Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms.

This study investigates differences in µ-opioid receptor mediated neurotransmission in healthy controls and overnight-abstinent smokers, and potential effects of the OPRM1 A118G genotype. It also examines the effects of smoking denicotinized (DN) and average nicotine (N) cigarettes on the µ-opioid system. Positron emission tomography with (11)C-carfentanil was used to determine regional brain µ-opioid receptor (MOR) availability (non-displaceable binding potential, BPND) in a sample of 19 male smokers and 22 nonsmoking control subjects. Nonsmokers showed greater MOR BPND than overnight abstinent smokers in the basal ganglia and thalamus. BPND in the basal ganglia was negatively correlated with baseline craving levels and Fagerström scores. Interactions between group and genotype were seen in the nucleus accumbens bilaterally and the amygdala, with G-allele carriers demonstrating lower BPND in these regions, but only among smokers. After smoking the DN cigarette, smokers showed evidence of MOR activation in the thalamus and nucleus accumbens. No additional activation was observed after the N cigarette, with a mean effect of increases in MOR BPND (i.e., deactivation) with respect to the DN cigarette effects in the thalamus and left amygdala. Changes in MOR BPND were related to both Fagerström scores and changes in craving. This study showed that overnight-abstinent smokers have lower concentrations of available MORs than controls, an effect that was related to both craving and the severity of addiction. It also suggests that nicotine non-specific elements of the smoking experience have an important role in regulating MOR-mediated neurotransmission, and in turn modulating withdrawal-induced craving ratings.

Regional brain [(11)C]carfentanil binding following tobacco smoking.

OBJECTIVE: To determine if overnight tobacco abstinent carriers of the AG or GG (*G) vs. the AA variant of the human mu opioid receptor (OPRM1) A118G polymorphism (rs1799971) differ in [(11)C]carfentanil binding after tobacco smoking. METHODS: Twenty healthy American male smokers who abstained from tobacco overnight were genotyped and completed positron emission tomography (PET) scans with the mu opioid receptor agonist, [(11)C]carfentanil. They smoked deniconized (denic) and average nicotine (avnic) cigarettes during the PET scans. RESULTS: Smoking avnic cigarette decreased the binding potential (BPND) of [(11)C]carfentanil in the right medial prefrontal cortex (mPfc; 6, 56, 18), left anterior medial prefrontal cortex (amPfc; -2, 46, 44), right ventral striatum (vStr; 16, 3, -10), left insula (Ins; -42, 10, -12), right hippocampus (Hippo; 18, -6, -14) and left cerebellum (Cbl; -10, -88, -34), and increased the BPND in left amygdala (Amy; -20, 0, -22), left putamen (Put; -22, 10, -6) and left nucleus accumbens (NAcc; -10, 12, -8). In the AA allele carriers, avnic cigarette smoking significantly changed the BPND compared to after denic smoking in most brain areas listed above. However in the *G carriers the significant BPND changes were confirmed in only amPfc and vStr. Free mu opioid receptor availability was significantly less in the *G than the AA carriers in the Amy and NAcc. CONCLUSION: The present study demonstrates that BPND changes induced by avnic smoking in OPRM1 *G carriers were blunted compared to the AA carriers. Also *G smokers had less free mu opioid receptor availability in Amy and NAcc.

Denicotinized versus average nicotine tobacco cigarette smoking differentially releases striatal dopamine.

INTRODUCTION: Nicotine has long been recognized as a necessary but insufficient component of tobacco cigarettes to maintain a psychophysiological need to smoke. This study examined venous plasma concentrations effects of nicotine in cigarette smoking after overnight abstinence to release striatal dopamine (DA). METHODS: Twenty-two male smokers smoked either denicotinized (denic) or average nicotine (nic) cigarettes under single blind conditions. Each was given [(11)C]raclopride and scanned in a positron emission tomography (PET) facility. RESULTS: Smoking either denic or nic cigarettes released striatal DA. Denic cigarette smoking released DA primarily in the right striatum, whereas nic cigarette smoking released DA in both striata, but especially in the left. Increases in venous plasma nicotine concentrations correlated positively with increased DA release in the left caudate nucleus. Smoking denic cigarettes reduced craving as much as smoking nic cigarettes. Craving reduction after nic tobacco smoking correlated with increases in plasma nicotine. CONCLUSIONS: Nonnicotine factors in tobacco smoking produce important right brain effects. Nicotine is a pharmacological factor during tobacco smoking that releases bilateral striatal DA, but more in the left brain.

Tobacco smoking produces greater striatal dopamine release in G-allele carriers with mu opioid receptor A118G polymorphism.

OBJECTIVE: To determine if carriers of the allelic expression of the G variant of the human mu opioid receptor (OPRM1) A118G polymorphism have greater increases in striatal dopamine (DA) release after tobacco smoking. METHODS: Nineteen of 20 genotyped male tobacco smokers, after overnight abstinence, smoked denicotinized (denic) and average nicotine (nic) containing tobacco cigarettes in a PET brain imaging study using [(11)C]raclopride. RESULTS: The right striatum had more free D(2) receptors than the left striatum pre- and post-tobacco smoking. After smoking the nic cigarettes, mean decreased DA binding was observed in the left dorsal caudate (-14 6 11; t=3.77), left and right ventral putamen (-26 3-8; t=4.27; 28 2 1; t=4.25, respectively), and right caudate (17 18 1; t=3.92). The effects of A118G genotype on the binding potentials for these four regions were then analyzed. Carriers of the G allele had larger magnitudes of DA release in response to nic smoking than those homozygous for the more prevalent AA allele in the right caudate and right ventral pallidum (t=3.03; p=0.008 and t=3.91; p=0.001). A voxel by voxel whole brain SPM analysis using an independent samples t test did not reveal any other differences between genotype groups. In addition, the venous plasma cortisol levels of the volunteers from 8:30 a.m. to 12:40 p.m. were lower in the AG/GG allele carriers. Nic smoking increased plasma cortisol in both groups, but they were higher in the AA group. CONCLUSION: This preliminary study indicates a difference in both brain striatal DA release and plasma cortisol in A118G polymorphic male tobacco smokers.

Venous plasma nicotine correlates of hormonal effects of tobacco smoking.

The present study resolves some of the discrepancies in the literature by correlating the effects of tobacco smoking on hormone release with venous plasma nicotine levels. Cortisol, prolactin, and beta-endorphin concentrations were measured. Habitual male tobacco users smoked denicotinized (very low nicotine) and average nicotine cigarettes in the morning after overnight tobacco abstinence. Several venous blood samples were withdrawn before and during the smoking sessions for subsequent analyses. The increases in plasma nicotine correlated well with plasma cortisol and prolactin levels (correlation coefficients r=0.66 and 0.53, respectively, p<0.05). This study quantifies the well known increase in plasma cortisol and prolactin after nicotine postsmoking for about 1h with peak plasma levels up to 35 ng/ml. Contrary to most abused drugs which release dopamine and decrease prolactin, nicotine concentration correlated with increased prolactin release. Increases in maximal plasma beta-endorphin levels following tobacco smoking were barely statistically significant with insufficient data to obtain a correlation coefficient.

Tobacco smoking produces widespread dominant brain wave alpha frequency increases.

The major pharmacological ingredient in tobacco smoke is nicotine, a mild stimulant known to alter brain electrical activity. The objective of this study was to determine if tobacco smoking in humans produces localized or widespread neocortical dominant alpha electroencephalographic (EEG) frequency increases consistent with nicotine stimulation of the brainstem activating system in animals. Twenty-two male volunteer non-deprived tobacco smokers were studied. They were asked not to smoke for at least 1h before the experiment in mid-morning as part of their usual smoking schedule. In the laboratory, they sham smoked and then smoked their favorite tobacco cigarette. Two experimental sessions (#1 and #2) were conducted, separated by a one to two month interval. In both sessions, there were minor statistically significant increases in the dominant alpha frequencies after sham smoking. In both sessions, after the subjects smoked a favorite tobacco cigarette there was a significant generalized increase in dominant alpha EEG frequencies in most scalp recording sites. This study demonstrates that tobacco smoking produces widespread bilateral neocortical increases in dominant alpha EEG frequencies consistent with the stimulant effects of nicotine on the brainstem reticular activating system.

Biperiden enhances L-DOPA methyl ester and dopamine D(l) receptor agonist SKF-82958 but antagonizes D(2)/D(3) receptor agonist rotigotine antihemiparkinsonian actions.

The effects of biperiden (0, 100, and 320 microg/kg), a selective muscarinic M(1)/M(4) receptor cholinergic antagonist, were studied alone and in combination with those of L-DOPA methyl ester (16.7 mg/kg), a selective dopamine D(1) receptor agonist SKF-82958 (74.8 microg/kg), or a selective D(2)/D(3) receptor agonist rotigotine (32 microg/kg) on circling behavior in MPTP induced hemiparkinsonian monkeys. The doses selected were given i.m. in approximately equieffective doses to produce contraversive circling. Biperiden alone with 5% dextrose vehicle produced a slight increase in contraversive circling in a dose related manner. When combined with L-DOPA methyl ester, it enhanced contraversive circling and decreased ipsiversive circling. When biperiden was combined with SKF-82958, contraversive circling also was enhanced and ipsiversive circling decreased. Exactly the opposite was observed with the combination of biperiden and rotigotine. The results indicate a dramatic difference in effects of a prototypic muscarinic M(1)/M(4) receptor cholinergic antagonist in combination with prototypic full dopamine D(1) or D(2)/D(3) receptor agonists. Biperiden interactions with L-DOPA methyl ester were more predominantly D(l) than D(2)/D(3) receptor-like in this animal model of hemiparkinsonism.

Smoking modulation of mu-opioid and dopamine D2 receptor-mediated neurotransmission in humans.

This is a pilot examination of the hypothesis that some of the effects of smoking cigarettes in humans are mediated through nicotine activation of opioid and dopamine (DA) neurotransmission. Neuroimaging was performed using positron emission tomography and the radiotracers [11C]carfentanil and [11C]raclopride, labeling mu-opioid and DA D2 receptors, respectively. Six healthy male smokers were abstinent overnight. After radiotracer administration, subjects smoked two denicotinized cigarettes, followed 45 min later by two average nicotine cigarettes. Dynamic data were acquired over 90 min, and transformed into parametric maps of receptor availability in vivo (binding potential, BP), corresponding to low and high nicotine smoking periods and analyzed on a voxel-by-voxel basis using SPM'99 and correction for multiple comparisons. Significant activation of mu-opioid receptor-mediated neurotransmission from denicotinized to average nicotine conditions was observed in the right anterior cingulate cortex. DA D2 neurotransmission was activated in the ventral basal ganglia, correlating with Fagerström scale nicotine dependence scores. Lower mu-opioid receptor BP was also detected during the denicotinized smoking condition in the smoker group, compared to baseline scans in non-smokers, in the cingulate cortex, thalamus, ventral basal ganglia, and amygdala. These reductions were reversed during the average nicotine condition in the thalamus, ventral basal ganglia and amygdala. These data point to both the feasibility of simultaneously examining opioid and DA neurotransmission responses to smoking in humans, as well as to the need to examine non-nicotine aspects of smoking to more fully understand the behavioral effects of this drug.

Regional cerebral blood flow responses to smoking in tobacco smokers after overnight abstinence.

OBJECTIVE: The purpose of the study was to determine the effects of cigarette smoking on brain regional function in a group of chronic smokers by using cerebral blood flow (CBF) measures and positron emission tomography (PET). METHOD: Nineteen tobacco smokers were studied after about 12 hours of smoking abstinence. Regional CBF (rCBF) measures were obtained with PET and [15O]H2O in six consecutive scans. Two average-nicotine-yield (1.0 mg) and one denicotinized (0.08 mg) research cigarettes with similar tar yields (9.5 mg and 9.1 mg, respectively) were smoked in a double-blind design, preceded and followed by baseline scans. The rCBF effects of smoking were compared to baseline measures and between cigarettes, as well as to subjective ratings of craving for cigarettes. RESULTS: Smoking the first cigarette of the day resulted in increases in rCBF in the visual cortex and the cerebellum and reductions in the anterior cingulate, the right hippocampus, and the ventral striatum, including the nucleus accumbens. Cigarette craving scores correlated with rCBF changes in the dorsal anterior cingulate and right hippocampus. Less pronounced effects were observed with the second cigarette and the denicotinized cigarette. CONCLUSIONS: Smoking affects rCBF not only in areas of the brain rich in nicotinic cholinergic receptors but also in areas implicated in the rewarding effects of drugs of abuse. Furthermore, craving for a cigarette in chronic smokers was correlated with rCBF in the right hippocampus, an area involved in associating environmental cues with drugs, and in the left dorsal anterior cingulate, an area implicated in drug craving and relapse to drug-seeking behavior.

Changes in craving for a cigarette and arterial nicotine plasma concentrations in abstinent smokers.

Although the relationship between nicotine and changes in heart rate and blood pressure has been demonstrated, the relationship between nicotine and subjective effects such as decreased craving, relaxation, sickness, and decreased nervousness, is less well delineated. In this study, arterial nicotine levels were drawn in 21 smokers who smoked two average nicotine (AN) cigarettes and one low nicotine (LN) cigarette. Craving for a cigarette, relaxation, sickness, and decreased nervousness were rated on a visual analog scale (VAS) before and after smoking each cigarette. None of these subjective measures except craving for a cigarette was changed significantly by smoking. The change in craving was significantly correlated with the area under the plasma nicotine concentration versus time curve (r = -0.57, p = 0.01) calculated from the arterial nicotine samples drawn up to 20 min after the initiation of smoking the first AN cigarette. Although well-documented behavioral manipulations, such as smoking denicotinized cigarettes, reduce craving, increases in plasma arterial nicotine concentrations after smoking the first cigarette of the day also reduce craving. Both the psychology and pharmacology of nicotine/tobacco smoking are involved in craving reduction.

Regional cerebral blood flow and plasma nicotine after smoking tobacco cigarettes.

The hypothesis for this research is that only in some brain areas, regional cerebral blood flow (rCBF) after tobacco smoking is correlated with arterial plasma nicotine concentrations. Twenty-one healthy adult tobacco smokers of both genders were studied after overnight tobacco abstinence. H(2)15O water was used to measure rCBF. Six separate scans were taken about 12 min apart with the subjects' eyes closed and relaxed. Research tobacco cigarettes smoked were of average (1.0 mg) and low (0.08 mg) nicotine but similar tar yield (9.5 and 9.1 mg). Increases in normalized rCBF were obtained in the occipital cortex, cerebellum, and thalamus, and decreases in the anterior cingulate, nucleus accumbens, amygdala, and hippocampus immediately after smoking the first average nicotine yield cigarette of the morning. After smoking the second average nicotine yield cigarette, the effects were less than smoking the first. Low-nicotine cigarettes produced fewer changes in rCBF than those after the first average cigarette. As expected, statistically significant correlations were found between increases in arterial plasma nicotine and HR. Correlations with arterial nicotine on rCBF were statistically significant in brain areas with the greatest changes in relative blood flow such as the cerebellum and occipital cortex. Nicotine delivery by tobacco smoking is only one of the factors, which contribute to changes in rCBF.

Effects of (+/-)-idazoxan alone and in combination with L-DOPA methyl ester in MPTP-induced hemiparkinsonian monkeys.

The effects of a combination of the alpha2-adrenergic receptor antagonist (+/-)-idazoxan with L-DOPA methyl ester were examined in three of four female adult monkeys (Macaca nemestrina) rendered hemiparkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). (+/-)-Idazoxan (0.16, 0.63, and 1.0 mg/kg) was given i.m. 10 min before L-DOPA methyl ester (12.5 mg/kg). (+/-)-Idazoxan reduced the maximum peak of contralateral circling elicited during the first hour following injection of L-DOPA methyl ester, but prolonged the duration of the circling response up to 50% (p < 0.05). The data support a role for alpha2-adrenergic receptor mechanisms in modulating the effects of L-DOPA on nigrostriatal dopamine function in the MPTP monkey model of hemiparkinsonism.

Comparative American and Japanese tobacco smoke uptake parameters after overnight tobacco deprivation.

American and Japanese overnight deprived tobacco smokers were compared with respect to expired CO, plasma nicotine and cotinine, and red cell carboxyhemoglobin. The participants were 51 of 59 American and 55 of 86 Japanese cigarette smokers of mixed gender who met similar strict criteria. Female and male American tobacco smokers were similar in mean age, number of cigarettes smoked per day, machine-rated nicotine and tar yield per cigarette and per 24 h plasma cotinine, calculated previous 24 h nicotine dose, and exhaled CO. Only mean plasma nicotine levels were significantly higher in American females. American and Japanese female smokers had similar tobacco uptake parameters. American and Japanese male smokers differed; the latter had higher plasma nicotine and lower cotinine levels as well as calculated 24 h dose of nicotine and lower exhaled CO. Japanese females and males were similar in all tobacco smoke uptake parameters. When the two racial groups were compared, irrespective of gender, the only statistically significant differences were lower mean exhaled CO levels and percent COHb in the Japanese. It is concluded that Japanese males inhale cigarettes in moderation compared to Americans. The results are discussed in relation to known ethnic, social, and genetic differences in CYP2A6 gene polymorphism.

Clinical phenotyping strategies in selection of tobacco smokers for future genotyping studies.

Various behavioral and chemical measures were studied as potential simplified phenotyping techniques in overnight abstinent tobacco smokers. Irrespective of the machine-rated nicotine delivery (yield) of the cigarette used, there was a statistically significant correlation between the number of cigarettes consumed per day and overnight abstinence plasma cotinine concentration (r=.88) and its calculated nicotine dose per day (r=.88). Exhaled carbon monoxide (CO) levels correlated well with the number of cigarettes smoked (r=.83) and the Fagerström dependence scores (r=.85). The greater the Fagerström scores, the greater the daily cigarette consumption and plasma cotinine concentrations. After overnight abstinence, the baseline mean+/-S.D. heart rate was 62.9+/-10.0/min, the systolic blood pressure was 115.6+/-13.3 mm Hg and the diastolic blood pressure was 67.1+/-10.9 mm Hg. There were no statistically significant gender differences. Persons who were outliers on any measure are potential candidates for future genotyping studies. Preliminary guidelines of what is needed are described.

Comparative effects of tobacco smoking and nasal nicotine.

OBJECTIVE: Compare the electroencephalographic (EEG) and cardiovascular effects of tobacco smoking and nasal nicotine in the same subjects. METHODS: Eleven volunteer smokers were studied after >10 h of overnight tobacco deprivation. Quantitative EEG was used to measure brain electrical changes produced by four different treatments. Each subject smoked a low (0.08 mg) and average nicotine (1 mg) yield cigarette on one test day and received placebo and nicotine nasal spray (0.5 mg/spray) on a second day in a counterbalanced design. EEG activity was measured from 16 scalp electrodes and analyzed as delta, theta, alpha (1), alpha (2), beta (1), and beta (2) frequency bands. Heart rate (HR), blood pressure (BP), and plasma venous nicotine concentrations (VNC) were monitored during both sessions. EEG data from all 16 channels at each of six frequencies were compared over 10 min using repeated measures ANOVA analysis. Changes in HR, BP, and VNC from baseline were compared using ANOVA followed by post hoc Scheffe's test. RESULTS: Smoking an average nicotine delivery cigarette resulted in highly significant decreases in alpha (1) activity, significant increases in alpha (2) activity, and significant increases in both HR and VNC compared to all other conditions. CONCLUSION: When smokers are allowed to pace themselves, cigarette smoking is far more effective than nasal nicotine in activating the EEG and increasing HR and VNC. This lack of equivalent physiological effects may explain the low success rate when nicotine nasal spray is used by those trying to quit smoking.