthy nonsmokers. Ten healthy nonsmoking volunteers underwent a baseline dual-isotope gastric scintigraphy with [111In]-diethylenetriaminepantaacetic acid (DTPA) and [99mTc]sulfur colloid isotopes to evaluate prospectively the gastric emptying of liquid and solid contents, respectively. The gastric scintigraphy was repeated after placing a transdermal nicotine patch (Habitrol) for 12 hr designed to deliver 14 mg of nicotine per day. Plasma nicotine level was measured prior to baseline gastric scintigraphy and after 12 hr placing the nicotine patch. Plasma nicotine was absent in all subjects at baseline and but was significantly elevated after 12 hr of nicotine patch (P < 0.009). The mean half-emptying times (T1/2) for the gastric emptying of liquids before and after nicotine patch placement were 31.2+/-23.3 and 25.6+/-8.4 min, respectively (P = 0.498). The mean T1/2s for the gastric emptying of solids before and after nicotine patch placement were 70.1+/-34.0 and 59.7+/-31.4 min, respectively (P = 0.202). There was no correlation between the plasma nicotine level and gastric emptying of liquid and solid contents (correlation coefficient = -0.23 and -0.01, respectively). In conclusion, acute transdermal delivery of nicotine does not affect the gastric emptying of solid and liquid contents in healthy nonsmoking subjects.

Why giving up smoking is a drag

Although a substantial body of evidence indicates that nicotine is the key constituent within tobacco smoke that leads to addiction, rather less is known about the mechanism through which this effect is mediated. Withdrawal from chronic nicotine administration does induce an abstinence syndrome in rats in keeping with the effects of withdrawal from other drugs of abuse, such as ethanol, sedative-hypnotics and opiates. However, the somatic symptoms that characterize these abstinence syndromes in animals are not thought to be as important to the motivational aspects of drug dependence in humans as the affective and emotional changes that occur. Epping-Jordan et al.[1xDramatic decrease in brain-reward function during nicotine withdrawal. Epping-Jordan, M.P. et al. Nature. 1998; 393: 76–79Crossref | PubMed | Scopus (471)See all References[1]now report that the emotional effects of nicotine withdrawal are similar to those observed during withdrawal from other addictive drugs, as measured by elevated intracranial self-stimulation (ICSS) brain-reward thresholds. These are suggested to represent a decrease in brain-reward function. Nicotine was administered to rats for a period of seven days via subcutaneous osmotic pumps. The levels of nicotine in the blood plasma were equivalent to those observed in smokers consuming 30 cigarettes a day. ICCS reward thresholds and somatic withdrawal signs were then measured following removal of the osmotic pumps. The elevated ICCS reward thresholds were observed four hours after pump removal and persisted for four days. The authors draw parallels between the decreased brain-reward function observed during nicotine withdrawal and the negative affective states reported by smokers during the first days of abstinence. These data could provide a model for the study of the affective effects of nicotine withdrawal in humans.

Abstracts of Literature

Abstracts of Literature

Dose-response relationship for nicotine-induced up-regulation of rat brain nicotinic receptors.

The chronic administration of nicotine to animals has been shown to result in an increase in brain nicotinic acetylcholine receptor (nAChR) density. It has been suggested that this agonist-induced receptor up-regulation is a consequence of long-term nAChR desensitization in vivo. In this study, the effects of different nicotine doses and administration schedules as well as the resulting blood and brain nicotine levels were determined to assess the effect of in vivo nicotine concentration on nAChR density in the brain. Rats with indwelling subcutaneous cannulas were infused for 10 days with 0.6-4.8 mg/kg/day nicotine either 2x, 4x, or 8x/day or by constant infusion. The nAChR density in cortical, striatal, and hippocampal tissue measured by [3H]cytisine binding as well as the corresponding plasma and brain nicotine levels measured by GC analysis were determined. The results showed a dose-dependent increase in nAChR density with significant increases achieved at 2.4 mg/kg/day in all three brain areas. It is surprising that at this dose there was little difference between the constant infusion of nicotine and twice-daily administration, whereas more frequent periodic injections were actually less effective at up-regulating nAChRs. An analysis of the blood and brain levels of nicotine compared with the concentrations that produce nAChR desensitization suggests that in vivo desensitization alone is not sufficient for nAChR up-regulation to occur.

Impaired cardiac function during postnatal hypoxia in rats exposed to nicotine prenatally: Implications for perinatal morbidity and mortality, and for sudden infant death syndrome

Maternal smoking correlates highly with parturitional/neonatal death including SIDS; nicotine exposure of fetal rats reproduces the increased mortality when animals are tested postnatally with hypoxia. In the current study, pregnant rats received nicotine infusions simulating smokers' plasma nicotine levels. At 1-2 days postpartum, the nicotine group displayed normal heart rates, EKG waveforms, and respiratory rates in normoxia. With hypoxia (5% O2, 10 min), controls showed initial tachycardia and a subsequent slight decline in heart rate; atrioventricular conduction was gradually impaired and repolarization abnormalities also appeared. The nicotine group showed no tachycardia and heart rate declined rapidly and precipitously within a few minutes after commencing hypoxia; otherwise, EKG alterations mimicked the controls'. Changes in respiration were identical in the two groups: initial tachypnea and subsequent decline. These results suggest that prenatal nicotine affects sinoatrial reactivity to hypoxia without impairing cardiac conduction per se. These mechanisms explain increased hypoxia-induced mortality in animals exposed to prenatal nicotine, and in man could account for increased morbidity/mortality and SIDS. Our results also indicate the need to test adverse effects of fetal drug exposure using conditions that challenge any given physiological system rather than relying solely on changes under basal conditions.

Impaired cardiac function during postnatal hypoxia in rats exposed to nicotine prenatally: implications for perinatal morbidity and mortality, and for sudden infant death syndrome.

Maternal smoking correlates highly with parturitional/neonatal death including SIDS; nicotine exposure of fetal rats reproduces the increased mortality when animals are tested postnatally with hypoxia. In the current study, pregnant rats received nicotine infusions simulating smokers' plasma nicotine levels. At 1-2 days postpartum, the nicotine group displayed normal heart rates, EKG waveforms, and respiratory rates in normoxia. With hypoxia (5% O2, 10 min), controls showed initial tachycardia and a subsequent slight decline in heart rate; atrioventricular conduction was gradually impaired and repolarization abnormalities also appeared. The nicotine group showed no tachycardia and heart rate declined rapidly and precipitously within a few minutes after commencing hypoxia; otherwise, EKG alterations mimicked the controls'. Changes in respiration were identical in the two groups: initial tachypnea and subsequent decline. These results suggest that prenatal nicotine affects sinoatrial reactivity to hypoxia without impairing cardiac conduction per se. These mechanisms explain increased hypoxia-induced mortality in animals exposed to prenatal nicotine, and in man could account for increased morbidity/mortality and SIDS. Our results also indicate the need to test adverse effects of fetal drug exposure using conditions that challenge any given physiological system rather than relying solely on changes under basal conditions.