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1.  Using electronic health records data to assess comorbidities of substance use and psychiatric diagnoses and treatment settings among adults 
Journal of psychiatric research  2013;47(4):555-563.
Objective
To examine prevalences of substance use disorders (SUD) and comprehensive patterns of comorbidities among psychiatric patients ages 18–64 years (N=40,099) in an electronic health records (EHR) database.
Method
DSM-IV diagnoses among psychiatric patients in a large university system were systematically captured: SUD, anxiety (AD), mood (MD), personality (PD), adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse-control, psychotic (schizophrenic), sexual/gender identity, sleep, and somatoform diagnoses. Comorbidities and treatment types among patients with a SUD were examined.
Results
Among all patients, 24.9% (n=9,984) had a SUD, with blacks (35.2%) and Hispanics (32.9%) showing the highest prevalence. Among patients with a SUD, MD was prevalent across all age groups (50.2–56.6%). Patients aged 18–24 years had elevated odds of comorbid PD, adjustment, childhood-onset, impulse-control, psychotic, and eating diagnoses. Females had more PD, AD, MD, eating, and somatoform diagnoses, while males had more childhood-onset, impulse-control, and psychotic diagnoses. Blacks had greater odds than whites of psychotic and cognitive/dementia diagnoses, while whites exhibited elevated odds of PA, AD, MD, childhood-onset, eating, somatoform, and sleep diagnoses. Women, blacks, and Native American/multiple-race adults had elevated odds of using inpatient treatment; men, blacks, and Hispanics had increased odds of using psychiatric emergency care. Comorbid MD, PD, adjustment, somatoform, psychotic, or cognitive/dementia diagnoses increased inpatient treatment.
Conclusion
Patients with a SUD, especially minority members, use more inpatient or psychiatric emergency care than those without. Findings provide evidence for research on understudied diagnoses and underserved populations in the real-world clinical settings.
doi:10.1016/j.jpsychires.2012.12.009
PMCID: PMC3581730  PMID: 23337131
anxiety disorders; comorbidity; comparative effectiveness research; electronic health records; mood disorders; personality disorders; substance-related disorders
2.  Episodic Heavy Drinking, Problem Drinking and Injuries – Results of the WHO/NIAAA Collaborative Emergency Room Study in South Korea 
Alcohol (Fayetteville, N.Y.)  2012;46(5):407-413.
Alcohol is the 5th leading risk factor to the global disease burden and disability and about half of the global alcohol burden was attributable to injuries. Despite a large body of evidence documenting the associations between alcohol and injuries, data from Asian countries including South Korea are sparse. The aim of this study was to investigate the associations between episodic heavy past-year drinking, problem drinking symptomatic of alcohol dependence and alcohol-related and intentional injuries. Data from 1,989 injured patients recruited for the WHO/NIAAA Collaborative Study on Alcohol and Injury in South Korea were analyzed with respect to the prevalence rates and associations between injuries and frequency of past-year episodic heavy drinking and problem drinking. In estimating the odds ratios (ORs) and the associated 95% confidence intervals between alcohol intake and injuries multivariable logistic models were employed to adjust for sociodemographic characteristics and selected drinking variables. All analyses were conducted using the SAS 9.2 software. Findings of this study were consistent with prior studies that the risk of alcohol-related or intentional injury was positively associated with the frequency of episodic heavy drinking. The magnitudes of the associations were larger with frequent consumption of 5+ drinks (OR=4.0 approximately) than with frequent consumption of 12+ drinks (OR=3.1). Strong associations were also noted between RAPS4-assessed alcohol dependence and alcohol-related and intentional injuries. Further, the prevalence of intentional injury and its association with alcohol increased sharply once the acute alcohol intake exceeded 90 ml. Our results were consistent with prior studies that episodic heavy consumption, acute intoxication and problem drinking are pervasive among emergency room patients. Results of our study also lent support for administering a single-item screener querying consumption of 5+ drinks at a sitting in the past 12 months as a triage tool in Korea.
doi:10.1016/j.alcohol.2012.03.002
PMCID: PMC3431286  PMID: 22579122
emergency room (ER) study; episodic heavy drinking; problem drinking; alcohol-related and intentional injury
3.  Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats 
Psychopharmacology  2010;211(2):161-174.
Rationale
Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2 nicotinic receptors with only modest receptor activation.
Objectives
The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.
Methods
P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on IV nicotine self-administration in P and NP rats were assessed.
Results
Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.
Conclusions
Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.
doi:10.1007/s00213-010-1878-8
PMCID: PMC3695635  PMID: 20535453
Alcoholism; P rats; Nicotinic agonists; Alcohol drinking; Naltrexone; Treatment; Animal model; Saccharin; Nicotine addiction
4.  Treatment Use and Barriers among Adolescents with Prescription Opioid Use Disorders 
Addictive behaviors  2011;36(12):1233-1239.
Background
This study examined national trends, patterns, correlates, and barriers to substance abuse treatment use by adolescents aged 12–17 years who met at least one of the past-year criteria for prescription opioid abuse or dependence (N=1788).
Methods
Data were from the 2005–2008 National Surveys of Drug Use and Health (NSDUH). Past-year substance use disorders, major depression, and treatment use were assessed by audio computer-assisted self-interviewing.
Results
About 17% of adolescents with opioid dependence (n=434) and 16% of those with opioid abuse (n=355) used any substance abuse treatment in the past year compared with 9% of subthreshold users, i.e., adolescents who reported 1–2 prescription opioid dependence criteria but no abuse criteria (n=999). Only 4.2% of adolescents with opioid dependence, 0.5% of those with abuse, and 0.6% of subthreshold users reported a perceived need for treatment of nonmedical opioid use. Self-help groups and outpatient rehabilitation were the most commonly used sources of treatment. Few black adolescents used treatment (medical settings, 3.3%; self-help groups, 1.7%) or reported a need for treatment (1.8%). Talking to parents/guardians about dangers of substance use increased the odds of treatment use. Barriers to treatment use included —wasn’t ready to stop substance use,” —didn't want others to find out,” and —could handle the problem without treatment.”
Conclusions
Adolescents with prescription opioid use disorders markedly underutilize treatment. Non-financial barriers are pervasive, including stigma and a lack of perceived treatment need.
doi:10.1016/j.addbeh.2011.07.033
PMCID: PMC3179790  PMID: 21880431
Opioid use disorders; Misuse of prescription opioids; Self-help groups; Substance abuse treatment
5.  Role of GABRA2 in Moderating Subjective Responses to Alcohol 
Background
Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the γ-aminobutyric acid A (GABAA) receptor α2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration.
Methods
One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis.
Results
Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence–associated allele regardless of ALDH2 genotype.
Conclusions
These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.
doi:10.1111/j.1530-0277.2010.01357.x
PMCID: PMC3472524  PMID: 21118274
GABA; GABRA2; Alcohol; Subjective Response; Alcohol Clamping; ALDH2
6.  Gender Differences in the Relationship of Internalizing and Externalizing Psychopathology to Alcohol Dependence: Likelihood, Expression and Course 
Drug and alcohol dependence  2010;112(1-2):9-17.
Objective
To determine whether internalizing and externalizing psychopathology were differentially associated with alcohol dependence in men and women.
Methods
Four categories of lifetime psychopathology were examined: neither internalizing nor externalizing (NINE), internalizing only (IO), externalizing only (EO) and both internalizing and externalizing (BIE). Multivariate models assessed gender differences in the adjusted associations of these categories with the odds of lifetime alcohol dependence in a representative sample of 43,093 U.S. adults 18 and older and with clinical course and expression in a subsample of 4,781 lifetime alcoholics.
Results
The excess odds of lifetime alcohol dependence associated with IO, EO and BIE were significantly greater for women than men, OR = 2.6, 8.8 and 10.7 versus 1.9, 4.0 and 6.5, respectively. Regardless of gender, the ORs were significantly higher for EO than IO and for BIE than EO. Gender differences in the expression and course of alcoholism were most pronounced for the categories of NINE and IO, with men having greater consumption, dependence severity and treatment but less familial alcoholism. Gender variation in the association of psychopathology with the expression and course of alcoholism most evident in the BIE category, where the associations were stronger for women. Lifetime externalizing psychopathology was associated with an increased likelihood of treatment utilization, especially among women.
Conclusions
Findings highlight the need to increase alcoholism screening, prevention and intervention among women with psychopathology, especially externalizing. The greater numbers of internalizing than externalizing alcoholics emphasizes the need to treat symptoms of depression and anxiety in alcohol treatment settings.
doi:10.1016/j.drugalcdep.2010.04.019
PMCID: PMC2953598  PMID: 20558014
alcohol dependence; psychopathology; gender; externalizing; internalizing
7.  Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat 
Background
Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift.
Methods
Rats were infused with solutions of sodium acetate, ethanol, or saline containing 13C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs’ cycle, acyl-coenzyme A (CoA) compounds, and amino acids.
Results
Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of 13C-glucose into the brain compared to controls and the concentration of brain 13C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg2+ in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, α-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD+]/[NADH] was lower, the free mitochondrial [NAD+]/[NADH] and [CoQ]/[CoQH2] were oxidized and the ΔG′ of ATP lowered by acetate infusion from −61.4 kJ to −59.9 kJ/mol.
Conclusions
Animals with elevated levels of blood ethanol or acetate had decreased 13C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in 13C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in ΔG′ of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form.
doi:10.1111/j.1530-0277.2009.01099.x
PMCID: PMC2958045  PMID: 19951290
Acetate; Brain; Energy Metabolism; 13C-Glucose; ΔG′ ATP
8.  Genomewide SNP Screen to Detect Quantitative Trait Loci for Alcohol Preference in the High Alcohol Preferring and Low Alcohol Preferring Mice 
Background
The high and low alcohol preferring (HAP1 and LAP1) mouse lines were selectively bred for differences in alcohol intake. The HAP1 and LAP1 mice are essentially noninbred lines that originated from the outbred colony of HS/Ibg mice, a heterogeneous stock developed from intercrossing 8 inbred strains of mice.
Methods
A total of 867 informative SNPs were genotyped in 989 HAP1 × LAP1 F2, 68 F1s, 14 parents (6 LAP1, 8 HAP1), as well as the 8 inbred strains of mice crossed to generate the HS/Ibg colony. Multipoint genome wide analyses were performed to simultaneously detect linked QTLs and also fine map these regions using the ancestral haplotypes.
Results
QTL analysis detected significant evidence of association on 4 chromosomes: 1, 3, 5, and 9. The region on chromosome 9 was previously found linked in a subset of these F2 animals using a whole genome microsatellite screen.
Conclusions
We have detected strong evidence of association to multiple chromosomal regions in the mouse. Several of these regions include candidate genes previously associated with alcohol dependence in humans or other animal models.
doi:10.1111/j.1530-0277.2008.00866.x
PMCID: PMC2867232  PMID: 19120064
Quantitative Trait Locus; Alcohol Consumption; Association
9.  A Critical Evaluation of Influence of Ethanol and Diet on Salsolinol Enantiomers in Humans and Rats 
Background
(R /S)-Salsolinol (SAL), a condensation product of dopamine (DA) with acetaldehyde, has been speculated to have a role in the etiology of alcoholism. Earlier studies have shown the presence of SAL in biological fluids and postmortem brains from both alcoholics and non-alcoholics. However, the involvement of SAL in alcoholism has been controversial over several decades, since the reported SAL levels and their changes after ethanol exposure were not consistent, possibly due to inadequate analytical procedures and confounding factors such as diet and genetic predisposition. Using a newly developed mass spectrometric method to analyze SAL stereoisomers, we evaluated the contribution of ethanol, diet, and genetic background to SAL levels as well as its enantiomeric distribution.
Methods
Simultaneous measurement of SAL enantiomers and DA were achieved by high performance liquid chromatography-tandem mass spectrometry (HPLC / MS / MS). Plasma samples were collected from human subjects before and after banana (a food rich in SAL) intake, and during ethanol infusion. Rat plasma and brain samples were collected at various time points after the administration of SAL or banana by gavage. The brain parts including nucleus accumbens (NAC) and striatum (STR) were obtained from alcohol-non-preferring (NP) or alcohol-preferring (P) rats as well as P-rats which had a free access to ethanol (P-EtOH).
Results
Plasma SAL levels were increased significantly after banana intake in humans. Consistently, administration of banana to rats also resulted in a drastic increase of plasma SAL levels, whereas brain SAL levels remained unaltered. Acute ethanol infusion did not change SAL levels or R / S ratio in plasma from healthy humans. The levels of both SAL isomers and DA were significantly lower in the NAC of P rats in comparison to NP rats. The SAL levels in NAC of P rats remained unchanged after chronic free-choice ethanol drinking. There were decreasing trends of SAL in STR and DA in both brain regions. No changes in enantiomeric ratio were observed after acute or chronic ethanol exposure.
Conclusions
SAL from dietary sources is the major contributor to plasma SAL levels. No significant changes of SAL plasma levels or enantiomeric distribution after acute or chronic ethanol exposure suggest that SAL may not be a biomarker for ethanol drinking. Significantly lower SAL and DA levels observed in NAC of P rats may be associated with innate alcohol preference.
doi:10.1111/j.1530-0277.2009.01087.x
PMCID: PMC2858379  PMID: 19951298
Salsolinol; Diet; Ethanol; Dopamine; Alcohol-Preferring Rats; Alcohol-Non-Preferring Rats; Nucleus Accumbens; Striatum; HPLC / MS / MS
11.  Transitions In and Out of Alcohol Use Disorders: Their Associations with Conditional Changes in Quality of Life Over a 3-Year Follow-Up Interval† 
Aims: The aim of this study was to investigate longitudinal changes in quality of life (QOL) as a function of transitions in alcohol use disorders (AUD) over a 3-year follow-up of a general US population sample. Methods: The analysis is based on individuals who drank alcohol in the year preceding the Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions and were reinterviewed at Wave 2 (n = 22,245). Using multiple linear regression models, changes in SF-12 QOL were estimated as a function of DSM-IV AUD transitions, controlling for baseline QOL and multiple potential confounders. Results: Onset and offset of AUD were strongly associated with changes in mental/psychological functioning, with significant decreases in mental component summary (NBMCS) scores among individuals who developed dependence and significant increases among those who achieved full and partial remission from dependence. The increases in overall NBMCS and its social functioning, role emotional and mental health components were equally great for abstinent and nonabstinent remission from dependence, but improvements in bodily pain and general health were associated with nonabstinent remission only. Onset of abuse was unrelated to changes in QOL, and the increase in NBMCS associated with nonabstinent remission from abuse only was slight. Individuals with abuse only or no AUD who stopped drinking had significant declines in QOL. Conclusions: These results suggest the possible importance of preventing and treating AUD for maintaining and/or improving QOL. They are also consistent with the sick quitter hypothesis and suggest that abuse is less a mental disorder than a maladaptive pattern of behavior.
doi:10.1093/alcalc/agn094
PMCID: PMC2605522  PMID: 19042925
12.  Transitions In and Out of Alcohol Use Disorders: Their Associations with Conditional Changes in Quality of Life Over a 3-Year Follow-Up Interval 
Aims
To investigate longitudinal changes in quality of life (QOL) as a function of transitions in alcohol use disorders (AUD) over a 3-year follow-up of a general U.S. population sample.
Methods
The analysis is based on individuals who drank alcohol in the year preceding the Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions and were reinterviewed at Wave 2 (n=22,245). Using multiple linear regression models, changes in SF-12 QOL were estimated as a function of DSM-IV AUD transitions, controlling for baseline QOL and multiple potential confounders.
Results
Onset and offset of AUD were strongly associated with changes in mental/psychological functioning, with significant decreases in mental component summary (NBMCS) scores among individuals who developed dependence and significant increases among those who achieved full and partial remission from dependence. The increases in overall NBMCS and its social functioning, role emotional and mental health components were equally great for abstinent and nonabstinent remission from dependence, but improvements in bodily pain and general health were associated with nonabstinent remission only. Onset of abuse was unrelated to changes in QOL, and the increase in NBMCS associated with nonabstinent remission from abuse only was slight. Individuals with abuse only or no AUD who stopped drinking had significant declines in QOL.
Conclusions
These results suggest the possible importance of preventing and treating AUD for maintaining and/or improving QOL. They are also consistent with the sick quitter hypothesis and suggest that abuse is less a mental disorder than a maladaptive pattern of behavior.
doi:10.1093/alcalc/agn094
PMCID: PMC2605522  PMID: 19042925
quality of life; QOL; HRQOL; alcohol use disorders; remission; transitions
13.  Autonomic activation associated with ethanol self-administration in adult female P rats 
The present study examined changes in heart rate (HR) prior to and during limited access ethanol drinking in adult female P rats. P rats were implanted with radiotelemetric transmitters to measure HR. Daily testing involved a 90-min pre-test period (water only available) and a subsequent 90-min test period [either water (W) or ethanol available]. After a week of habituation, one ethanol group had access to ethanol for 7 weeks (CE), and another ethanol group had access for 4 weeks, was deprived for 2 weeks and then had access for a final week (DEP). Analyses of HR revealed that CE and DEP rats had significantly higher HR than W rats during test periods that ethanol was present and that DEP rats displayed higher HR during the early test period of the ethanol deprivation interval, as well. These data indicate that ethanol drinking induces HR activation in adult female P rats, and that this activation can be conditioned to the test cage environment, paralleling reports on contextual conditioning and cue-reactivity in alcoholics exposed to alcohol-associated stimuli. Therefore, this behavioral test may prove advantageous in screening pharmacotherapies for reducing craving and relapse, which are associated with cue-reactivity in abstinent alcoholics.
doi:10.1016/j.pbb.2008.07.016
PMCID: PMC2592255  PMID: 18713644
Alcohol; stimulation; activation; autonomic; cue reactivity; heart rate; alcohol-preferring rats; contextual conditioning
14.  A Prospective Study of Risk Drinking: At Risk for What? 
Drug and alcohol dependence  2008;95(1-2):62-72.
Data from two waves of a nationally representative U.S. population sample were used to link frequency of risk drinking in the year preceding the Wave 1 interview with the incidence or occurrence of various adverse outcomes in the approximately 3-year period between the two interviews (n = 22,245 Wave 1 drinkers who were reinterviewed at Wave 2). Risk drinking was defined as consuming the equivalent of 5+ standard drinks in a day for men and the equivalent of 4+ standard drinks in a day for women. Controls included sociodemographic and health characteristics, mean quantity of drinks consumed on risk drinking days and average volume of intake on non-risk drinking days. The odds of nonhierarchical alcohol abuse and dependence, initiation of smoking and incidence of nicotine dependence were increased at all frequencies of risk drinking and showed a fairly continuous increase in magnitude with increasing frequency, reaching OR of 3.03 – 7.23 for daily/near daily risk drinking. The incidence of liver disease was strongly increased among weekly or more frequent risk drinkers (OR = 2.78 – 4.76). The odds of social harm, drug use and drug dependence were increased among daily/near daily risk drinkers (OR = 1.61 – 2.63), and the likelihood of marital disruption and drivers license revocation showed near-significant increases at all frequencies of risk drinking. Frequency of risk drinking interacted with volume of intake on non-risk drinking days in predicting alcohol abuse and illicit drug use and with duration of drinking in predicting alcohol dependence. Risk drinking poses a threat of many types of harm, both directly and indirectly through its association with smoking initiation and nicotine dependence. These findings have illustrative value for prevention programs, and they indicate that frequent risk drinker is a strong marker for alcoholism.
doi:10.1016/j.drugalcdep.2007.12.00
PMCID: PMC2366117  PMID: 18243584
risk drinking; prospective risk
15.  The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption 
PLoS Medicine  2009;6(3):e1000050.
Philip Brooks and colleagues discuss evidence linking the alcohol flushing response (predominantly due to ALDH2 deficiency) with a much higher risk of esophageal cancer from alcohol consumption.
doi:10.1371/journal.pmed.1000050
PMCID: PMC2659709  PMID: 19320537
16.  Innate differences in protein expression in the nucleus accumbens and hippocampus of inbred alcohol-preferring and -nonpreferring rats 
Proteomics  2003;3(7):1335-1344.
Two-dimensional gel electrophoresis (2-DE) was used to separate protein samples solubilized from the nucleus accumbens and hippocampus of alcohol-naïve, adult, male inbred alcohol-preferring (iP) and alcohol-nonpreferring (iNP) rats. Several protein spots were excised from the gel, destained, digested with trypsin, and analyzed by mass spectrometry. In the hippocampus, 1629 protein spots were matched to the reference pattern, and in the nucleus accumbens, 1390 protein spots were matched. Approximately 70 proteins were identified in both regions. In the hippocampus, only 8 of the 1629 matched protein spots differed in abundance between the iP and iNP rats. In the nucleus accumbens, 32 of the 1390 matched protein spots differed in abundance between the iP and iNP rats. In the hippocampus, the abundances of all 8 proteins were higher in the iNP than iP rat. In the nucleus accumbens, the abundances of 31 of 32 proteins were higher in the iNP than iP rat. In the hippocampus, only 2 of the 8 proteins that differed could be identified, whereas in the nucleus accumbens 21 of the 32 proteins that differed were identified. Higher abundances of cellular retinoic acid-binding protein 1 and a calmodulin-dependent protein kinase (both of which are involved in cellular signaling pathways) were found in both regions of the iNP than iP rat. In the nucleus accumbens, additional differences in the abundances of proteins involved in (i) metabolism (e.g., calpain, parkin, glucokinase, apolipoprotein E, sorbitol dehydrogenase), (ii) cyto-skeletal and intracellular protein transport (e.g., β-actin), (iii) molecular chaperoning (e.g., grp 78, hsc70, hsc 60, grp75, prohibitin), (iv) cellular signaling pathways (e.g., protein kinase C-binding protein), (v) synaptic function (e.g., complexin I, γ-enolase, syndapin IIbb), (vi) reduction of oxidative stress (thioredoxin peroxidase), and (vii) growth and differentiation (hippocampal cholinergic neurostimulating peptide) were found. The results of this study indicate that selective breeding for disparate alcohol drinking behaviors produced innate alterations in the expression of several proteins that could influence neuronal function within the nucleus accumbens and hippocampus.
doi:10.1002/pmic.200300453
PMCID: PMC2652869  PMID: 12872235
Alcohol-preferring P rats; Hippocampus; Nucleus accumbens; Two-dimensional gel electrophoresis
18.  Research Funding: The View From NIH 
The American journal of psychiatry  2006;163(12):2043-2045.
doi:10.1176/appi.ajp.163.12.2043
PMCID: PMC2225455  PMID: 17151151
19.  What Is Addiction? 
Alcohol Research & Health  2008;31(2):93-95.
This issue of Alcohol Research & Health examines addiction to multiple substances—that is, combined dependence on alcohol and other drugs (AODs), including marijuana, cocaine, and opioids. It seems fitting, then, to begin the issue with a look at what constitutes “addiction.” The Oxford English Dictionary (pp. 24–25) traces the term addiction to Roman law, under which addiction was a “formal giving over by sentence of court; hence, a dedication of person to a master.” This notion of relinquishment of control by the addicted person is the central feature of many lay and professional definitions of the term. The study of addictive behavior crosses several disciplines, including, among others, behavioral neuroscience, epidemiology, genetics, molecular biology, pharmacology, psychology, psychiatry, and sociology. Articles in this issue examine aspects of AOD use disorders from the perspective of some of these varied disciplines.
PMCID: PMC3860451  PMID: 23584810
Addiction; alcohol and other drug (AOD) use; abuse and dependence; AOD use disorders (AODUDs); substance abuse; substance dependence; Diagnostic and Statistical Manual of Mental Disorders (DSM)
20.  Prolonged Increase in the Sensitivity of the Posterior Ventral Tegmental Area to the Reinforcing Effects of Ethanol following Repeated Exposure to Cycles of Ethanol Access and Deprivation 
The posterior ventral tegmental area (VTA) is a neuroanatomical substrate mediating the reinforcing effects of ethanol in rats. Repeated alcohol deprivations produce robust ethanol intakes of alcohol-preferring (P) rats during relapse and increase the reinforcing effects of oral alcohol self-administration. The objective of this study was to test the hypothesis that alcohol drinking and repeated alcohol deprivations will increase the reinforcing effects of ethanol within the posterior VTA of P rats. Groups of female P rats were used (alcohol-naive, continuous access, and repeatedly deprived). Each rat was implanted with a guide cannula aimed at the posterior VTA. Depression of the active lever produced the infusion of 100 nl of artificial cerebrospinal fluid (CSF) or ethanol (25–300 mg%). Each rat was given only one ethanol concentration during the 4-h sessions conducted every other day. Compared with the infusions of artificial CSF, the alcohol-naive group reliably self-infused 75 and 150 mg% ethanol, but not the lower or higher concentrations. On the other hand, the continuous access group had significantly higher self-infusions of 50, 75, 150, and 300 mg% ethanol compared with artificial CSF infusions. The repeatedly deprived group also self-infused significantly more of 50, 75, 150, and 300 mg% ethanol than artificial CSF; moreover, the number of infusions for all four concentrations was higher in the repeatedly deprived versus the continuous access group. Chronic alcohol drinking by P rats increased the reinforcing effects of ethanol within the posterior VTA, and repeated alcohol deprivations produced a further increase in these reinforcing effects of ethanol.
doi:10.1124/jpet.105.084350
PMCID: PMC1924682  PMID: 16076936
21.  Response to: “Rescuing the NIH before it is too late” 
Journal of Clinical Investigation  2006;116(6):1462-1464.
We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.
doi:10.1172/JCI28894
PMCID: PMC1449952  PMID: 16648877
22.  Vitamin B6 Metabolism in Chronic Alcohol Abuse 
Journal of Clinical Investigation  1974;53(3):693-704.
The plasma pyridoxal-5′-phosphate (PLP) level of alcoholic subjects has been compared with that of non-alcoholic individuals in order to ascertain the incidence of abnormal vitamin B6 metabolism in chronic alcohol abuse. 66 alcoholic subjects were selected on the basis that they did not exhibit abnormal liver function tests and hematologic findings. 35 of them had plasma PLP concentrations less than 5 ng/ml, the lowest value encountered in 94 control subjects, indicating a high incidence of deranged PLP metabolism in alcoholic patients even when hepatic and hematologic abnormalities are absent. The biochemical basis for the altered PLP metabolism in chronic alcohol abuse was examined. Low plasma PLP levels in alcoholics were not accompanied by decreased pyridoxal kinase and pyridoxine phosphate oxidase activities in erythrocytes. Further studies with erythrocytes demonstrated that the cellular content of PLP is determined not only by the activities of these PLP-synthesizing enzymes but also by the activity of a phosphate-sensitive, membrane-associated, neutral phosphatase, which hydrolyzes phosphorylated B6 compounds.
Acetaldehyde, but not ethanol, impaired the net formation of PLP from pyridoxal, pyridoxine, and pyridoxine phosphate by erythrocytes. However, when the B6-phosphate phosphatase activity was inhibited by 80 mM phosphate, this effect of acetaldehyde was abolished. By the use of broken cell preparations, it was possible to demonstrate directly that the action of acetaldehyde is mediated by the phosphatase, resulting in an acceleration of the degradation of the phosphorylated B6 compounds in erythrocytes.
PMCID: PMC333049  PMID: 4359937
23.  Neuroscience Networks 
PLoS Biology  2003;1(1):e17.
To study the brain from molecules to behaviour, neuroscientists face the challenge of communicating an emerging wealth of information in coherent accessible forms
doi:10.1371/journal.pbio.0000017
PMCID: PMC212696  PMID: 14551914

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