Tobacco Smoking and Brain Endogenous Opioid Release: More Than Nicotine Alone.

INTRODUCTION: The effects of smoking denicotinized (denic) and average nicotine (avnic) tobacco cigarettes were studied on brain mu opioid receptor binding by positron emission tomography with 11C carfentanil. The results indicated the importance of physiological and psychological effects induced by denic smoking. METHODS: Regional mu opioid binding potential (nondisplaceable binding potential, BPND) was measured in 20 adult male overnight abstinent chronic tobacco smokers. The denic sessions were conducted about 8:00 am followed by avnic sessions about 2 hours later. Venous plasma nicotine levels and scores of craving to smoke were assessed before and after each smoking session. Fagerstrom scores of nicotine dependence were determined. Pearson's and Spearman's correlation tests were used to examine associations between BPND and other smoking parameters. RESULTS: Surprisingly, the very low plasma nicotine peak levels after denic smoking (mean ± SD: 3.3 ± 1.8 ng/mL) were significantly correlated with BPND after denic and avnic smoking. Equally surprising no association was found between nicotine levels after avnic smoking and BPND. Delta craving scores and Fagerstrom scores were correlated with both BPND after denic and avnic in several brain regions. CONCLUSIONS: Very small amounts of nicotine, psychological and behavioral effects of denic smoking appear to have important actions on the endogenous mu opioid system. IMPLICATIONS: Associations between very low venous plasma nicotine levels after denic smoking and regional brain mu opioid receptor availability are a surprising "placebo" effect. Delta craving and Fagerstrom scores were correlated with BPND in several brain regions including amygdala, hippocampus, insula, nucleus accumbens, putamen, and ventral striatum. This study is limited by modest Power (mean 1 - ß = 0.6) for all correlation analyses.

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.

The association between BDNF C270T genetic variants and smoking in patients with mental disorders and in healthy controls.

Studies investigating the association between smoking and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reported inconclusive results, while the studies on the association of smoking status with BDNF C270T polymorphism are missing. We aimed to determine the association of smoking and BDNF Val66Met and C270T genetic variants in control subjects and patients with mental disorders. This study included 3502 Caucasian subjects: 918 healthy controls and 2584 patients with mental disorders (519 individuals with posttraumatic stress disorder (PTSD), 419 patients with depression, 996 patients with schizophrenia, and 650 patients with alcohol dependence). The frequency of the BDNF Val66Met and C270T variants were presented in codominant, dominant and recessive models. BDNF C270T, but not BDNF Val66Met polymorphism, was significantly associated with smoking in all groups, since the presence of the C270T T allele was more frequently found in smokers compared to non-smokers. Significant predictors of smoking were sex, age and BDNF C270T genetic variants. However, after detailed analysis of the separate diagnostic entities, the significant association of BDNF C270T polymorphism was confirmed only in healthy subjects, but not in patients with mental disorders; and was not related to number of cigarettes smoked per day. In patients with alcohol dependence, the severity of smoking was significantly associated with BDNF Val66Met variants. This is a first report of the significant association between the BDNF C270T polymorphism and smoking status in the large groups of Caucasian cases/controls.

5-Hydroxytryptophan attenuates somatic signs of nicotine withdrawal.

Abrupt nicotine cessation after chronic use disrupts monoaminergic systems and causes withdrawal signs/symptoms. In this study, the precursor of serotonin 5-hydroxytryptophan (5-HTP) relieved nicotine withdrawal signs. (-)-Nicotine bitartrate or equimolar sodium tartrate was infused into each rat via a s.c. osmotic minipump for 7 days. Somatic abstinence signs (teeth-chattering/chews and shakes, etc.) were counted one day after pump removal. Somatic signs were attenuated by the i.p. injection of 5-HTP, but not by NSD-1015, a centrally-acting L-aromatic amino acid decarboxylase inhibitor, indicating that 5-HTP mitigates somatic signs mainly through its conversion to 5-HT.

Taming the ketamine tiger. 1965.

Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were determined in 20 volunteers from a prison population. The results indicate that this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0 mg per kilogram. With intravenous administration the onset of action is within 1 min and the effects last for about 5 to 10 min, depending on dosage level and individual variation. No tachyphylaxis was evident on repeat doses. Respiratory depression was slight and transient. Hypertension, tachycardia, and psychic changes are undesirable characteristics of the drug. Whether these can be modified by preanesthetic medication was not determined in this study. Recovery from analgesia and coma usually took place within 10 min, although from electroencephalographic evidence it may be assumed that subjects were not completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity was obtained. CI-581 produces pharmacologic effects similar to those reported for phencyclidine, but of shorter duration. The drug deserves further pharmacologic and clinical trials. It is proposed that the words "dissociative anesthetic" be used to describe the mental state produced by this drug.

Ketamine's dose related multiple mechanisms of actions: Dissociative anesthetic to rapid antidepressant.

Ketamine induces safe and effective anesthesia and displays unusual cataleptic properties that gave rise to the term dissociative anesthesia. Since 1970, clinicians only utilized the drug as an anesthetic or analgesic for decades, but ketamine was found to have rapid acting antidepressant effects in 1990s. Accumulated evidence exhibits NMDAR antagonism may not be the only mechanism of ketamine. The contributions of AMPA receptor, mTor signal pathway, monoaminergic system, sigma-1 receptor, cholinergic, opioid and cannabinoid systems, as well as voltage-gated calcium channels and hyperpolarization cyclic nucleotide gated channels are discussed for the antidepressant effects. Also the effects of ketamine's enantiomers and metabolites are reviewed. Furthermore ketamine's anesthetic and analgesic mechanisms are briefly revisited. Overall, pharmacology of ketamine, its enantiomers and metabolites is very unique. Insight into multiple mechanisms of action will provide further development and desirable clinical effects of ketamine.

Significant association of mu-opioid receptor 1 haplotype with tobacco smoking in healthy control subjects but not in patients with schizophrenia and alcohol dependence.

Tobacco smoking is highly prevalent in patients with schizophrenia and alcohol dependence. The underlying neurobiology of nicotine addiction is complex. Rewarding effects of nicotine from cigarettes are associated, among others, with mu-opioid receptors encoded by the OPRM1 gene. The aim of the study was to evaluate the association between two OPRM1 gene polymorphisms, rs1799971 and rs510769, and tobacco smoking in Caucasian patients with schizophrenia, alcohol dependence, and healthy control subjects. The study included 1058 Caucasians (277 patients with schizophrenia, 359 patients with alcohol dependence, and 422 healthy control subjects), subdivided according to the nicotine dependence into smokers (i.e. current smokers) and non-smokers. A significant association was found between the GC haplotype (OPRM1 rs1799971 and rs510769) and smoking in healthy controls, but not in patients with schizophrenia and alcohol dependence. A nominal association was detected in all cases/controls, but this significance did not survive the correction for the multiple testing. This is the first study to reveal that nicotine dependence is associated with the GC haplotype of the OPRM1 rs1799971 and rs510769 in all subjects or specifically in healthy controls. These results did not confirm the strong connection between OPRM1 polymorphisms and nicotine dependence in schizophrenia or alcohol dependence.

Estimation of D2-like receptor occupancy by dopamine in the putamen of hemiparkinsonian Monkeys.

To advance understanding of the neurochemical changes in Parkinson's disease (PD), we compared D2-like dopamine receptor occupancy by dopamine in the control and lesioned putamen of four pig-tailed macaques treated unilaterally with MPTP. PET and in vitro binding techniques were used to measure binding potential (BP(*)) and density of D2-like dopamine receptors (B(max)), respectively. As would be expected in PD, relatively higher values of BP(*) and B(max) and less amphetamine-induced decrease in [(11)C]raclopride binding were observed in the lesioned compared with the contralateral putamen in each animal. The percent differences between lesioned and contralateral sides were similar whether the measurements were of [(11)C]raclopride BP(*) or B(max) values, measured in vivo and in vitro, respectively. As [(11)C]raclopride BP(*) is a measure of the density of D2-like dopamine receptors available for radioligand binding (i.e., not occupied by dopamine), these findings suggest that the fractional occupancy of receptors by endogenous dopamine in the lesioned putamen is nearly equal to that in the contralateral putamen. Therefore, the absolute number of receptors occupied by dopamine, which is a product of receptor density and fractional occupancy by dopamine, is greater in the lesioned than in the contralateral putamen. One possible explanation for the lack of differences in fractional occupancy of D2 receptors by dopamine (despite a loss in available dopamine) is a lesion-induced increase in a portion of low-affinity D2 receptors to a state of high affinity for dopamine.

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.

Tobacco/nicotine and endogenous brain opioids.

Smoking is a major public health problem with devastating health consequences. Although many cigarette smokers are able to quit, equal numbers of others cannot! Standard medications to assist in smoking cessation, such as nicotine replacement therapies and bupropion, are ineffective in many remaining smokers. Recent developments in the neurobiology of nicotine dependence have identified several neurotransmitter systems that may contribute to the process of smoking maintenance and relapse. These include: especially dopamine, but also norepinephrine, 5-hydroxytryptamine, acetylcholine, endogenous opioids, gamma-aminobutyric acid (GABA), glutamate, and endocannabinoids. The present review examines the limited contribution of the endogenous opioid system to the complex effects of nicotine/tobacco smoking.

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.

Genetic Variation of the Mu Opioid Receptor (OPRM1) and Dopamine D2 Receptor (DRD2) is Related to Smoking Differences in Patients with Schizophrenia but not Bipolar Disorder.

It is not known why mentally ill persons smoke excessively. Inasmuch as endogenous opioid and dopaminergic systems are involved in smoking reinforcement, it is important to study mu opioid receptor (OPRM1) A118G (rs1799971), dopamine D2 receptor (DRD2) Taq1A (rs1800497) genotypes, and sex differences among patients with schizophrenia or bipolar disorder. Smokers and nonsmokers with schizophrenia (n=177) and bipolar disorder (n=113) were recruited and genotyped. They were classified into three groups: current smoker, former smoker, and never smoker by tobacco smoking status self-report. The number of cigarettes smoked per day was used as the major tobacco smoking parameter. In patients with schizophrenia, tobacco smoking prevalence was greater in males than in females as expected, but women had greater daily cigarette consumption (p<0.01). Subjects with schizophrenia who had the OPRM1 *G genotype smoked more cigarettes per day than the AA allele carriers with schizophrenia (p<0.05). DRD2 Taq1A genotype differences had no effect on the number of cigarettes smoked per day. However, female smokers with schizophrenia who were GG homozygous of the DRD2 receptor smoked more than the *A male smokers with schizophrenia (p<0.05). In bipolar patients, there were no OPRM1 and DRD2 Taq1A genotype differences in smoking status. There also were no sex differences for smoking behavior among the bipolar patients. The results of this study indicate that single nucleotide polymorphism (SNP) of the less functional mu opioid receptor increases tobacco smoking in patients with schizophrenia. Alteration of DRD2 receptor function also increased smoking behavior in females with schizophrenia.

Cortisol in schizophrenia: No association with tobacco smoking, clinical symptoms or antipsychotic medication.

Cigarette smoking is associated with higher cortisol levels in healthy subjects. In schizophrenia this relationship is not clear. There are divergent results on the association between cortisol with smoking, clinical symptoms and medication in schizophrenia. This study evaluated this association in 196 Caucasian inpatients with schizophrenia (51.30±26.68years old), subdivided into 123 smokers and 73 non-smokers. Basal salivary cortisol levels were measured twice, at 08.00 and 09.00AM, 90-120min after awakening. The effect of smoking on cortisol was evaluated according to current smoking status, the number of cigarettes/day and the nicotine addiction intensity. The influence of clinical symptoms and/or antipsychotic medication on cortisol was determined using the Positive and Negative Syndrome Scale (PANSS), and chlorpromazine equivalent doses. Non-smokers were older, received lower doses of antipsychotics, had higher PANSS scores, and had longer duration of illness than smokers. Salivary cortisol was similar in schizophrenic patients subdivided according to the smoking status, the number of cigarettes/day and nicotine addiction intensity. No significant correlation was found between salivary cortisol and PANSS scores, chlorpromazine equivalent doses, age of onset or the duration of illness. The findings revealed no association between salivary cortisol and smoking, nicotine addiction intensity, or clinical symptoms. Our preliminary data showed no correlation between salivary cortisol and chlorpromazine equivalent doses and/or antipsychotic medication. Our findings suggest that smoking does not affect the cortisol response in schizophrenic patients as it has been shown in healthy individuals. Future studies should investigate a possible desensitization of the stress system to smoking.

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 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.

Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys.

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D(1)R binding is increased, whereas D(2)R binding is not.

Nicotine normalizes increased prefrontal cortical dopamine D1 receptor binding and decreased working memory performance produced by repeated pretreatment with MK-801: a PET study in conscious monkeys.

The effects of acute nicotine were determined on dopamine (DA) D(1) (D(1)R) and D(2) (D(2)R) receptor binding in the neocortex of conscious monkeys under control conditions as well as after chronic pretreatment with MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Extrastriatal neocortical D(1)R and D(2)R binding was evaluated with [(11)C]NNC112 and [(11)C]FLB457 with high-specific radioactivity using positron emission tomography (PET). Acute administration of nicotine bitartrate, given as an intravenous (i.v.) bolus plus infusion for 30 min at doses of 32 microg/kg+0.8 microg/kg/min or 100 microg/kg+2.53 microg/kg/min as base, induced slight but significant dose-dependent increases of DA in the extracellular fluid of prefrontal cortex (PFC) as determined by microdialysis. However, acute nicotine did not affect either [(11)C]NNC112 or [(11)C]FLB457 binding to D(1)R or D(2)R, respectively, in any cortical region. Chronic MK-801 (0.03 mg/kg, intramuscularly (i.m.), twice daily for 13 days) increased [(11)C]NNC112 binding to D(1)R in PFC. No significant changes were detected in [(11)C]FLB457 binding to PFC D(2)R. Although chronic MK-801 lowered baseline DA and glutamate levels in PFC, acute nicotine normalized reduced DA to control levels. Acute nicotine dose-dependently normalized the increased binding of [(11)C]NNC112 to D(1)R produced by chronic MK-801 but [(11)C]FLB457 binding to PFC D(2)R did not change. Working memory performance, impaired after chronic MK-801, was partially improved by acute nicotine. These results demonstrate that acute nicotine normalizes MK-801-induced PFC abnormality of D(1)R in PFC.

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.

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.

N-methyl-D-aspartate antagonists as drug models of schizophrenia: a surprising link to tobacco smoking.

The pros and cons of N-methyl-D-aspartate (NMDA) antagonists as drug models of schizophrenia are discussed in relation to the neuropathology of this complex mental spectrum of diseases. The role of acetylcholine, dopamine, gamma aminobutyric acid, glutamic acid, and serotonin emphasizes that multiple neurotransmitter system abnormalities are involved, even though current drug therapy involves primarily dopamine (D(2))/serotonin (5 HT(2)) antagonists. Only some of the fundamental aspects of schizophrenia are replicated by NMDA receptor antagonists of glutamic acid. Subchronic NMDA antagonism in an animal model results in decreased levels of dopamine in prefrontal cortex and increased D(1) receptor binding. The results of PET studies of schizophrenic patients imply decreased dopamine levels in their prefrontal cortex. Tobacco-smoking schizophrenic patients transiently normalize prepulse inhibition. Nicotine appears to be one factor that may help explain some of these phenomena.