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.

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.

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.

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.

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.

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.

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.

Direct electron transfer from pseudoazurin to nitrous oxide reductase in catalytic N2O reduction.

Pseudoazurin (PAz), a well-characterized blue copper electron-transfer protein, is shown herein to be capable of mediating electron transfer to the nitrous oxide reductase (N(2)OR) from Achromobacter cycloclastes (Ac). Spectroscopic measurements demonstrate that reduced PAz is efficiently re-oxidized by a catalytic amount of N(2)OR in the presence of N(2)O. Fits of the kinetics resulted in K(M) (N(2)O) and k(cat) values of 19.1±3.8 µM and 89.3±4.2s(-1) respectively. The K(M) (PAz) was 28.8±6.6 µM. The electrochemistry of Ac pseudoazurin (AcPAz) in the presence of Ac nitrous oxide reductase (AcN(2)OR) and N(2)O displayed an enhanced cathodic sigmoidal current-potential curve, in excellent agreement with the re-oxidation of reduced AcPAz during the catalytic reduction of N(2)O by AcN(2)OR. Modeling the structure of the AcPAz-AcN(2)OR electron transfer complex indicates that AcPAz binds near Cu(A) in AcN(2)OR, with parameters consistent with the formation of a transient, weakly-bound complex. Multiple, potentially efficient electron-transfer pathways between the blue-copper center in AcPAz and Cu(A) were also identified. Collectively, the data establish that PAz is capable of donating electrons to N(2)OR in N(2)O reduction and is a strong candidate for the physiological electron donor to N(2)OR in Ac.