Skip to main content

David Nielsen

Followers

28

Following

10

Co-authors

10

Public Views

Malcolm Thorburn

University of Toronto

Melanie O'Brien

The University of Western Australia

LUISS Guido Carli

Gabriel Doménech-Pascual

University of Valencia

Ariel M. Slipak

Universidad de Buenos Aires

Diego M. Papayannis

Universitat de Girona

Universidad de Chile

UFBA - Federal University of Bahia

Dragos Simandan

Brock University

Güneş Okuyucu Ergün

Ankara University

Interests

Uploads

Papers by David Nielsen

Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction

Psychiatric Genetics, Oct 1, 2010

Objectives-We have used genome-wide association studies to identify variants that are associated ... more Objectives-We have used genome-wide association studies to identify variants that are associated with vulnerability to develop heroin addiction. Methods-DNA from 325 methadone stabilized, former severe heroin addicts and 250 control subjects were pooled by ethnicity (Caucasian and African American) and analyzed using the Affymetrix GeneChip Mapping 100K Set. Genome-wide association tests were conducted. Results-The strongest association with vulnerability to develop heroin addiction, with experiment-wise significance (P = 0.035), was found in Caucasians with the variant rs10494334, a variant in an unannotated region of the genome (1q23.3). In African Americans, the variant most significantly associated with heroin addiction vulnerability was rs950302, found in the cytosolic dual specificity phosphatase 27 gene DUSP27 (point-wise P = 0.0079). Furthermore, analysis of the top 500 variants with the most significant associations (point-wise P ≤ 0.0036) in Caucasians showed that three of these variants are clustered in the regulating synaptic membrane exocytosis protein 2 gene RIMS2. Of the top 500 variants in African Americans (point-wise P ≤ 0.0238), three variants are in the cardiomyopathy associated 3 gene CMYA3. Conclusions-This study identifies new genes and variants that may increase an individual's vulnerability to develop heroin addiction.

A highly sensitive, mixed-phase assay for chloramphenicol acetyltransferase activity in transfected cells

Analytical Biochemistry, May 1, 1989

We describe a simple, rapid yet extremely sensitive assay for chloramphenicol acetyltransferase (... more We describe a simple, rapid yet extremely sensitive assay for chloramphenicol acetyltransferase (CAT) activity in extracts from transfected eukaryotic cells. Using our modified reaction conditions and the mixed-phase assay, less than 0.000010 unit of CAT activity in transfected cells can be reliably detected. The mixed-phase assay is based on the inability of the polar [3H]-acetyl-Coenzyme A (CoA) substrate to partition out of a urea containing aqueous phase into the nonpolar scintillation fluor, while the [3H]chloramphenicol reaction products partition into the toluene scintillation fluor and are quantitated by scintillation counting. The increased sensitivity of this assay is due to the optimization of the acetyl-CoA concentration, to a urea-containing aqueous phase which lowers the assay background, and to the use of extract blanks. The mixed-phase assay is simpler, is quantitative, uses less costly substrates, and is far more sensitive than the most widely used CAT assays, which require solvent extraction followed by thin-layer chromatography to separate the unreacted substrate from product.

Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach

Zhurnal Nevrologii I Psikhiatrii Imeni S S Korsakova, 2015

Цель исследования -выявить влияние полиморфных вариантов генов опиоидной и дофаминовой систем на ... more Цель исследования -выявить влияние полиморфных вариантов генов опиоидной и дофаминовой систем на эффективность противорецидивной терапии опийной наркомании имплантируемой и пероральной лекарственных форм налтрексона. Материал и методы. Было проведено двойное слепое рандомизированное плацебо-контролируемое исследование с двойной маскировкой. 306 больных опийной наркоманией были рандомизированы в 3 группы по 102 человека в каждой. Больным 1-й группы назначались имплант 1000 мг налтрексона (3 имплантации с интервалом 2 мес, всего на 6 мес) и таблетки плацебо, больным 2-й группы -плацебо-имплант и пероральный налтрексон (50 мг в сутки), больным 3-й группы -двойное плацебо (имплант и таблетки). Генотипирование больных проводили по следующим вариантам полиморфизма генов: опиоидных рецепторов типов мю (OPRM1) и каппа (OPRК1), фермента катехол-орто-метил-трансферазы (COMT), дофаминовых рецепторов 2 (DRD2) и 4 (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белкатрансмембранного переносчика дофамина (SLC6A3, DAT1). Результаты. Было установлено, что вне зависимости от вида противорецидивной терапии ряд полиморфных вариантов повышает риск рецидива зависимости: аллель L (2 повтора по 120 н.п.) DRD4120bp (р=0,05; OR (95% ДИ)=3,3(1,1-10,1)); аллель С DRD2NcoI (р=0,051; OR (95% ДИ)=2,86 (1,09-7,52)); генотип 9,9 DATVNTR40bp (р=0,04; RR (95% ДИ)=1,4(1,3-1,5)); напротив, варианты полиморфизма (СС+СТ)-(ТТ)) по сочетанию генов (OPRK1-DRD2Ncol) повышают вероятность завершения программы лечения (р=0,004; OR (95% ДИ)=7,4 (1,8-30,4)), анализ выживаемости Каплана-Мейера (р=0,016). В группе перорального налтрексона носители этих же вариантов (OPRK1-DRD2Ncol) имели более высокую вероятность завершения программы лечения (р=0,016), однако эффект был обратным в группе двойного плацебо (р=0,015) и не проявлялся вообще в группе с имплантом налтрексона (р=0,33). Заключение. Имплант налтрексона является высокоэффективным препаратом для лечения опийной наркомании, превосходящим по эффективности пероральный налтрексон и плацебо-имплант. По результатам генотипирования вероятно выявление потенциальных респондеров при терапии пациентов, что может повысить эффективность лечения.

miR-124-3p target genes identify globus pallidus role in suicide ideation recovery in borderline personality disorder

npj Mental Health Research

Borderline personality disorder (BPD) is characterized by patterns of unstable affect, unstable i... more Borderline personality disorder (BPD) is characterized by patterns of unstable affect, unstable interpersonal relationships, and chronic suicidal tendencies. Research on the genetics, epigenetics, and brain function of BPD is lacking. MicroRNA-124-3p (miR-124-3p) was recently identified in a Genome-Wide Association Study as likely associated with BPD. Here, we identified the anatomical brain expression of genes likely modulated by miR-124-3p and compared morphometry in those brain regions in BPD inpatients vs. controls matched for psychiatric comorbidities. We isolated lists of targets likely modulated by miR-124-3p from TargetScan (v 8.0) by their preferentially conserved targeting (Aggregate PCT > 0.99, see Supplementary Table 1). We applied Process Genes List (PGL) to identify regions of interest associated with the co-expression of miR-124-3p target genes. We compared the gray matter volume of the top region of interest co-expressing those genes between BPD inpatients (n = 11...

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

ABSTRACTBackgroundMany psychiatric outcomes are thought to share a common etiological pathway ref... more ABSTRACTBackgroundMany psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans’ health, such as suicide-related behaviors, substance use disorders, and other medical conditions.MethodsWe conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (N= 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (Europ...

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder

ABSTRACTObjectivePersons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at hi... more ABSTRACTObjectivePersons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies.MethodsIn this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize speci...

Specific miRNAs associated with treatment response during hospitalization for suicidal ideation

Brain epigenetic microRNAs (miRNA) can provide integrated and rapid brain regulation during recov... more Brain epigenetic microRNAs (miRNA) can provide integrated and rapid brain regulation during recovery from suicidal ideation (SI), and because brain miRNA enter the circulation, plasma miRNA may be markers for SI recovery. Therefore, we used genome-wide miRNA expression profiling to measure plasma miRNA changes during resolution of SI and assessed mRNA-targets using functional annotation analyses. We correlated plasma miRNA with Columbia-Suicide Severity Rating Scores (C-SSRS), depression and anxiety in 42 SI and 26 non-SI inpatients at admission and 4–6 weeks later in recovery (C-SSRS = 0). The 42 SI patients showed down-regulation of four miRNAs (hsa-miR-424-5p, hsa-miR-378i, hsa-miR-6724-5p, and hsa-miR-10b-5p) after recovery from SI, while these four miRNAs showed no change for non-SI patients. We validated these differentially expressed (DE) miRNAs by qRT-PCR, and luciferase assays confirmed miRNA functional activity in Clusterin for miR-424-5p and in SDC1 for miR-10b-5p. Depres...

A Clinical Trial of Entolimod a TLR-5 Adjuvant for Vaccines Using Diphtheria or Tetanus as Carrier Proteins

Vaccines

Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient ti... more Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient titer or duration of antibodies (AB), but new adjuvants enhance both AB titers and efficacy duration. This clinical trial assessed AB titers after a single booster of commercial tetanus-diphtheria (Td) vaccine in 40 males randomized as 15 to Td alone and 25 to Td combined with the TLR5 adjuvant, Entolimod (Ent). Ent significantly increased ABs against diphtheria (DPT) (0.46 vs. 0.29 IU/mL increase; n = 40, p < 0.05), but against tetanus (TT) only if baseline TT AB was below 3 IU/mL (3.1 vs. 2.1 IU/mL; n = 20; p < 0.05). These 20 participants also showed a two-fold increase in anti-TT AB titer more often when given Ent than non-Ent (33% vs. 82%) (p < 0.03). Anti-Ent AB was low and appeared unlikely to reduce Ent efficacy after repeated Ent administration. Medical safety was excellent, and a TLR5 missense polymorphism reduced anti-DPT AB production, but Ent increased anti-DPT AB tit...

Hospital Stay in Synthetic Cannabinoid Users With Bipolar Disorder, Schizophrenia, or Other Psychotic Disorders Compared With Cannabis Users

Journal of Studies on Alcohol and Drugs, 2019

Objective: The use of synthetic cannabinoid (SC) products has become popular in recent years, but... more Objective: The use of synthetic cannabinoid (SC) products has become popular in recent years, but data regarding their impact on hospital stays are limited. The impact of SC and cannabis use on hospital length of stay and doses of antipsychotics at discharge was assessed in this study. Method: The sample consisted of inpatients with discharge diagnoses of bipolar disorder, schizophrenia, or other psychotic disorders. Medical records of patients with self-reported SC use and negative urine drug screens (SC group, n = 77), with cannabis use confirmed by urine drug screen (cannabis group, n = 248), and with no drug use confirmed by urine drug screen (no-drug group, n = 1,336) were examined retrospectively. Results: Length of stay (mean [SD] days) significantly differed (p < .001) among the SC (8.29 [4.29]), cannabis (8.02 [5.21]), and no-drug groups (10.19 [9.08]). Antipsychotic doses (chlorpromazine milligram equivalent doses) also significantly differed (p = .002) among the SC (254.64 [253.63]), cannabis (219.16 [216.71]), and no-drug groups (294.79 [287.85]). Unadjusted and adjusted pairwise comparisons showed that the cannabis group had a shorter length of stay (p < .001) and received lower doses of antipsychotics (p = .003) than the no-drug group. SC users did not differ significantly from the other two groups in either length of stay or doses of antipsychotics. Conclusions: Our findings suggest that acute SC exposure is not predictive of a more prolonged time for response to antipsychotic medications or of a need for larger doses of these medications compared with cannabis users. (J.

A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine

Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova, 2016

Цель исследования. Выявление влияния полиморфных вариантов генов опиоидной и дофаминовой систем м... more Цель исследования. Выявление влияния полиморфных вариантов генов опиоидной и дофаминовой систем мозга на эффективность комбинированной терапии налтрексоном и гуанфацином у больных с опиоидной зависимостью в рамках двойного слепого рандомизированного плацебо-контролируемого исследования с двойной маскировкой. Материал и методы. Обследовали 301 больного с опиоидной зависимостью, которые были рандомизированы в четыре группы: налтрексон (NTX) 50 мг/день+гуанфацин (GFC) 1 мг/день (Н+Г); NTX+GFC-плацебо (Н+ГП); NTX-плацебо+GFC (НП+Г) и двойное плацебо (НП+ГП). Показателем эффективности терапии было удержание пациентов в программе лечения. Пациенты были генотипированы по полиморфным вариантам генов: опиоидных рецепторов типов µ (OPRM1) и каппа (OPRК1), фермента катехол-орто-метилтрансферазы (COMT), дофаминовых рецепторов 2-го (DRD2) и 4-го (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белка -трансмембранного переносчика дофамина (SLC6A3, DAT1) и альфа-2А-адренорецептора (ADRA2A)-фармакологической мишени гуанфацина. Результаты. Комбинация налтрексона и гуанфацина была сравнима по эффективности с монотерапией налтрексоном. Независимо от вида терапии ряд генетических вариантов повышает шанс завершения программы лечения: аллель Т DRD4 521 (rs1800955) (р=0,039; OR (95% ДИ)=3,7 (1,1-12,7); лог-ранк критерий: р=0,01); аллель С DRD2 С957Т (rs 6277) (р=0,03; HR=0,6 (0,34-0,95); сочетания генотипов: DRD4 VNTR (LL)+OPRM1 A118G (rs1799971)(AA), р=0,051; DRD2 C957T (ТТ)+OPRM1 (rs1074287) (СС), р=0,025; DRD2 -141С (II)+OPRM1 (rs510769) (АА), р=0,035; DBH Fau(СС)+OPRM1 (rs1074287) (СС), р=0,0497. Независимо от вида терапии ряд генетических вариантов повышает риск рецидива: аллель Т (rs510769) OPRM1 (р=0,053), аллель А (rs1799971, A118G) OPRM1 (р=0,056), аллель S (количество повторов менее 7) экзон III 48 bp DRD4 VNTR (р=0,001; HR=3,1 (ДИ 95% 1,57-6,18); сочетания генотипов: DRD4 521 С/Т (ТТ)+DRD2 Nco I (TT), р=0,026; DRD4 521 С/Т (ТТ)+DRD2 -141 С (II), р=0,011; DRD4 521 С/Т (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,011; DRD2 Nco I (ТТ)+ADRA2A (СС), р=0,012; DRD2 Nco I (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,02. Эффекты, зависящие от вида терапии: 1) только в группе пациентов, получавших налтрексон и гуанфацин (Н+Г), носители генотипа ТT локуса DRD4 521(rs1800955) достоверно более длительное время удерживались в программе терапии, чем остальные пациенты (генотипы СС и СТ) (логранк критерий: p=0,002); 2) только в группе двойного плацебо (НП+ГП) носители аллеля Т локуса rs510769 OPRM1 имели больший риск рецидива зависимости по сравнению с генотипом СС (р=0,016) и носители аллеля А локуса rs1799971 (A118G) OPRM1имели больший риск рецидива по сравнению с генотипом GG (р=0,008) (FDR р<0,0125). Заключение. Показано совместное влияние генов дофаминовой и опиоидной систем мозга на эффективность налтрексона и гуанфацина и стабилизацию ремиссии у больных c опиоидной наркоманией. Генетические варианты локуса DRD4 521(rs1800955) гена дофаминового рецептора типа 4 проявляются только в группе пациентов, получавших активные препараты, и в наибольшей степени связаны именно с фармакологическим эффектом налтрексона и гуанфацина. Полиморфизм гена µ-опиоидного рецептора, в особенности функционального варианта rs1799971 (A118G), в наибольшей степени проявляется в группе двойного плацебо, что заставляет предполагать существенное влияние этого гена на черты личности, темперамента и характера, особенно в контексте комплаенса. По результатам генотипирования возможно выявление высокорезистентных к терапии пациентов, а предварительное проведение генотипирования перед назначением вариантов фармакотерапии может повысить эффективность лечения опиоидной зависимости.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes

Psychiatric genetics, Oct 6, 2017

This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the modera... more This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carr...

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals

Pharmacogenetics and genomics, Sep 1, 2016

We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective ... more We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype...

Variations in opioid receptor genes in neonatal abstinence syndrome

Drug and Alcohol Dependence, 2015

Background-There is significant variability in the severity of neonatal abstinence syndrome (NAS)... more

Human molecular genetics of opioid addiction

Principles of Psychiatric Genetics

Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

Translational Psychiatry, 2014

Cocaine dependence remains a challenging public health problem with relapse cited as a major dete... more Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocainedependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT 2C R protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT 2C R agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT 2C R system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.

The Impact of Disulfiram Treatment on the Reinforcing Effects of Cocaine: A Randomized Clinical Trial

PLoS ONE, 2012

Background: Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one s... more Background: Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users. Methods: Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebocontrolled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05-16) and in the other cocaine (20 mg) or money. Results: Participants chose cocaine more than saline under both disulfiram and placebo conditions (p,0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p,0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p,0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's,0.05-0.01). Conclusions: Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research.

Bidirectional translational research: Progress in understanding addictive diseases

Neuropharmacology, 2009

The focus of this review is primarily on recent developments in bidirectional translational resea... more The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including: a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating "binge"). b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches described above.

Larger globus pallidus volumes among bipolar patients carrying CACNA1C gene risk allele

F1000Research, 2014

Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence

NeuroImage, 2016

Neuroimaging and genetic studies provide distinct and complementary information about the structu... more Neuroimaging and genetic studies provide distinct and complementary information about the structural and biological aspects of a disease. Integrating the two sources of data facilitates the investigation of the links between genetic variability and brain mechanisms among different individuals for various medical disorders. This article presents a general statistical framework for integrative Bayesian analysis of neuroimaging-genetic (iBANG) data, which is motivated by a neuroimaging-genetic study in cocaine dependence. Statistical inference necessitated the integration of spatially dependent voxel-level measurements with various patient-level genetic and demographic characteristics under an appropriate probability model to account for the multiple inherent sources of variation. Our framework uses Bayesian model averaging to integrate genetic information into the analysis of voxel-wise neuroimaging data, accounting for spatial correlations in the voxels. Using multiplicity controls based on the false discovery rate, we delineate voxels associated with genetic and demographic features that may impact diffusion as measured by fractional anisotropy (FA) obtained from DTI images. We demonstrate the benefits of accounting for model uncertainties in both model fit and prediction. Our results suggest that cocaine consumption is associated with FA reduction in most white matter regions of interest in the brain. Additionally, gene polymorphisms associated with GABAergic, serotonergic and dopaminergic neurotransmitters and receptors were associated with FA.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene

European Journal of Clinical Pharmacology, 2022

PURPOSE The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers mo... more PURPOSE The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction

Psychiatric Genetics, Oct 1, 2010

Objectives-We have used genome-wide association studies to identify variants that are associated ... more Objectives-We have used genome-wide association studies to identify variants that are associated with vulnerability to develop heroin addiction. Methods-DNA from 325 methadone stabilized, former severe heroin addicts and 250 control subjects were pooled by ethnicity (Caucasian and African American) and analyzed using the Affymetrix GeneChip Mapping 100K Set. Genome-wide association tests were conducted. Results-The strongest association with vulnerability to develop heroin addiction, with experiment-wise significance (P = 0.035), was found in Caucasians with the variant rs10494334, a variant in an unannotated region of the genome (1q23.3). In African Americans, the variant most significantly associated with heroin addiction vulnerability was rs950302, found in the cytosolic dual specificity phosphatase 27 gene DUSP27 (point-wise P = 0.0079). Furthermore, analysis of the top 500 variants with the most significant associations (point-wise P ≤ 0.0036) in Caucasians showed that three of these variants are clustered in the regulating synaptic membrane exocytosis protein 2 gene RIMS2. Of the top 500 variants in African Americans (point-wise P ≤ 0.0238), three variants are in the cardiomyopathy associated 3 gene CMYA3. Conclusions-This study identifies new genes and variants that may increase an individual's vulnerability to develop heroin addiction.

A highly sensitive, mixed-phase assay for chloramphenicol acetyltransferase activity in transfected cells

Analytical Biochemistry, May 1, 1989

We describe a simple, rapid yet extremely sensitive assay for chloramphenicol acetyltransferase (... more We describe a simple, rapid yet extremely sensitive assay for chloramphenicol acetyltransferase (CAT) activity in extracts from transfected eukaryotic cells. Using our modified reaction conditions and the mixed-phase assay, less than 0.000010 unit of CAT activity in transfected cells can be reliably detected. The mixed-phase assay is based on the inability of the polar [3H]-acetyl-Coenzyme A (CoA) substrate to partition out of a urea containing aqueous phase into the nonpolar scintillation fluor, while the [3H]chloramphenicol reaction products partition into the toluene scintillation fluor and are quantitated by scintillation counting. The increased sensitivity of this assay is due to the optimization of the acetyl-CoA concentration, to a urea-containing aqueous phase which lowers the assay background, and to the use of extract blanks. The mixed-phase assay is simpler, is quantitative, uses less costly substrates, and is far more sensitive than the most widely used CAT assays, which require solvent extraction followed by thin-layer chromatography to separate the unreacted substrate from product.

Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach

Zhurnal Nevrologii I Psikhiatrii Imeni S S Korsakova, 2015

Цель исследования -выявить влияние полиморфных вариантов генов опиоидной и дофаминовой систем на ... more Цель исследования -выявить влияние полиморфных вариантов генов опиоидной и дофаминовой систем на эффективность противорецидивной терапии опийной наркомании имплантируемой и пероральной лекарственных форм налтрексона. Материал и методы. Было проведено двойное слепое рандомизированное плацебо-контролируемое исследование с двойной маскировкой. 306 больных опийной наркоманией были рандомизированы в 3 группы по 102 человека в каждой. Больным 1-й группы назначались имплант 1000 мг налтрексона (3 имплантации с интервалом 2 мес, всего на 6 мес) и таблетки плацебо, больным 2-й группы -плацебо-имплант и пероральный налтрексон (50 мг в сутки), больным 3-й группы -двойное плацебо (имплант и таблетки). Генотипирование больных проводили по следующим вариантам полиморфизма генов: опиоидных рецепторов типов мю (OPRM1) и каппа (OPRК1), фермента катехол-орто-метил-трансферазы (COMT), дофаминовых рецепторов 2 (DRD2) и 4 (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белкатрансмембранного переносчика дофамина (SLC6A3, DAT1). Результаты. Было установлено, что вне зависимости от вида противорецидивной терапии ряд полиморфных вариантов повышает риск рецидива зависимости: аллель L (2 повтора по 120 н.п.) DRD4120bp (р=0,05; OR (95% ДИ)=3,3(1,1-10,1)); аллель С DRD2NcoI (р=0,051; OR (95% ДИ)=2,86 (1,09-7,52)); генотип 9,9 DATVNTR40bp (р=0,04; RR (95% ДИ)=1,4(1,3-1,5)); напротив, варианты полиморфизма (СС+СТ)-(ТТ)) по сочетанию генов (OPRK1-DRD2Ncol) повышают вероятность завершения программы лечения (р=0,004; OR (95% ДИ)=7,4 (1,8-30,4)), анализ выживаемости Каплана-Мейера (р=0,016). В группе перорального налтрексона носители этих же вариантов (OPRK1-DRD2Ncol) имели более высокую вероятность завершения программы лечения (р=0,016), однако эффект был обратным в группе двойного плацебо (р=0,015) и не проявлялся вообще в группе с имплантом налтрексона (р=0,33). Заключение. Имплант налтрексона является высокоэффективным препаратом для лечения опийной наркомании, превосходящим по эффективности пероральный налтрексон и плацебо-имплант. По результатам генотипирования вероятно выявление потенциальных респондеров при терапии пациентов, что может повысить эффективность лечения.

miR-124-3p target genes identify globus pallidus role in suicide ideation recovery in borderline personality disorder

npj Mental Health Research

Borderline personality disorder (BPD) is characterized by patterns of unstable affect, unstable i... more Borderline personality disorder (BPD) is characterized by patterns of unstable affect, unstable interpersonal relationships, and chronic suicidal tendencies. Research on the genetics, epigenetics, and brain function of BPD is lacking. MicroRNA-124-3p (miR-124-3p) was recently identified in a Genome-Wide Association Study as likely associated with BPD. Here, we identified the anatomical brain expression of genes likely modulated by miR-124-3p and compared morphometry in those brain regions in BPD inpatients vs. controls matched for psychiatric comorbidities. We isolated lists of targets likely modulated by miR-124-3p from TargetScan (v 8.0) by their preferentially conserved targeting (Aggregate PCT > 0.99, see Supplementary Table 1). We applied Process Genes List (PGL) to identify regions of interest associated with the co-expression of miR-124-3p target genes. We compared the gray matter volume of the top region of interest co-expressing those genes between BPD inpatients (n = 11...

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

ABSTRACTBackgroundMany psychiatric outcomes are thought to share a common etiological pathway ref... more ABSTRACTBackgroundMany psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans’ health, such as suicide-related behaviors, substance use disorders, and other medical conditions.MethodsWe conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (N= 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (Europ...

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder

ABSTRACTObjectivePersons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at hi... more ABSTRACTObjectivePersons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies.MethodsIn this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize speci...

Specific miRNAs associated with treatment response during hospitalization for suicidal ideation

Brain epigenetic microRNAs (miRNA) can provide integrated and rapid brain regulation during recov... more Brain epigenetic microRNAs (miRNA) can provide integrated and rapid brain regulation during recovery from suicidal ideation (SI), and because brain miRNA enter the circulation, plasma miRNA may be markers for SI recovery. Therefore, we used genome-wide miRNA expression profiling to measure plasma miRNA changes during resolution of SI and assessed mRNA-targets using functional annotation analyses. We correlated plasma miRNA with Columbia-Suicide Severity Rating Scores (C-SSRS), depression and anxiety in 42 SI and 26 non-SI inpatients at admission and 4–6 weeks later in recovery (C-SSRS = 0). The 42 SI patients showed down-regulation of four miRNAs (hsa-miR-424-5p, hsa-miR-378i, hsa-miR-6724-5p, and hsa-miR-10b-5p) after recovery from SI, while these four miRNAs showed no change for non-SI patients. We validated these differentially expressed (DE) miRNAs by qRT-PCR, and luciferase assays confirmed miRNA functional activity in Clusterin for miR-424-5p and in SDC1 for miR-10b-5p. Depres...

A Clinical Trial of Entolimod a TLR-5 Adjuvant for Vaccines Using Diphtheria or Tetanus as Carrier Proteins

Vaccines

Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient ti... more Anti-drug vaccines previously failed clinical trials because they did not provide a sufficient titer or duration of antibodies (AB), but new adjuvants enhance both AB titers and efficacy duration. This clinical trial assessed AB titers after a single booster of commercial tetanus-diphtheria (Td) vaccine in 40 males randomized as 15 to Td alone and 25 to Td combined with the TLR5 adjuvant, Entolimod (Ent). Ent significantly increased ABs against diphtheria (DPT) (0.46 vs. 0.29 IU/mL increase; n = 40, p < 0.05), but against tetanus (TT) only if baseline TT AB was below 3 IU/mL (3.1 vs. 2.1 IU/mL; n = 20; p < 0.05). These 20 participants also showed a two-fold increase in anti-TT AB titer more often when given Ent than non-Ent (33% vs. 82%) (p < 0.03). Anti-Ent AB was low and appeared unlikely to reduce Ent efficacy after repeated Ent administration. Medical safety was excellent, and a TLR5 missense polymorphism reduced anti-DPT AB production, but Ent increased anti-DPT AB tit...

Hospital Stay in Synthetic Cannabinoid Users With Bipolar Disorder, Schizophrenia, or Other Psychotic Disorders Compared With Cannabis Users

Journal of Studies on Alcohol and Drugs, 2019

Objective: The use of synthetic cannabinoid (SC) products has become popular in recent years, but... more Objective: The use of synthetic cannabinoid (SC) products has become popular in recent years, but data regarding their impact on hospital stays are limited. The impact of SC and cannabis use on hospital length of stay and doses of antipsychotics at discharge was assessed in this study. Method: The sample consisted of inpatients with discharge diagnoses of bipolar disorder, schizophrenia, or other psychotic disorders. Medical records of patients with self-reported SC use and negative urine drug screens (SC group, n = 77), with cannabis use confirmed by urine drug screen (cannabis group, n = 248), and with no drug use confirmed by urine drug screen (no-drug group, n = 1,336) were examined retrospectively. Results: Length of stay (mean [SD] days) significantly differed (p < .001) among the SC (8.29 [4.29]), cannabis (8.02 [5.21]), and no-drug groups (10.19 [9.08]). Antipsychotic doses (chlorpromazine milligram equivalent doses) also significantly differed (p = .002) among the SC (254.64 [253.63]), cannabis (219.16 [216.71]), and no-drug groups (294.79 [287.85]). Unadjusted and adjusted pairwise comparisons showed that the cannabis group had a shorter length of stay (p < .001) and received lower doses of antipsychotics (p = .003) than the no-drug group. SC users did not differ significantly from the other two groups in either length of stay or doses of antipsychotics. Conclusions: Our findings suggest that acute SC exposure is not predictive of a more prolonged time for response to antipsychotic medications or of a need for larger doses of these medications compared with cannabis users. (J.

A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine

Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova, 2016

Цель исследования. Выявление влияния полиморфных вариантов генов опиоидной и дофаминовой систем м... more Цель исследования. Выявление влияния полиморфных вариантов генов опиоидной и дофаминовой систем мозга на эффективность комбинированной терапии налтрексоном и гуанфацином у больных с опиоидной зависимостью в рамках двойного слепого рандомизированного плацебо-контролируемого исследования с двойной маскировкой. Материал и методы. Обследовали 301 больного с опиоидной зависимостью, которые были рандомизированы в четыре группы: налтрексон (NTX) 50 мг/день+гуанфацин (GFC) 1 мг/день (Н+Г); NTX+GFC-плацебо (Н+ГП); NTX-плацебо+GFC (НП+Г) и двойное плацебо (НП+ГП). Показателем эффективности терапии было удержание пациентов в программе лечения. Пациенты были генотипированы по полиморфным вариантам генов: опиоидных рецепторов типов µ (OPRM1) и каппа (OPRК1), фермента катехол-орто-метилтрансферазы (COMT), дофаминовых рецепторов 2-го (DRD2) и 4-го (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белка -трансмембранного переносчика дофамина (SLC6A3, DAT1) и альфа-2А-адренорецептора (ADRA2A)-фармакологической мишени гуанфацина. Результаты. Комбинация налтрексона и гуанфацина была сравнима по эффективности с монотерапией налтрексоном. Независимо от вида терапии ряд генетических вариантов повышает шанс завершения программы лечения: аллель Т DRD4 521 (rs1800955) (р=0,039; OR (95% ДИ)=3,7 (1,1-12,7); лог-ранк критерий: р=0,01); аллель С DRD2 С957Т (rs 6277) (р=0,03; HR=0,6 (0,34-0,95); сочетания генотипов: DRD4 VNTR (LL)+OPRM1 A118G (rs1799971)(AA), р=0,051; DRD2 C957T (ТТ)+OPRM1 (rs1074287) (СС), р=0,025; DRD2 -141С (II)+OPRM1 (rs510769) (АА), р=0,035; DBH Fau(СС)+OPRM1 (rs1074287) (СС), р=0,0497. Независимо от вида терапии ряд генетических вариантов повышает риск рецидива: аллель Т (rs510769) OPRM1 (р=0,053), аллель А (rs1799971, A118G) OPRM1 (р=0,056), аллель S (количество повторов менее 7) экзон III 48 bp DRD4 VNTR (р=0,001; HR=3,1 (ДИ 95% 1,57-6,18); сочетания генотипов: DRD4 521 С/Т (ТТ)+DRD2 Nco I (TT), р=0,026; DRD4 521 С/Т (ТТ)+DRD2 -141 С (II), р=0,011; DRD4 521 С/Т (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,011; DRD2 Nco I (ТТ)+ADRA2A (СС), р=0,012; DRD2 Nco I (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,02. Эффекты, зависящие от вида терапии: 1) только в группе пациентов, получавших налтрексон и гуанфацин (Н+Г), носители генотипа ТT локуса DRD4 521(rs1800955) достоверно более длительное время удерживались в программе терапии, чем остальные пациенты (генотипы СС и СТ) (логранк критерий: p=0,002); 2) только в группе двойного плацебо (НП+ГП) носители аллеля Т локуса rs510769 OPRM1 имели больший риск рецидива зависимости по сравнению с генотипом СС (р=0,016) и носители аллеля А локуса rs1799971 (A118G) OPRM1имели больший риск рецидива по сравнению с генотипом GG (р=0,008) (FDR р<0,0125). Заключение. Показано совместное влияние генов дофаминовой и опиоидной систем мозга на эффективность налтрексона и гуанфацина и стабилизацию ремиссии у больных c опиоидной наркоманией. Генетические варианты локуса DRD4 521(rs1800955) гена дофаминового рецептора типа 4 проявляются только в группе пациентов, получавших активные препараты, и в наибольшей степени связаны именно с фармакологическим эффектом налтрексона и гуанфацина. Полиморфизм гена µ-опиоидного рецептора, в особенности функционального варианта rs1799971 (A118G), в наибольшей степени проявляется в группе двойного плацебо, что заставляет предполагать существенное влияние этого гена на черты личности, темперамента и характера, особенно в контексте комплаенса. По результатам генотипирования возможно выявление высокорезистентных к терапии пациентов, а предварительное проведение генотипирования перед назначением вариантов фармакотерапии может повысить эффективность лечения опиоидной зависимости.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes

Psychiatric genetics, Oct 6, 2017

This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the modera... more This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carr...

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals

Pharmacogenetics and genomics, Sep 1, 2016

We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective ... more We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype...

Variations in opioid receptor genes in neonatal abstinence syndrome

Drug and Alcohol Dependence, 2015

Background-There is significant variability in the severity of neonatal abstinence syndrome (NAS)... more

Human molecular genetics of opioid addiction

Principles of Psychiatric Genetics

Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

Translational Psychiatry, 2014

Cocaine dependence remains a challenging public health problem with relapse cited as a major dete... more Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocainedependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT 2C R protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT 2C R agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT 2C R system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.

The Impact of Disulfiram Treatment on the Reinforcing Effects of Cocaine: A Randomized Clinical Trial

PLoS ONE, 2012

Background: Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one s... more Background: Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users. Methods: Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebocontrolled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05-16) and in the other cocaine (20 mg) or money. Results: Participants chose cocaine more than saline under both disulfiram and placebo conditions (p,0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p,0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p,0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's,0.05-0.01). Conclusions: Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research.

Bidirectional translational research: Progress in understanding addictive diseases

Neuropharmacology, 2009

The focus of this review is primarily on recent developments in bidirectional translational resea... more The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including: a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating "binge"). b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches described above.

Larger globus pallidus volumes among bipolar patients carrying CACNA1C gene risk allele

F1000Research, 2014

Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence

NeuroImage, 2016

Neuroimaging and genetic studies provide distinct and complementary information about the structu... more Neuroimaging and genetic studies provide distinct and complementary information about the structural and biological aspects of a disease. Integrating the two sources of data facilitates the investigation of the links between genetic variability and brain mechanisms among different individuals for various medical disorders. This article presents a general statistical framework for integrative Bayesian analysis of neuroimaging-genetic (iBANG) data, which is motivated by a neuroimaging-genetic study in cocaine dependence. Statistical inference necessitated the integration of spatially dependent voxel-level measurements with various patient-level genetic and demographic characteristics under an appropriate probability model to account for the multiple inherent sources of variation. Our framework uses Bayesian model averaging to integrate genetic information into the analysis of voxel-wise neuroimaging data, accounting for spatial correlations in the voxels. Using multiplicity controls based on the false discovery rate, we delineate voxels associated with genetic and demographic features that may impact diffusion as measured by fractional anisotropy (FA) obtained from DTI images. We demonstrate the benefits of accounting for model uncertainties in both model fit and prediction. Our results suggest that cocaine consumption is associated with FA reduction in most white matter regions of interest in the brain. Additionally, gene polymorphisms associated with GABAergic, serotonergic and dopaminergic neurotransmitters and receptors were associated with FA.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene

European Journal of Clinical Pharmacology, 2022

PURPOSE The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers mo... more PURPOSE The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.