Zuo L.,Yale University |
Gelernter J.,Yale University |
Gelernter J.,Alcohol Research Center |
Zhang C.K.,Yale University |
And 14 more authors.
Neuropsychopharmacology | Year: 2012
Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant geneKIAA0040that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369≤r≤0.824; 2.8 × 10 -9 ≤p≤0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 × 10 11 p1.5 × 10 -6) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system. © 2012 American College of Neuropsychopharmacology. All rights reserved.
Dickerson D.,University of California at Los Angeles |
Pittman B.,Yale University |
Ralevski E.,Yale University |
Ralevski E.,VA Connecticut Healthcare System |
And 13 more authors.
Journal of Psychopharmacology | Year: 2010
The γ-aminobutyric acid-A (GABAA) and N-methyl-D-aspartate (NMDA) receptors mediate aspects of the behavioural effects of alcohol. Prior studies reported drugs that block NMDA receptors or facilitate GABAA receptor function produce ethanol-like effects in humans. The purpose of this study was to compare the ethanol-related effects of two pharmacological agents with known NMDA and GABAA receptor activity. As part of an ongoing, larger study, 28 subjects (age, 21-30) with no personal or family histories of alcoholism were administered subanesthetic doses of the GABAA receptor agonist thiopental, the NMDA receptor antagonist, ketamine and placebo on three separate test days. Various ethanol-related measures were administered. At doses of thiopental and ketamine that produced similar levels of sedation and cognitive effects, both agents produced significant ethanol-like effects and subjective intoxication. However, the intensity of the ethanol-like effects of ketamine was greater than that of thiopental. In addition, ketamine produced alterations in perception that were not produced by thiopental. These data provide further support for a model where GABAA receptor facilitation may contribute significantly to ethanol effects associated with social drinking, whereas NMDA receptor antagonism may contribute to relatively greater extent to features of ethanol intoxication. © 2010 British Association for Psychopharmacology.
D'Souza D.C.,Yale University |
D'Souza D.C.,Clinical Neuroscience Research Unit |
Singh N.,Yale University |
Elander J.,Yale University |
And 10 more authors.
Neuropsychopharmacology | Year: 2012
Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors. © 2012 American College of Neuropsychopharmacology. All rights reserved.
Angarita G.A.,Yale University |
Angarita G.A.,Clinical Neuroscience Research Unit |
Canavan S.V.,Yale University |
Canavan S.V.,Clinical Neuroscience Research Unit |
And 9 more authors.
Drug and Alcohol Dependence | Year: 2014
Background: Former sleep studies among non-treatment seeking chronic cocaine users had captured polysomnographic changes for as long as three weeks of abstinence. Methods: 20 cocaine dependent participants, randomized to placebo in an ongoing clinical trial, received 12 days of inpatient substance abuse treatment followed by 6 weeks of outpatient cognitive behavioral therapy. Polysomnographic recording was performed on consecutive nights during the 1st and 2nd inpatient and 3rd and 6th outpatient weeks. Number of days abstinent was determined from thrice weekly urine toxicology and self-report. Polysomnographic sleep was compared between study week 1 and 2, using paired t-tests. Trajectory of total sleep time (TST) was modeled both as a linear and a quadratic function of days abstinent. Results: Despite reporting an improvement in overall sleep quality, polysomnographic sleep worsened from week 1 to 2. Among all participants, TST and stage 2 sleep time decreased, while REM sleep latency increased. Among participants who began the study with a positive urine test, there was also a decrease in REM and a trend for decreased slow wave sleep. TST compared to number of days abstinent (up to 54 days) was best fit with a quadratic model (p= 0.002), suggesting the possibility of an improvement in total sleep time with extended abstinence. Conclusions: This is the first polysomnographic characterization of sleep in a large sample of cocaine users in treatment. Present findings confirm earlier results of poor and deteriorating sleep early in abstinence, and raise the possibility of improvement after an extended abstinence. © 2013 Elsevier Ireland Ltd.
Ranganathan M.,Yale University |
Ranganathan M.,VA Connecticut Healthcare System |
Ranganathan M.,Clinical Neuroscience Research Unit |
Carbuto M.,Yale University |
And 17 more authors.
International Journal of Neuropsychopharmacology | Year: 2012
Although a wealth of preclinical evidence indicates an interplay between the μ-opioid (MOR) and cannabinoid 1 receptor (CB1R) systems, the precise nature of the cross modulation in humans is unclear. The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist, naltrexone, on the subjective, behavioural and cognitive effects of the CB1R agonist, Δ9-tetrahydrocannabinol (THC), in healthy human subjects. Healthy human subjects, screened carefully for any medical or psychiatric illness, were administered either placebo or active naltrexone (25 mg) orally on each test day, followed 45 min later by placebo and 165 min later by active i.v. THC (0.025 mg/kg) in a randomized, fixed-order, double-blind manner. Subjective, behavioural and cognitive effects were assessed before and at several points after each drug administration. THC produced expected effects, including euphoria, anxiety, transient perceptual alterations, transient psychotomimetic effects and cognitive impairments. However, naltrexone did not produce any effects alone, nor did it attenuate any of THC's effects. Thus, in healthy human subjects who use cannabis intermittently, MOR antagonism does not modulate the common acute subjective, behavioural and cognitive effects of THC. © © CINP 2012.
PubMed | Clinical Neuroscience Research Unit and University of Chicago
Type: Journal Article | Journal: Biological psychiatry | Year: 2015
Animal and clinical studies suggest a link between inflammation and oxidative stress. Because oxidative stress is an inherent part of inflammation, and inflammation is associated with behavioral aggression in lower mammals and humans, we hypothesized that markers of oxidative stress would be related to aggression in human subjects. In this case-control study, markers of oxidative stress and aggression were assessed in human subjects with histories of recurrent, problematic, impulsive aggressive behavior and in nonaggressive comparator subjects.Plasma levels of 8-hydroxy-2-deoxyguanosine and 8-isoprostane were examined in the context of measures of aggression and impulsivity in physically healthy subjects with intermittent explosive disorder (n = 69), nonaggressive subjects with Axis I or II disorders (n = 61), and nonaggressive subjects with no history of Axis I or II disorders (n = 67).Levels of plasma 8-hydroxy-2-deoxyguanosine and 8-isoprostane were significantly higher in subjects with intermittent explosive disorder compared with psychiatric or normal control subjects. In addition, both oxidative stress markers correlated with a composite measure of aggression; more specifically, 8-hydroxy-2-deoxyguanosine correlated with measures reflecting a history of actual aggressive behavior in all subjects.These data suggest a positive relationship between plasma markers of oxidative stress and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of aggression in human subjects.