Effects of Cd vacancies and unconventional spin dynamics in the Dirac semimetal Cd3As2.

Cd3As2 is a Dirac semimetal that is a 3D analog of graphene. We investigated the local structure and nuclear-spin dynamics in Cd3As2 via 113Cd NMR. The wideline spectrum of the static sample at 295 K is asymmetric and its features are well described by a two-site model with the shielding parameters extracted via Herzfeld-Berger analysis of the magic-angle spinning spectrum. Surprisingly, the 113Cd spin-lattice relaxation time (T1) is extremely long (T1 = 95 s at 295 K), in stark contrast to conductors and the effects of native defects upon semiconductors; but it is similar to that of 13C in graphene (T1 = 110 s). The temperature dependence of 1/T1 revealed a complex bipartite mechanism that included a T2 power-law behavior below 330 K and a thermally activated process above 330 K. In the high-temperature regime, the Arrhenius behavior is consistent with a field-dependent Cd atomic hopping relaxation process. At low temperatures, a T2 behavior consistent with a spin-1/2 Raman-like process provides evidence of a time-dependent spin-rotation magnetic field caused by angular oscillations of internuclear vectors due to lattice vibrations. The observed mechanism does not conform to the conventional two-band model of semimetals, but is instead closer to a mechanism observed in high-Z element ionic solids with large magnetorotation constant [A. J. Vega et al., Phys. Rev. B 74, 214420 (2006)].

Impact of a multicomponent screening, brief intervention, and referral to treatment (SBIRT) training curriculum on a medical residency program.

BACKGROUND: Substance-related disorders are a growing problem in the United States. The patient-provider setting can serve as a crucial environment to detect and prevent at-risk substance use. Screening, brief intervention, and referral to treatment (SBIRT) is an integrated approach to deliver early intervention and treatment services for persons who have or are at risk for substance-related disorders. SBIRT training components can include online modules, in-person instruction, practical experience, and clinical skills assessment. This paper will evaluate the impact of multiple modes of training on acquisition of SBIRT skills as observed in a clinical skills assessment. METHODS: Residents were part of an SBIRT training program, from 2009 through 2013, consisting of lecture, role-play, online modules, patient encounters, and clinical skills assessment (CSA). Differences were assessed across satisfactory and unsatisfactory CSA performance. RESULTS: Seventy percent of the residents satisfactorily completed CSA. Demographics, type of components completed, and number of components completed were similar among residents who demonstrated satisfactory clinical skills compared with those who did not. All components of the training program were accepted equally across specialties and resident matriculation cohorts. CONCLUSION: The authors conclude that the components employed in SBIRT training do not have to be numerous or of a particular mode of training in order to see observable demonstration of SBIRT skills among medical residents. Thus, residency educators who have limited time or resources may utilize as few as 1 mode of training to effectually disseminate SBIRT skills among health care providers. As SBIRT continues to evolve as a promising tool to address at-risk substance-related disorders, it is critical to train medical residents and other health professionals.

Evaluation of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in African Americans.

INTRODUCTION: The relationship between alcohol dehydrogenase (ADH) polymorphisms and alcohol use disorders in populations of African descent has not been clearly established. This study examined the effect of ADH1B polymorphisms on alcohol metabolism and subjective response, following intravenous (IV) alcohol administration, and the influence of gender, recent drinking history, and family history of alcoholism (FHA), in nondependent African American drinkers. MATERIALS: The sample included eighty-seven 21- to 35-year-old, light social drinkers of African descent. Participants included 39 sib pairs, 2 sibships with 3 siblings each, and 3 individuals who were not part of a sibship. Participants received infusions via the use of the clamp method that refers to the goal of controlling breath alcohol concentration in 2 randomized sessions at 0.06 g% ethanol and 0 mg% (placebo), and a battery of subjective scales at predefined time points. Dependent measures included alcohol elimination rates (AERs), alcohol disappearance rates (ADRs), subjective measures peak scores, and area under the curve. General linear model and mixed models were performed to examine the relationship between ADH1B genotype, dependent measures, and influence of covariates. RESULTS: Participants with ADH1B1/1 genotypes showed higher number of drinks (p = 0.023) and drinks per drinking day (p = 0.009) compared with the persons with ADH1B1/3 genotype. AER (adjusted for body weight) was higher in ADH1B*1 homozygotes (p = 0.045) compared with ADH1B1/3 heterozygotes. ADR differed significantly between males and females (p = 0.002), regardless of body weight (p = 0.004) and lean body mass (p < 0.001) adjustments. Although a few subjective measures differed across genotype, all measures were higher in alcohol sessions compared with placebo sessions (p < 0.001). These observations were mediated by drinks per drinking day, gender, and FHA. CONCLUSIONS: ADH1B polymorphism had a marginal effect on alcohol pharmacokinetics following IV alcohol administration in nondependent drinkers of African descent. Session (alcohol vs. placebo) and ADH1B genotype did, however, influence subjective response to alcohol with some variation by gender, FHA, and drinks per drinking day.

NMR probe of metallic states in nanoscale topological insulators.

A 125Te NMR study of bismuth telluride nanoparticles as a function of particle size revealed that the spin-lattice relaxation is enhanced below 33 nm, accompanied by a transition of NMR spectra from the single to the bimodal regime. The satellite peak features a negative Knight shift and higher relaxivity, consistent with core polarization from p-band carriers. Whereas nanocrystals follow a Korringa law in the range 140-420 K, micrometer particles do so only below 200 K. The results reveal increased metallicity of these nanoscale topological insulators in the limit of higher surface-to-volume ratios.

Alcohol dependence and health care utilization in African Americans.

OBJECTIVE: Ethnic and cultural differences in patterns of alcohol use disorders must be understood in order to address improvement in prevention of such disorders and accessibility to health care services. The purpose of this study was to evaluate factors that influence the utilization of medical and mental health services among alcohol-dependent and non-alcohol-dependent African Americans. METHOD: A cohort of 454 African Americans was evaluated. Alcohol-dependent participants were recruited from various inpatient treatment facilities in the Washington, DC, metropolitan area and through advertisement and word of mouth. Non-alcohol-dependent participants were recruited by advertisements. Each participant was administered the Semi-Structured Assessment for the Genetics of Alcoholism to assess alcohol dependency and the Family History Assessment module to access family history of alcoholism. Xl Test and analysis of variance were used to analyze the data. RESULTS: Alcohol dependence was more prevalent among men, those with lower income, those with less education, and they utilized mental health counseling as opposed to medical-based therapy. Increased reports of medical conditions such as migraine (p<.001), loss of consciousness (p=.001), and sexually transmitted diseases: (p<.001) were also associated with alcohol dependency. Other factors, including visits to inpatient treatment programs, were directly related to incidence of alcohol dependency regardless of gender status (p<.001). CONCLUSIONS: This study suggests an association exists among alcohol dependence, medical conditions, health care, and mental care utilization among African Americans. Future research may benefit from investigating if an association exists between alcohol use disorders and health care utilization for other ethnic groups.

Screening, brief intervention, and referral to treatment: public health training for primary care.

OBJECTIVES: The purpose of this study was to elucidate changes in attitudes, experiences, readiness, and confidence levels of medical residents to perform screening, brief intervention, and referral to treatment (SBIRT) and factors that moderate these changes. METHODS: A cohort of 121 medical residents received an educational intervention. Self-reported experience, readiness, attitude, and confidence toward SBIRT-related skills were measured at baseline and at follow-up. Analyses were conducted to evaluate the effects of medical specialization. RESULTS: The intervention significantly increased experience (P<.001), attitude (P<.05), readiness (P<.001), and confidence (P<.001). Residents were more likely to report that their involvement influenced patients' substance use. However, experience applying SBIRT skills varied by country of birth, specialty, and baseline scores. CONCLUSIONS: This study suggested that SBIRT training was an effective educational tool that increased residents' sense of responsibility. However, application of skills might differ by specialization and other variables. Future studies are needed to explore and evaluate SBIRT knowledge obtained, within the context of cultural awareness and clinical skills.

Institutional incorporation of screening, brief intervention, and referral to treatment (SBIRT) in residency training: achieving a sustainable curriculum.

The success of implementing a screening, brief intervention and referral to treatment (SBIRT) program within a medical residency program for sustainability is contingent upon a well-crafted training curriculum that incorporates substance abuse education and clinical practice skills. The goal of the Howard University (HU) SBIRT program is to train residents in providing culturally competent evidence-based screening, brief intervention and referral to treatment for patients who have a substance use disorder or who are at risk for developing the disorder. Utilizing the Office of Graduate Medical Education (GME) allows all residents to be trained in SBIRT techniques and receive continuing education in SBIRT and SBIRT-related topics through new resident orientation and the core lecture series. The utilization of Graduate Medical Education office has allowed a robust SBIRT training program to be implemented into medical residency education, contributing to the sustainability of SBIRT as a component of patient care.

The 5-HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent.

Covault et al. [Covault et al. (2007); Biol Psychiatry 61(5): 609-616] reported that the common functional polymorphism, 5-HTTLPR, in the serotonin transporter gene moderated the association between past-year stressful events and daily reports of drinking in a sample of European-American (EA) college students. We examined this effect in college students of African descent. Students recruited at a Historically Black University (n = 564) completed web-based measures of past-year stressful life experiences and daily reports of drinking and heavy drinking over a 30-day period. Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism and dichotomized as low-activity S' allele carriers or high-activity L' homozygotes. Generalized linear models were used to examine the effects of life stress, genotype, and their interaction on the two drinking measures. In students who completed 15 or more daily surveys (n = 393), there was a significant interaction of past-year stressful events, 5-HTTLPR genotype, and gender on the number of drinking days (P = 0.002). Similar findings were obtained in relation to heavy drinking days (P = 0.007). Men showed a main effect of past-year stressful events on both drinking outcomes (P's < 0.001), but no main or moderator effects of genotype. In women, the S' allele moderated the impact of past-year life stressors on the frequency of drinking and heavy drinking days (P's < 0.001). In college students of African descent, past-year stressful events were associated with more frequent drinking and heavy drinking, an effect that was moderated by the 5-HTTLPR polymorphism. However, in contrast to the findings in EA students, in the current sample, 5-HTTLPR moderated the association only among women.

Effects of an educational intervention on female biomedical scientists' research self-efficacy.

Women and people of color continue to be underrepresented among biomedical researchers to an alarming degree. Research interest and subsequent productivity have been shown to be affected by the research training environment through the mediating effects of research self-efficacy. This article presents the findings of a study to determine whether a short-term research training program coupled with an efficacy enhancing intervention for novice female biomedical scientists of diverse racial backgrounds would increase their research self-efficacy beliefs. Forty-three female biomedical scientists were randomized into a control or intervention group and 15 men participated as a control group. Research self-efficacy significantly increased for women who participated in the self-efficacy intervention workshop. Research self-efficacy within each group also significantly increased following the short-term research training program, but cross-group comparisons were not significant. These findings suggest that educational interventions that target sources of self-efficacy and provide domain-specific learning experiences are effective at increasing research self-efficacy for women and men. Further studies are needed to determine the longitudinal outcomes of this effort.

Microbial quality of surface water and subsurface soil after wildfire.

Runoff from wildfire affected areas typically carries high concentrations of fine burned residues or eroded sediment and deposits them in surface water bodies or on subsurface soils. Although the role of wildfire residues in increasing the concentration of chemical contaminants in both environments is known, whether and to what degree wildfire residues may affect microbial contaminants is poorly understood. To examine the effect of wildfire residues on growth and die-off of Escherichia coli (E. coli) -a pathogen indicator, we mixed stormwater with E. coli and suspended particles from the pre- and post-wildfire area in batch reactors and monitored E. coli concentration. E. coli grew initially in the presence of all particles, but the relative E. coli concentration was 10 times lower in the presence of wildfire residues than in natural soil from unaffected areas. Wildfire residues also decreased the persistence of E. coli during a 15-day incubation period. These results indicate that the growth or persistence of E. coli in surface water in the presence of wildfire residues was less than that in the presence of unburned soil particles, potentially due to depletion of nutrient concentration and/or loss of viability of bacteria in the presence of wildfire residues. To examine the transport potential of wildfire residues and their ability to facilitate the transport of E. coli in the subsurface system, suspensions containing wildfire residues and/or E. coli were injected through unsaturated sand columns-a model subsurface system. Transport of wildfire residues in sand columns increased with decreases in the depth and increases in the concentration of particles, but increased transport of wildfire residues did not result in the increased transport of E. coli, suggesting wildfire residues do not facilitate the transport of E. coli. Overall, the results indicate that wildfire residues may not increase the risk of the microbial contamination of surface water or groundwater via subsurface infiltration.

Author Correction: A cell-free platform for the prenylation of natural products and application to cannabinoid production.

In the original version of this Article, the genotype of the M30 mutant presented in Fig. 3b was given incorrectly as Y288V/A232S, and the M31 mutant was given incorrectly as M1/A232S. The correct genotype of the M30 mutant is Y288A/A232S and for M31 it is Y288V/A232S. In addition, to keep consistency in genotype formatting, the genotype of the M27 mutant should be Y288V/G286S. The errors have been corrected in both the PDF and HTML versions of the Article.

A cell-free platform for the prenylation of natural products and application to cannabinoid production.

Prenylation of natural compounds adds structural diversity, alters biological activity, and enhances therapeutic potential. Because prenylated compounds often have a low natural abundance, alternative production methods are needed. Metabolic engineering enables natural product biosynthesis from inexpensive biomass, but is limited by the complexity of secondary metabolite pathways, intermediate and product toxicities, and substrate accessibility. Alternatively, enzyme catalyzed prenyl transfer provides excellent regio- and stereo-specificity, but requires expensive isoprenyl pyrophosphate substrates. Here we develop a flexible cell-free enzymatic prenylating system that generates isoprenyl pyrophosphate substrates from glucose to prenylate an array of natural products. The system provides an efficient route to cannabinoid precursors cannabigerolic acid (CBGA) and cannabigerovarinic acid (CBGVA) at >1 g/L, and a single enzymatic step converts the precursors into cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA). Cell-free methods may provide a powerful alternative to metabolic engineering for chemicals that are hard to produce in living organisms.

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.

Disruption of agonist and ligand activity in an AMPA glutamate receptor splice-variable domain deletion mutant.

The mechanisms by which agonists and other ligands bind ligand-gated ion channels are important determinants of function in neurotransmitter receptors. The partial agonist, kainic acid (KA) activates a less desensitized, and more robust AMPA receptor (AMPAR) current than full agonists, glutamate or AMPA. Cyclothiazide (CTZ), the allosteric modulator of AMPARs, potentiates receptor currents by inhibiting receptor desensitization resulting from agonist activation. We have constructed an AMPAR GluR1 subunit deletion mutant GluR1L3T(Delta739-784) by deleting the splice-variable "flip/flop" region of the L3 domain in the wild-type receptor and compared its function to that of the wild-type GluR1 receptor and an AMPAR substitution mutant GluR1A782N. When compared to GluR1, the potency of glutamate activation of GluR1L3T was increased, in contrast to a decrease in potency of activation and reduced sensitivity to optimal concentrations of KA. Furthermore, GluR1L3T was totally insensitive to CTZ potentiation of KA and glutamate-activated currents in Xenopus laevis oocytes. The potency of glutamate and KA activation of GluR1A782N was not significantly different from that of the wild-type GluR1 receptor although the mutant receptor currents were more sensitive to CTZ potentiation than the wild-type receptor current. This result is an indication that glutamate and KA binding to the agonist (S1/S2) domain on AMPAR can be modulated by an expendable splice-variable region of the receptor. Moreover, the effect of the allosteric modulator, CTZ on agonist activation of AMPAR can also be modified by a non-conserved amino acid residue substitution within the splice-variable "flip/flop" region.

Ferroportin Q248h, dietary iron, and serum ferritin in community African-Americans with low to high alcohol consumption.

BACKGROUND: Alcohol consumption is associated with increased iron stores. In sub-Saharan Africa, high dietary ionic iron and the ferroportin Q248H allele have also been implicated in iron accumulation. We examined the associations of ferroportin Q248H, alcohol and dietary iron with serum ferritin, aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) concentrations in African-Americans. METHODS: Inner-city African-Americans (103 men, 40 women) were recruited from the community according to reported ingestion of >4 alcoholic drinks/d or <2/wk. Typical daily heme iron, nonheme iron and alcohol were estimated using University of Hawaii's multiethnic dietary questionnaire. Based on dietary questionnaire estimates we established categories of < versus > or =56 g alcohol/d, equivalent to 4 alcoholic drinks/d assuming 14 g alcohol per drink. RESULTS: Among 143 participants, 77% drank <56 g alcohol/d and 23%> or =56 g/d as estimated by the questionnaire. The prevalence of ferroportin Q248H was 23.3% with alcohol >56 g/d versus 7.5% with lower amounts (p = 0.014). Among subjects with no history of HIV disease, serum ferritin concentration had positive relationships with male gender (p = 0.041), alcohol consumption (p = 0.021) and ALT concentration (p = 0.0001) but not with dietary iron intake or ferroportin Q248H. Serum AST and ALT concentrations had significant positive associations with male gender and hepatitis C seropositivity but not with alcohol or dietary iron intake or ferroportin Q248H. CONCLUSIONS: Our findings suggest a higher prevalence of ferroportin Q248H with greater alcohol consumption, and this higher prevalence raises the possibility that the allele might ameliorate the toxicity of alcohol. Our results suggest that alcohol but not dietary iron contributes to higher body iron stores in African-Americans. Studies with larger numbers of participants are needed to further clarify the relationship of ferroportin Q248H with the toxicity of alcohol consumption.

Alterations in ethyl alcohol pharmacokinetics during oral consumption of malt liquor beverages in African Americans.

BACKGROUND: Malt liquor (ML) beverages have become increasingly popular among urban minority groups, due partly to their inexpensive price and targeted advertising. We hypothesized that nonfermented by-products contained in ML beverages will alter the pharmacokinetics (PK) and pharmacodynamic (PD) effects of its ethanol content. In addition, we determined the effect of alcohol dehydrogenase (ADH) genotypes on the PK following consumption of ML beverages. METHODS: The study was conducted in 31 healthy adult African-American social drinkers, mean +/- SD age of 22.3 +/- 1.3 years, and weight of 70.7 +/- 10.9 kg. Participants were administered ethanol, in randomized order, 2-weeks apart, in the form of oral ML beverage (6%v/v), or isocaloric solution of diet soda-ethanol (DS-Etoh) beverage (6%v/v). During each session the beverage was consumed over 4 minutes and breath alcohol concentrations (BrAC) as well as subjective and behavioral effects of ethanol were evaluated over 180 minutes. Pharmacokinetic parameters of ethanol were calculated using Michaelis-Menten elimination kinetics. The effect of ML and ADH genotype on PK was evaluated using the Wilcoxon rank-sum test and the Wilcoxon signed rank test, respectively. RESULTS: Results show a slower mean rate of absorption, K(a), (0.12 vs. 0.15 min(-1), p = 0.03) and a longer time to reach maximum concentration, T(max), (28 vs. 23 minute, p < 0.01) for the ML compared with DS-Etoh beverage. The ML beverage resulted in a larger area under the BrAC-time curve compared with DS-Etoh beverage (8.4 vs. 6.8 min g/dl, p = 0.02). There was no difference in the subjective PD effects between the 2 beverages. CONCLUSION: Results show that exposure to ethanol following the consumption of ML beverages is different compared to that following nonmalt beverages in African-Americans. These differences may be related to nonfermented by-products present in commercially available ML products. These PK differences do not appear to result in significant perceived alcohol PD changes, nor are they related to ADH genotype.

Desipramine blocks alcohol-induced anxiety- and depressive-like behaviors in two rat strains.

Epidemiological studies indicate significant co-morbid expression of alcoholism, anxiety, and depression. These symptoms are often under-diagnosed and under-treated and can worsen prognostic and treatment outcome for alcoholism. Nonetheless, a causal relationship between alcoholism and these conditions is yet to be established. In this study we sought to determine the effects of daily alcohol administration on the indices of anxiety and depression in two rat strains, one of which exhibits inherent depressive-like characteristics. Moreover, it was of relevance to examine the effects of a clinically useful antidepressant on alcohol-induced behavioral changes. Wistar-Kyoto (WKY) rats derived from Wistar stock show low levels of locomotor activity in an open field and high levels of immobility in the forced swim test (FST) which is considered a measure of their helplessness and hence are considered a putative animal model of depression. Adult female WKY and Wistar rats were exposed for 3 hrs daily to 95% ethanol vapor to achieve a mean blood alcohol level (BAL) of approximately 150 mg/dL. Controls were exposed to air in similar inhalation chambers. Sixteen to 18 hrs following 7 or 14 days of exposure to alcohol, locomotor activity (LCA) in open field, duration of time spent in the open arm of the elevated plus-maze (EPM), reflective of anxiety-like behavior and immobility in FST were evaluated. Alcohol exposure for 7 or 14 days reduced LCA only in Wistar rats but enhanced FST immobility in both strains at both time points. Only 14 day alcohol exposure reduced EPM open arm time in both WKY and Wistar rats. Daily treatment with desipramine (8 mg/kg) blocked all the changes induced by alcohol in both strains. Thus, subchronic (7 day) exposure to alcohol induces depressive-like characteristics in Wistar rats and exacerbates that of WKY rats. Chronic (14 day) exposure, however, also induces an anxiety-like effect in both strains. The depressive- and anxiety-like behaviors induced by alcohol were blocked by daily treatment with a tricyclic antidepressant. It may be suggested that prophylactic treatment of alcoholics with an antidepressant prior to detoxification may improve treatment outcome for alcoholism.

Low Vs. High Alcohol: Central Benefits Vs. Detriments.

The dose-dependent effects of alcohol, where the initial euphoric and stimulant effects initiated by the exposure to low ethanol levels can quickly lead to a deadly consequence are well established. Thus, high blood alcohol concentration (BAC), as seen in alcoholics, can cause significant damage to various organs. At low concentrations (e.g., 10 mg% or lower), however, beneficial effects of alcohol, particularly on cardiovascular function have been reported. Although, the latter assertion has been challenged by recent epidemiological studies, protective effects of low alcohol concentrations in vitro and in vivo relevant to the central nervous system (CNS) is well documented. In this review, the mechanism(s) leading to the detrimental effects of high BAC, as well as the beneficial effects of low BAC will be discussed. In addition, gender consideration is touched upon. Although further investigation is clearly warranted, it may be concluded that at least some of the beneficial outcomes of low BAC, including possible neuroprotection and antidepressant-like effects, may be due to elevation of the neurotropic factors and reduction of inflammatory mediators, whereas detrimental outcomes associated with high BAC, including neurotoxicity and depressive-like behavior may be due to reduction in neurotropic factors and elevation of inflammatory mediators. Furthermore, new research strategies are suggested.

Antiapoptotic effects of nicotine in its protection against salsolinol-induced cytotoxicity.

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a metabolite of dopamine, may act as an endogenous neurotoxin and contribute to the etiology of Parkinson's disease (PD). The inverse relationship between smoking and PD prompted our previous investigation and the report of protective effects of nicotine against salsolinol-induced toxicity in cultured SH-SY5Y cells (Copeland et al., Neurotox. Res. 8:289, 2005). These cells, derived from human neuroblastoma cells, express dopaminergic activity and are used as a model of nigral dopaminergic cells, the major site of pathology in PD. The purpose of the current study was to investigate whether apoptotic or antiapoptotic mechanisms were responsible for the observed effects of salsolinol and nicotine, respectively. Moreover, it was of interest to determine whether the actions of nicotine are mediated through nicotinic receptors. SH-SY5Y cells were exposed to 0.4 or 0.7 mM salsolinol with and without pretreatment in combination of 0.1 mM nicotine and 0.1 mM mecamylamine and were exposed for 24 and 48 h. Various parameters including cell cycle perturbations (reflected in propidium iodide DNA staining); cell cycle regulator retinoblastoma protein (reflected in the Western blot), apoptosis (reflected in annexin V/propidium iodide staining followed by flow cytometry) were analyzed. Salsolinol caused an arrest of the cells in G1-phase of cell cycle and an increase in apoptotic indices, whereas pretreatment with nicotine attenuated or completely blocked the effects of salsolinol. Nicotine effects in turn, were totally blocked by mecamylamine (0.1 mM). The results suggest that apoptosis is a major mechanism for salsolinol-induced toxicity and that antiapoptotic effects of nicotine, mediated by nicotinic receptors, may play a primary role in its neuroprotective effects. Hence, nicotinic agonists in combination with other antiapoptotic agents may be of substantial benefit in at least a subpopulation of Parkinson patients.