Intravenous Administration Of Nicotine Research Articles

Nicotine loaded dissolving microneedles for nicotine replacement therapy

Nicotine replacement therapy is a medically approved means to quit smoking. Microneedle devices could be engineered in such a way to provide rapid delivery of nicotine. The main objective of this study was to explore the feasibility of nicotine delivery from microneedles via the transdermal route. Nicotine loaded microneedles were prepared using a mold casting technique with polyvinylpyrrolidone as the water-soluble polymer. The microneedles were characterized for their height, diameter, and tip width by microscopic observation. The nicotine loaded microneedles were characterized for in vitro release profile and skin permeation profile. The pharmacokinetic parameters of nicotine loaded microneedles were compared with an intravenous administration of nicotine in Sprague Dawley rats. The in vivo skin resealing kinetics was studied using TEWL (Transepidermal water loss) measurements after insertion of microneedles as an indicator of skin barrier function. In vivo, pharmacokinetic studies revealed that nicotine from microneedles showed immediate release profile with Cmax (70.10 ± 3.55 ng/mL) being achieved within the first hour. Overall, nicotine loaded into microneedles could be a potential pain-free and minimally invasive treatment option for nicotine replacement therapy.

Smoking and Nicotine Effects on Surgery: Is Nicotine Replacement Therapy (NRT) a Safe Option?

Smoking and Nicotine Effects on Surgery: Is Nicotine Replacement Therapy (NRT) a Safe Option?

Effects of nicotine on regional blood flow in the olfactory bulb in response to olfactory nerve stimulation

This study examined the effect of olfactory nerve stimulation on regional cerebral blood flow and assessed the effect of intravenous nicotine administration on this response in anesthetized rats. Regional cerebral blood flow was measured with laser Doppler flowmetry or laser speckle contrast imaging. Unilateral olfactory nerve stimulation for 5 s produced current (≥ 100 μA) and frequency-dependent (≥ 5 Hz) increases in blood flow in the olfactory bulb ipsilateral to the stimulus. The increased olfactory bulb blood flow peaked at 30 ± 7% using stimulus parameters of 300 μA and 20 Hz. Nerve stimulation did not change frontal cortical blood flow or mean arterial pressure. The intravenous injection of nicotine (30 μg/kg) augmented the olfactory bulb blood flow response to nerve stimulation (20 Hz, 300 μA) by approximately 1.5-fold (60-s area after the stimulation). These results indicate that olfactory nerve stimulation increases olfactory bulb blood flow, and the response is potentiated by the activation of nicotinic cholinergic transmission.

How Intravenous Nicotine Administration in Smokers Can Inform Tobacco Regulatory Science.

Reducing the negative health effects caused by tobacco products continues to be a public health priority. The Family Smoking Prevention and Tobacco Control Act of 2009 gives the Food Drug Administration authority to pursue several new strategies, including regulating levels of nicotine and other ingredients in tobacco products. A nicotine reduction strategy proposed by Benowitz and Henningfield aims to reduce the nicotine content of tobacco products to an amount below a threshold that supports neither the development nor maintenance of addiction. Many factors must be considered to determine the viability and efficacy of this approach. For example, the policy should be based on precise information on the dose-dependent effects of nicotine on reinforcement and factors that contribute to individual differences in these effects. However, there have been few studies on these topics in humans. Here, we briefly review nicotine pharmacology and reinforcement then present several studies illustrating the application of intravenous (IV) nicotine delivery to study nicotine reinforcement in humans. We discuss how nicotine delivery by IV infusion may be uniquely suited for studying nicotine's dose-dependent effects, and how this can inform tobacco regulatory science to facilitate the development of effective tobacco control policies.

Different Lines of Rats Selectively-Bred for High Alcohol-Drinking Demonstrate Disparate Preferences for Nicotine Self-Administration

Background. Alcohol and nicotine are commonly co- abused. The search for a common core of neural, behavioral, and genetic factors underlying addiction has been the goal of addiction research. Purpose. Genetic predisposition to high alcohol intake has been studied in rats by selectively breeding rats that have high preference for alcohol. The current experiments were conducted to determine if the level of intravenous nicotine administration for the various lines of alcohol-preferring rats differs from that for nonalcohol-preferring controls. Study design. Adult alcohol-na¨ selectively-bred alcohol-preferring male rats from four lines (P, AA, HAD-1, sP) and their control nonalcohol-preferring rats (NP, ANA, LAD-1, sNP) were trained and given access to self-administer nicotine (0.03 mg/kg/infusion). Results. The results show that the P rats self- administered significantly more nicotine than NP rats. In contrast, there were no significant differences in nicotine self-administration between the sP and sNP or the AA and ANA rats. Unexpectedly, high alcohol-drinking HAD-1 rats self-administered significantly less nicotine than low alcohol-drinking LAD-1 rats. Conclusion. This suggests that some genetic factors that underlie high-alcohol intake have more general effects in promoting high nicotine intake tendencies, while other genetic factors are more specific to only heavy drinking.

Intravenous nicotine injection induces rapid, experience‐dependent sensitization of glutamate release in the ventral tegmental area and nucleus accumbens

Although numerous data suggest that glutamate (GLU) is involved in mediating the neural effects of nicotine, direct data on nicotine-induced changes in GLU release are still lacking. Here, we used high-speed amperometry with enzyme-based GLU and enzyme-free GLU-null biosensors to examine changes in extracellular GLU levels in the ventral tegmental area (VTA) and nucleus accumbens shell (NAcc) induced by intravenous nicotine in a low, behaviorally active dose (30 μg/kg) in freely moving rats. Using this approach, we found that the initial nicotine injection in drug-naive conditions induces rapid, transient, and relatively small GLU release (~ 90 nM; latency ~ 15 s, duration ~ 60 s) that is correlative in the VTA and NAcc. Following subsequent nicotine injections within the same session, this phasic GLU release was supplemented by stronger tonic increases in GLU levels (100-300 nM) that paralleled increases in drug-induced locomotor activation. GLU responses induced by repeated nicotine injections were more phasic and stronger in the NAcc than in VTA. Therefore, GLU is phasically released within the brain's reinforcement circuit following intravenous nicotine administration. Robust enhancement of nicotine-induced GLU responses following repeated injections suggests this change as an important mediator of sensitized behavioral and neural effects of nicotine. By using high-speed amperometry with glutamate (GLU) biosensors, we show that i.v. nicotine at a low, behaviorally relevant dose induces rapid GLU release in the NAcc and VTA that is enhanced following repeated drug injections. This is the first study reporting second-scale fluctuations in extracellular GLU levels induced by nicotine in two critical structures of the motivation-reinforcement circuit and rapid sensitization of GLU responses coupled with locomotor sensitization.

Effect of a Nicotine Vaccine on Nicotine Binding to β2*-Nicotinic Acetylcholine Receptors In Vivo in Human Tobacco Smokers

Nicotine promotes smoking partly by binding to β2-containing nicotinic acetylcholine receptors (β2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of β2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty. Developing nicotine vaccines could improve treatments. The authors used [123I]5-I-A-85380 single photon emission computed tomography (SPECT) to evaluate the effect of 3'-AmNic-rEPA on the amount of nicotine that binds to β2*-nAChRs in smokers' brain cortical and subcortical regions. Eleven smokers who smoked an average of 19 cigarettes per day, had smoked for 10 years on average, and met criteria for nicotine dependence were given SPECT scans on two days: before and after immunization with 4-400 μg of 3'-AmNic-rEPA. On scan days, three 30-minute baseline emission scans were followed by intravenous administration of nicotine (1.5 mg/70 kg body weight) and up to nine 30-minute emission scans. β2*-nAChR availability was quantified as VT/fP (total distribution volume divided by free plasma concentration), and nicotine binding was derived by the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding. Nicotine bound to β2*-nAChRs correlated positively with nicotine injected before but not after vaccination. The daily number of cigarettes and desire for a cigarette decreased after vaccination. This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to β2*-nAChRs and disrupt the relationship between administered nicotine and nicotine available to occupy β2*-nAChRs.

The effects of extended intravenous nicotine administration on body weight and meal patterns in male Sprague–Dawley Rats

Increased appetite and weight gain after cessation is a deterrent for quitting smoking. Attempts to understand the mechanism for these effects using animals have been hampered by the difficulty or inconsistency of modeling the effects seen in humans. To examine the effects of extended daily access to intravenous nicotine, via programmed infusions, on body weight and meal patterns in rats. Intravenous (IV) nicotine infusions (0.06 mg/kg/inf) were administered noncontingently, every 30 min throughout the dark cycle and the last 3 h of the light cycle, to emulate self-administration. The effect of these infusions on food intake, meal patterns, and weight change were examined relative to a control group during treatment and in a post-nicotine phase. Nicotine-treated rats gained half the weight that vehicle treated animals gained and ate approximately 20 % less food overall than vehicle-treated rats. Whereas a compensatory increase in meal frequency occurred during the dark period to account for smaller meals, no compensation was observed throughout the light period. In a post-nicotine phase, the nicotine group maintained a lower weight for 1 week and then gained weight back to control levels. The rate of weight gain post-cessation was faster in animals that had received nicotine compared to controls. Compared to previous studies examining the effects of minipump or intraperitoneal injections of nicotine on food intake, the present study was able to detect previously unknown circadian differences in meal patterns which will be important in the development of smoking cessation and weight gain prevention drugs.

Non‐suicidal self‐injury by intravenous application of nicotine in a patient with borderline personality disorder resulting in substance dependence

Non-suicidal self-injury in many different forms is a classic struggle for those diagnosed with borderline personality disorder (BPD). Some common ways of NSSI are cutting, scratching and head-banging. A 23-year old woman with BPD presented in our clinic with a 4-month history of intravenous application of a liquid dosage form of nicotine that is generally used for nasal application. Accordingly, the patient developed nicotine dependency (ICD-10 F17.25). Before her admission to our ward the daily intravenous nicotine application was around 33 mg. The in-patient detoxification proceeded without a remarkable withdrawal syndrome. A case of regular intravenous administration of nicotine has been observed, apparently resulting in nicotine dependence in a person with borderline personality disorder. The original intent appears to have been self-harm.

Nicotinic receptor agonist-induced salivation and its cellular mechanism in parotid acini of rats

Cigarette smoking and nicotine enhance parotid saliva secretion, however, the underlying mechanism is unclear. To address the mechanism of nicotine-induced salivation and to explore the possibility that nicotinic receptor agonists act as sialogogues, we investigated the effects of nicotinic receptor agonists on salivary secretion in vivo and on intracellular Ca 2+ concentration in digested parotid acini in vitro in rats. In urethane-anesthetized rats, intravenous administration of nicotinic receptor agonists, nicotine and cytisine, at 3 μmol/kg increased whole saliva output accompanied by a pressor response with nicotine, but not with cytisine. Using Ca 2+-imaging system on digested parotid acini in which autonomic nerve terminals were kept intact, nicotine and cytisine dose-dependently increased intracellular Ca 2+ concentration at μM level. This was not observed in single acinar cells containing no nerve terminal. The nicotine-induced Ca 2+ response was largely blocked by a muscarinic receptor antagonist and partly blocked by an adrenergic receptor antagonist. Furthermore, the same nicotine-induced Ca 2+ response was blocked by mecamylamine, a relatively selective nicotinic antagonist for α3β4 subtype receptor, but not by other selective antagonists, dihydro-β-erythroidine for α4-containing receptor and methyllycaconitine for α7 nicotinic receptors. These results suggest that nicotinic agonists-induced salivation is due to a release of acetylcholine and noradrenaline from autonomic nerve terminals through activation of α3β4 nicotinic receptor subtype. In addition, considering the blood pressure response and development of addiction with nicotine, cytisine may be a better therapeutic candidate to serve as a sialogogue for xerostomia patients.

Low doses of nicotine-induced fetal cardiovascular responses, hypoxia, and brain cellular activation in ovine fetuses

Prenatal exposure to nicotine is associated with a variety of adverse outcomes. The present study investigated the effect of low doses of nicotine during pregnancy on fetal blood gases, cardiovascular system, and cellular activation in the brain. Intravenous administration of nicotine 10 or 25 μg/kg into ewe did not affect maternal blood gases, blood pressure, and heart rate. Maternal administration of nicotine also had no effect on fetal blood electrolyte concentrations, osmolality levels, and lactic acid levels. However, it significantly reduced fetal blood pO 2 levels and oxygen saturation, increased fetal arterial blood pressure and decreased heart rate in utero. In addition, exposure to low doses of nicotine increased the expression of Fos in the paraventricular nucleus (PVN) and subfornic organ (SFO) in the fetal brain. The data demonstrated that even low doses of nicotine could impact significantly on fetal cardiovascular and central nervous systems, as well as oxygen status, and suggested a toxic risk to fetuses of exposure to low levels nicotine or second-hand smoking during pregnancy.

Abnormal response of dopaminergic neurons to nicotine without perturbation of nicotinic receptors in αCGRP knock-out mice

Alpha-calcitonin gene-related peptide (αCGRP) is a neuropeptide with multiple biological properties, including the regulation of nicotinic acetylcholine receptors (nAChRs). We have previously reported a reduction of somatic withdrawal symptoms in αCGRP knock-out mice exposed to chronic nicotine, leading us to investigate the contribution of αCGRP to the regulations of ventral tegmental area (VTA) neurons and their response to nicotine. The electrophysiological activity of VTA dopaminergic (DA) neurons was recorded in vivo, under anesthesia. These neurons displayed identical spontaneous electrophysiogical activities in wild-type and αCGRP−/− mice. However, we found that intravenous administration of nicotine (30 μg/kg) had no significant effect on the activity of DA neurons in αCGRP−/− mice, whereas it induced a doubling of the firing rate in wild-type animals. A higher dose (90 μg/kg) produced a significant excitation in both strains, but this effect remained smaller in the mutants. To investigate this difference, we have studied the functional state of nAChRs in wild-type and αCGRP−/− mice. Both strains exhibited identical expression of α 7 and α 4β 2 nAChRs as revealed by autoradiographical studies in the VTA. In addition, focal application of acetylcholine on DA neurons recorded by patch-clamp revealed identical currents mediated by nAChRs in mutant animals, as compared to wild-type mice. These data outline the possibility of a contribution of αCGRP to the effects of nicotine on DA neurons, by a physiological pathway independent of VTA nicotinic receptors.

Motivational effects of nicotine as measured in a runway model of drug self-administration

Traditional operant self-administration and conditioned place preference methods have yielded inconsistent results in studies of nicotine reinforcement thereby hindering efforts to identify the neurobiological systems underlying the drug's motivation and reinforcement. This study was designed to assess the motivation of subjects to seek nicotine using a runway self-administration procedure. Male Sprague-Dawley rats (N=67) were trained to run a straight alley for a single daily intravenous injection of nicotine (0.01-0.09 mg/kg/injection) on each of 21 consecutive trials. Run Speed (1/Run Time) served as the dependent measure for the animals' motivation to traverse the alley and enter a goal-box associated with intravenous nicotine administration. Nicotine induced an inverted U-shaped dose-response curve with the 0.03 mg/kg dose producing optimal runway performance over trials. Subjects running for doses larger or smaller than the optimal dose exhibited slower running and took longer to enter the goal-box. Thus, the runway procedure proved to be an effective methodology for reliably assessing the motivation of trained but nondrugged animals to seek intravenous nicotine.

Effects of maternal intravenous nicotine administration on locomotor behavior in pre-weanling rats

Maternal tobacco use is associated with adverse developmental outcomes in offspring, including hyperactivity. Animal studies attempting to model this phenomenon have primarily used continuous s.c. nicotine infusion as the method of nicotine administration, which does not model the intermittent bolus delivery of nicotine associated with smoking in humans. The purpose of the present experiment was to examine the locomotor activity of pre-weanling offspring of pregnant rats exposed to an i.v. nicotine dosing protocol that approximates the pattern of nicotine exposure in moderate to heavy smokers. Pregnant rats were administered an i.v. bolus of 0.03 mg/kg nicotine ( N = 13) or saline ( N = 10) every 14 min for 16 h/day, resulting in a total daily dose of 2 mg/kg (base), from gestational day 4 to delivery. Pups from each litter were tested for spontaneous locomotor activity on postnatal days (PND) 19–21 and nicotine-induced locomotor activity on PND 22. Mean birth weight was significantly lower in nicotine-exposed pups compared to controls, but body weights were equivalent between groups by the time of behavioral testing. Mean total distance traveled, vertical counts, and stereotypy counts were lower on PND 19 in nicotine-exposed pups compared to controls, but only the difference in mean stereotypy counts was statistically significant. Within-session analysis revealed that both distance traveled and stereotypy were significantly decreased in nicotine-exposed pups in the first 5 min of the session on PND 19. Total time spent in the center of the field was also lower in nicotine-exposed pups. Nicotine-induced increases in activity on PND 22 did not differ according to gestational exposure. These findings demonstrate that prenatal nicotine exposure in a model that mimics the pattern of nicotine exposure from cigarette smoking in humans results in offspring that exhibit low birth weight and hypoactivity in a novel environment.

Comments on “Hindbrain chemical mediators of reflex-induced inhibition of gastric tone produced by esophageal distension and intravenous nicotine”

The purpose of this study was to activate a vagovagal reflex by using esophageal distension and nicotine and test whether hindbrain nitric oxide and norepinephrine are involved in this reflex function. We used double-labeling immunocytochemical methods to determine whether esophageal distension (and nicotine) activates c-Fos expression in nitrergic and noradrenergic neurons in the nucleus tractus solitarii (NTS). We also studied c-Fos expression in the dorsal motor nucleus of the vagus (DMV) neurons projecting to the periphery. Esophageal distension caused 19.7 ± 2.3% of the noradrenergic NTS neurons located 0.60 mm rostral to the calamus scriptorius (CS) to be activated but had little effect on c-Fos in DMV neurons. Intravenous administration of nicotine caused 19.7 ± 4.2% of the noradrenergic NTS neurons 0.90 mm rostral to CS to be activated and, as reported previously, had no effect on c-Fos expression in DMV neurons. To determine whether norepinephrine and nitric oxide were central mediators of esophageal distension-induced decrease in intragastric pressure (balloon recording), NG-nitro-l-arginine methyl ester microinjected into the NTS ( n = 5), but not into the DMV, blocked the vagovagal reflex. Conversely, α2-adrenergic blockers microinjected into the DMV ( n = 7), but not into the NTS, blocked the vagovagal reflex. These data, in combination with our earlier pharmacological microinjection data with nicotine, indicate that both esophageal distension and nicotine produce nitric oxide in the NTS, which then activates noradrenergic neurons that terminate on and inhibit DMV neurons.

Hindbrain chemical mediators of reflex-induced inhibition of gastric tone produced by esophageal distension and intravenous nicotine

The purpose of this study was to activate a vagovagal reflex by using esophageal distension and nicotine and test whether hindbrain nitric oxide and norepinephrine are involved in this reflex function. We used double-labeling immunocytochemical methods to determine whether esophageal distension (and nicotine) activates c-Fos expression in nitrergic and noradrenergic neurons in the nucleus tractus solitarii (NTS). We also studied c-Fos expression in the dorsal motor nucleus of the vagus (DMV) neurons projecting to the periphery. Esophageal distension caused 19.7 +/- 2.3% of the noradrenergic NTS neurons located 0.60 mm rostral to the calamus scriptorius (CS) to be activated but had little effect on c-Fos in DMV neurons. Intravenous administration of nicotine caused 19.7 +/- 4.2% of the noradrenergic NTS neurons 0.90 mm rostral to CS to be activated and, as reported previously, had no effect on c-Fos expression in DMV neurons. To determine whether norepinephrine and nitric oxide were central mediators of esophageal distension-induced decrease in intragastric pressure (balloon recording), N(G)-nitro-L-arginine methyl ester microinjected into the NTS (n = 5), but not into the DMV, blocked the vagovagal reflex. Conversely, alpha2-adrenergic blockers microinjected into the DMV (n = 7), but not into the NTS, blocked the vagovagal reflex. These data, in combination with our earlier pharmacological microinjection data with nicotine, indicate that both esophageal distension and nicotine produce nitric oxide in the NTS, which then activates noradrenergic neurons that terminate on and inhibit DMV neurons.

Sex differences and repeated intravenous nicotine: behavioral sensitization and dopamine receptors

The present study examined the sex-dependent expression of behavioral sensitization as well as changes of dopamine (DA) transporters and D 1, D 2, and D 3 receptors following repeated intravenous nicotine administration. Male and female Sprague–Dawley rats were implanted with indwelling jugular catheters, equipped with subcutaneous intravenous injection ports. Rats were habituated to activity chambers for 3 days and were subsequently administered 15-s bolus injections of intravenous nicotine (50 μg/kg/ml) 1/day for 21 days. Animals were placed in activity chambers for 60 min immediately after the 1st and 21st nicotine injection. Observational time sampling was also performed. Brains were subsequently removed and frozen for autoradiographic DA transporter/DA receptor analysis on the afternoon females were in proestrus. With one exception, no robust sex differences were observed for locomotor activity or any rearing measures either during baseline or after initial nicotine injection. Females exhibited markedly more behavioral sensitization of locomotor activity, rearing, duration of rearing, and incidence of observed rearing. There were no sex differences in the number of D 1 or D 2 receptors. Females exhibited an increased number of DA transporters and decreased D 3 receptors in the NAcc, relative to males. Multiple regression analyses suggest that D 3 receptors and DA transporters in various striatal and NAcc subregions differentially predicted nicotine-induced behaviors for males and females. Collectively, these findings demonstrate that repeated intravenous nicotine produces sex differences in the expression of behavioral sensitization, and suggest that nicotine-induced changes of DA transporters and D 3 receptors are partly responsible for increased behavioral sensitization in female rats.

Excitatory and inhibitory responses of dopamine neurons in the ventral tegmental area to nicotine.

In the present electrophysiological study the mechanisms by which nicotine activates dopamine neurons in the ventral tegmental area in anesthetized Sprague-Dawley rats were analyzed. Intravenous administration of nicotine caused a dose-dependent increase in firing rate and percentage of spikes fired in bursts of ventral tegmental area dopamine neurons. However, this activation was preceded by an instantaneous but short-lasting inhibition of the firing rate. The excitation of dopamine neurons by nicotine (1.5-400 microg/kg i.v.) was antagonized and even reversed into an inhibitory response by elevated levels (four-fold) of the endogenous glutamate receptor antagonist kynurenic acid, as induced by a potent inhibitor of kynurenine 3-hydroxylase (PNU 156561A, 40 mg/kg, i.v., 5-9 h). The antagonistic action induced by PNU 156561A pretreatment was prevented by administration of D-cycloserine (128 mg/kg, i.v., 5 min). Administration of the GABA(B)-receptor antagonist CGP 35348 (200 mg/kg, i.v., 3 min) facilitated the nicotine-induced increase in burst firing activity of dopamine neurons and antagonized the short-lasting decrease in firing rate by nicotine. The results of the present study show that nicotine produces both inhibition and excitation of ventral tegmental area dopamine neurons, actions that appear to be related to the release of GABA and glutamate, respectively. Whereas the excitatory action of nicotine may be associated with motivational processes underlying learning and cognitive behavior, the inhibitory action of the drug may play a more prominent role in the situation of a profound dysregulation of the mesocorticolimbic dopamine system and may help to explain the high prevalence of tobacco-smoking in schizophrenics.

Behavioral Sensitization Following Repeated Intravenous Nicotine Administration: Gender Differences and Gonadal Hormones

Repeated intermittent administration of stimulants is well known to produce behavioral sensitization in male animals. The present studies explored whether 1) behavioral sensitization occurred with the IV route of administration, 2) sensitization was greater in females than in males, 3) sensitization was modulated by gonadectomy, 4) intact adult female rats maintained normal estrous cytology patterns in response to repeated nicotine administration, and 5) the pharmacokinetics of IV nicotine dosing. Adult male, female, castrated, and ovariectomized Sprague–Dawley rats ( n = 48) were surgically implanted with an intravenous access port. Animals received 50 μg/kg IV nicotine once/day for 14 days. Immediately after the initial nicotine injection and the final day 14 nicotine injection, animals were placed in IR photocell activity chambers for 60 min. Observational time sampling of behavior was also simultaneously performed by an observer blind to treatment condition. An increase in behavioral activity of greater than 120% occurred across the 14-day time course of IV nicotine injections. The magnitude of the increase, however, varied as a function of component of activity, gender, and gonadectomy. The behavioral observation data further suggested that the females demonstrated an increased sensitivity to repeated nicotine, as evidenced in a more rapid response, for example, grooming. These behavioral observations were associated with peak arterial levels of nicotine (∼25 ng/ml) no greater than the average venous levels of nicotine commonly maintained by cigarette smokers. Repeated IV nicotine, at a dose of 50 μg/kg, did not interfere with intact female vaginal cytology or body weight; the failure to detect such alterations were not due to inadequate statistical power. Moreover, no nicotine-treated animals displayed persistent vaginal estrous or were acyclic. Collectively, these data suggest that the IV nicotine model may be particularly useful in exploring the gender-dependent effects of nicotine.

Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction

An understanding of drug addiction requires knowledge of the effective drug concentrations to which receptors in the nervous system are exposed. It has often been thought that smoking of abused substances such as nicotine or cocaine produces much higher drug concentrations in the arterial blood than those achieved following any other route of administration. However, to date no studies have sampled arterial blood following cigarette smoking with the rapidity necessary to evaluate this hypothesis. We measured arterial plasma nicotine concentrations in samples collected every 5 s from 13 cigarette smokers during cigarette smoking and during administration of nicotine by intravenous injections. Our results show that, for both routes of administration, concentrations of nicotine in arterial blood were more than 10 times lower than expected. Thus, the delivery of nicotine into arterial blood is substantially slower than would be predicted if nicotine were absorbed as rapidly as has generally been assumed. A plausible explanation of these results is that lung uptake of nicotine considerably slows the entry of nicotine into the systemic circulation, as has been shown for other amines. These results have significant implications for theories of addiction to nicotine as well as other drugs such as cocaine that may be subject to binding by lung tissue.