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1.  Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects 
Neuropharmacology  2012;67C:337-348.
The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF1) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically-selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF1 antagonist in msP, Sprague-Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABAA-inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague-Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF1 antagonist (R121919, 1 μM) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF1 antagonist in msP rats, suggesting increased GABA release and decreased CRF1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naïve mSP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence.
doi:10.1016/j.neuropharm.2012.11.026
PMCID: PMC3562384  PMID: 23220399
amygdala; GABA; alcohol; CRF; CRF1 antagonist; electrophysiology
2.  Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism 
Drug and alcohol dependence  2013;128(3):175-186.
Background
Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking.
Methods
We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence.
Results
The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation.
Conclusions
Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence.
doi:10.1016/j.drugalcdep.2012.12.017
PMCID: PMC3596012  PMID: 23294766
corticotropin-releasing factor or hormone receptor antagonist; CRF or CRH; anxiety disorder; major depression; alcohol or ethanol; drug addiction or alcoholism or alcohol dependence or alcohol use disorder or binge drinking; acute or protracted withdrawal or abstinence; treatment or clinical trial; stress-induced relapse or reinstatement or craving
3.  A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats 
The Journal of Neuroscience  2013;33(24):10132-10142.
The Neuropeptide S receptor, a Gs/Gq-coupled GPCR expressed in brain regions involved in mediating drug reward, has recently emerged as a candidate therapeutic target in addictive disorders. Here, we describe the in vitro and in vivo pharmacology of a novel, selective and brain penetrant NPSR antagonist with nanomolar affinity for the NPSR, NCGC00185684. In vitro, NCGC00185684 shows biased antagonist properties, and preferentially blocks ERK-phosphorylation over intracellular cAMP or calcium responses to NPS. In vivo, systemic NCGC00185684 blocks alcohol-induced ERK-phosphorylation in the rat central amygdala, a region involved in regulation of alcohol intake. NCGC00185684 also decreases operant alcohol self-administration, and lowers motivation for alcohol reward as measured using progressive ratio responding. These effects are behaviorally specific, in that they are observed at doses that do not influence locomotor activity or reinstatement responding following extinction. Together, these data provide an initial validation of the NPSR as a therapeutic target in alcoholism.
doi:10.1523/JNEUROSCI.4742-12.2013
PMCID: PMC3682378  PMID: 23761908
4.  Binge-Like Ethanol Consumption Increases Corticosterone Levels and Neurodegneration whereas occupancy of Type II Glucocorticoid Receptors with Mifepristone is Neuroprotective 
Addiction biology  2012;10.1111/j.1369-1600.2012.00451.x.
Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing basal, medium or high Cort. Intragastric EtOH or an isocaloric control solution was given 3 times daily for 4 days to achieve blood alcohol levels (BALs) ranging between 200-350 mg/dl. Mean 24 hour (24-hr) plasma Cort levels were ~110 ng/ml and ~40 ng/ml in intact EtOH treated and intact control, respectively. Basal Cort replacement in EtOH-treated Adx animals animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement resulting in levels 2-fold higher (medium) than normal, or higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocortocoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone treated animals in the EC, as determined by Fluoro Jade B staining. These results suggest that Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.
doi:10.1111/j.1369-1600.2012.00451.x
PMCID: PMC3561503  PMID: 22500955
ethanol; corticosterone; neurodegeneration; mifepristone. dentate gyrus; Fluoro Jade B; RU38486; entorhinal cortex
5.  Stress related neuropeptides and addictive behaviors: Beyond the usual suspects 
Neuron  2012;76(1):192-208.
Summary
Addictive disorders are chronic, relapsing conditions that cause extensive disease burden. Genetic factors partly account for susceptibility to addiction, but environmental factors such as stressful experiences and prolonged exposure of the brain to addictive drugs promote its development. Progression to addiction involves neuroadaptations within neurocircuitry that mediates stress responses, and is influenced by several peptidergic neuromodulators. While corticotropin releasing factor is the prototypic member of this class, recent work has identified several additional stress-related neuropeptides that play an important role in regulation of drug intake and relapse, including the urocortins, nociceptin, substance P and neuropeptide S. Here, we review this emerging literature, discussing to what extent the properties of these neuromodulators are shared or distinct and considering their potential as drug targets.
doi:10.1016/j.neuron.2012.09.026
PMCID: PMC3495179  PMID: 23040815
6.  Correction: Low Vitamin D Status and Suicide: A Case-Control Study of Active Duty Military Service Members 
PLoS ONE  2013;8(9):10.1371/annotation/9af84cbe-5576-4c4b-871c-f7ab0c64b9fd.
doi:10.1371/annotation/9af84cbe-5576-4c4b-871c-f7ab0c64b9fd
PMCID: PMC3782564  PMID: 24086215
7.  Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence 
A key deficit in alcohol dependence is disrupted prefrontal function leading to excessive alcohol seeking, but the molecular events underlying the emergence of addictive responses remain unknown. Here we show by convergent transcriptome analysis that the pyramidal neurons of the infralimbic cortex are particularly vulnerable for the long-term effects of chronic intermittent ethanol intoxication. These neurons exhibit a pronounced deficit in mGluR2. Also, alcohol dependent rats do not respond to mGluR2/3 agonist treatment with reducing extracellular glutamate levels in the nucleus accumbens. Together these data imply a loss of autoreceptor feedback control. Alcohol dependent rats show escalation of ethanol seeking, which was abolished by restoring mGluR2 expression in the infralimbic cortex via viral-mediated gene transfer. Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR2 transcripts compared to control subjects suggesting that mGluR2 loss in the rodent and human cortico-accumbal neurocircuitry may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse. Normalization of mGluR2 function within this brain circuit may be of therapeutic value.
doi:10.1523/JNEUROSCI.4062-12.2013
PMCID: PMC3711176  PMID: 23407939
8.  Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST 
Neuropharmacology  2012;63(2):181-189.
A hyperglutamatergic state has been hypothesized to drive escalation of alcohol intake. This hypothesis predicts that an impairment of glutamate clearance through inactivation of the astrocytic glutamate transporter, GLAST (EAAT1), will result in escalation of alcohol consumption. Here, we used mice with a deletion of GLAST to test this prediction. WT and GLAST KO mice were tested for alcohol consumption using two-bottle free-choice drinking. Alcohol reward was evaluated using conditioned place preference (CPP). Sensitivity to depressant alcohol effects was tested using the accelerating rotarod, alcohol-induced hypothermia, and loss of righting reflex. Extracellular glutamate was measured using microdialysis, and striatal slice electrophysiology was carried out to examine plasticity of the cortico-striatal pathway as a model system in which adaptations to the constitutive GLAST deletion can be studied. Contrary to our hypothesis, GLAST KO mice showed markedly decreased alcohol consumption, and lacked CPP for alcohol, despite a higher locomotor response to this drug. Alcohol-induced ataxia, hypothermia, and sedation were unaffected. In striatal slices from GLAST KO mice, long-term depression (LTD) induced by high frequency stimulation, or by post-synaptic depolarization combined with the L-type calcium channel activator FPL 64176 was absent. In contrast, normal synaptic depression was observed after application of the cannabinoid 1 (CB1) receptor agonist WIN55,212-2. Constitutive deletion of GLAST unexpectedly results in markedly reduced alcohol consumption and preference, associated with markedly reduced alcohol reward. Endocannabinoid signaling appears to be down-regulated upstream of the CB1 receptor as a result of the GLAST deletion, and is a candidate mechanism behind the reduction of alcohol reward observed.
doi:10.1016/j.neuropharm.2012.01.027
PMCID: PMC3372600  PMID: 22342743
glutamate transporter; alcohol; reward; endocannabinoid
9.  Impact of Multiple Types of Childhood Trauma Exposure on Risk of Psychiatric Comorbidity among Alcoholic Inpatients 
Background
This study examined the prevalence of single- and multiple-type childhood trauma exposure (CTE) among alcoholic patients undergoing in-patient detoxification and treatment. The relationships between various types of CTE and lifetime psychiatric comorbidites and suicide attempts were also explored.
Methods
A total of 196 alcoholic inpatients were assessed by Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and Childhood Trauma Questionnaire (CTQ) for CTE history.
Results
The overall prevalence of CTE of the entire sample was high (55.1%). Specifically, the prevalence of emotional abuse was 21.4%, physical abuse 31.1%, sexual abuse 24.0%, emotional neglect 20.4%, and physical neglect 19.9%. Regarding multiple types of CTE, 31.7% and 18.9% reported at least two and at least three CTE types respectively. Strikingly, among those with at least one positive CTQ category, more than half reported two or more CTE types. A history of emotional abuse increased the risk of mood disorder, in particular major depressive disorder, as well as PTSD. Physical abuse contributed to the prediction of suicide attempts, while sexual abuse was associated with a diagnosis of anxiety disorder, PTSD, and multiple comobidities (e.g., anxiety and mood disorder).The number of reported CTE types or the total scores of the CTQ predicted an increased risk of having single or multiple psychiatric comorbidities as well as suicide attempts.
Conclusions
We observed high rates of a broad range of CTE types and a trend for CTE-specific enhancement of risk for various psychiatric outcomes among alcoholic inpatients. Of notion, a dose-response relationship between number of CTE types and risk of psychiatric comorbidities as well as suicide attempts was found. We suggest a wide range of CTE should be included when exploring the effects of CTE or developing prevention and treatment strategies among alcoholic subjects.
doi:10.1111/j.1530-0277.2011.01695.x
PMCID: PMC3370064  PMID: 22420670
Childhood Trauma; Alcohol Dependence; Psychiatric Comorbidity; Suicide
10.  The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety 
Addiction Biology  2012;17(3):634-647.
The role of kappa-opioid receptors (KOR) in regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety (“hangover anxiety”). JDTic dose-dependently reversed hangover anxiety when given 48 h prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 h prior to testing, but not at longer pretreatment times. For comparison, we determined that the prototypical KOR antagonist nor-BNI can suppress self-administration of alcohol at 2h pretreatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress-induced reinstatement of alcohol seeking, self administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2h pretreatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism.
doi:10.1111/j.1369-1600.2012.00455.x
PMCID: PMC3334348  PMID: 22515275
Alcoholism; Dynorphin; Ethanol; Reinstatement; Self-administration; Stress
11.  Medications Development to Treat Alcohol Dependence: A Vision for the Next Decade 
Addiction biology  2012;17(3):513-527.
More than 76 million people worldwide are estimated to have diagnosable Alcohol Use Disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The U.S. Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism’s (NIAAA’s) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: 1) to make the drug development process more efficient; 2) to identify more efficacious medications, personalize treatment approaches, or both, and 3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options, and ultimately lessen the impact of this devastating disorder.
doi:10.1111/j.1369-1600.2012.00454.x
PMCID: PMC3484365  PMID: 22458728
alcohol; medications; drug development; Alcohol Use Disorders; alcohol dependence
12.  Role of a Genetic Polymorphism in the Corticotropin-Releasing Factor Receptor 1 Gene in Alcohol Drinking and Seeking Behaviors of Marchigian Sardinian Alcohol-Preferring Rats 
Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol, are highly sensitive to stress and stress-induced alcohol seeking. Genetic analysis showed that over-expression of the corticotropin-releasing factor (CRF) system of msP rats is correlated with the presence of two single nucleotide polymorphisms (SNPs) occurring in the promoter region (position −1836 and −2097) of the CRF1 receptor (CRF1-R) gene. Here we examined whether these point mutations were associated to the innate alcohol preference, stress-induced drinking, and seeking. We have recently re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and the point mutations (AA), respectively. The phenotypic characteristics of these two lines were compared with those of unselected Wistar rats. Both AA and GG rats showed similar patterns of voluntary alcohol intake and preference. Similarly, the pharmacological stressor yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) elicited increased operant alcohol self-administration under fixed and progressive ratio reinforcement schedules in all three lines. Following extinction, yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) significantly reinstated alcohol seeking in the three groups. However, at the highest dose this effect was no longer evident in AA rats. Treatment with the CRF1-R antagonist antalarmin (0, 5, 10, and 20 mg/kg) significantly reduced alcohol-reinforced lever pressing in the AA line (10 and 20 mg/kg) while a weaker or no effect was observed in the Wistar and the GG group, respectively. Finally, antalarmin significantly reduced yohimbine-induced increase in alcohol drinking in all three groups. In conclusion, these specific SNPs in the CRF1-R gene do not seem to play a primary role in the expression of the msP excessive drinking phenotype or stress-induced drinking but may be associated with a decreased threshold for stress-induced alcohol seeking and an increased sensitivity to the effects of pharmacological blockade of CRF1-R on alcohol drinking.
doi:10.3389/fpsyt.2013.00023
PMCID: PMC3624086  PMID: 23630503
CRF; SNP; self-administration; msP; yohimbine; relapse
13.  Relationship between liver function and brain shrinkage in patients with alcohol dependence 
Background
Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The study aim was to assess the correlations between liver function and brain volume measurements in patients with alcohol dependence.
Methods
We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as hematocrit (Hct) and albumin were assayed shortly after admission. MRI examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage.
Results
Patients with alcohol dependence had lower brain volume (BV), and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), and brain ratio (BR) and higher CSF ratio (CSFR) compared to their healthy counterparts. Age and sex were significantly correlated with some brain volume measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with brain volume indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients, but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage.
Conclusions
Our results showed that the higher levels of liver function indices, especially GGT, correlated with brain volume shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence, but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.
doi:10.1111/j.1530-0277.2011.01662.x
PMCID: PMC3262075  PMID: 21995416
alcohol dependence; MRI; liver function; brain shrinkage
14.  Brain-Specific Inactivation of the Crhr1 Gene Inhibits Post-Dependent and Stress-Induced Alcohol Intake, but Does Not Affect Relapse-Like Drinking 
Neuropsychopharmacology  2011;37(4):1047-1056.
Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic–pituitary–adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1NestinCre) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1NestinCre mice as compared with control animals. Crhr1NestinCre mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.
doi:10.1038/npp.2011.297
PMCID: PMC3280644  PMID: 22113086
alcoholism; stress; relapse; post-dependent drinking; alcohol deprivation effect (ADE); conditional Crhr1NestinCre-knockout mice; alcohol and alcoholism; biological psychiatry; neurochemistry; animal models; stress; relapse; post-dependent drinking; alcohol deprivation effect; CRH
15.  Acamprosate suppresses magnetic resonance spectroscopy measures of central glutamate in detoxified alcoholics: A randomized controlled experimental medicine study 
Archives of general psychiatry  2010;67(10):1069-1077.
Context
Acamprosate is approved for treatment of alcoholism, but its mechanism of action remains unclear. Animal studies suggest that a persistent hyperglutamatergic state contributes to the pathophysiology of alcoholism, and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.
Objective
To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol dependent patients, as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS).
Design
A 4 week, double-blind, placebo-controlled randomized controlled experimental medicine study, with 1H-MRS measures obtained on day 4 and 25.
Setting
NIAAA inpatient research unit at the NIH Clinical Center.
Patients
Thirty three patients who met the DSM-IV criteria for alcohol dependence and were admitted for medically supervised withdrawal from ongoing alcohol use.
Intervention
Four weeks of acamprosate (initial oral loading followed by 1998mg daily) or matched placebo, initiated at the time of admission.
Outcome measures
The main outcome was the glutamate/creatine ratio (Glu) as determined by single voxel 1H-MRS within the anterior cingulate. Exploratory neuroendocrine, biochemical and behavioral outcomes were also collected, as well as safety/tolerability – related measures.
Result
There was a highly significant suppression of Glu over time by acamprosate (time × treatment interaction: F[1, 29]=13.5, p<0.001). Cerebrospinal fluid (CSF) levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and were unaffected by treatment, but were strongly correlated (R2=0.48, p<0.001) with alcohol dependence severity. Other exploratory outcomes, including repeated Dex/CRH tests, as well as psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate treated subjects, in agreement with the established profile of acamprosate.
Conclusion
MRS measures of central glutamate are reduced over time when acamprosate is initiated at the onset of alcohol abstinence.
Trial registration
www.clinicaltrials.gov Identifier: NCT00106106
doi:10.1001/archgenpsychiatry.2010.125
PMCID: PMC3583213  PMID: 20921123
acamprosate; alcohol; magnetic resonance spectroscopy; glutamate
16.  Low Vitamin D Status and Suicide: A Case-Control Study of Active Duty Military Service Members 
PLoS ONE  2013;8(1):e51543.
Objective
Considering that epidemiological studies show that suicide rates in many countries are highest in the spring when vitamin D status is lowest, and that low vitamin D status can affect brain function, we sought to evaluate if a low level of 25-hydroxyvitamin D [25(OH)D] could be a predisposing factor for suicide.
Method
We conducted a prospective, nested, case-control study using serum samples stored in the Department of Defense Serum Repository. Participants were previously deployed active duty US military personnel (2002–2008) who had a recent archived serum sample available for analysis. Vitamin D status was estimated by measuring 25(OH) D levels in serum samples drawn within 24 months of the suicide. Each verified suicide case (n = 495) was matched to a control (n = 495) by rank, age and sex. We calculated odds ratio of suicide associated with categorical levels (octiles) of 25(OH) D, adjusted by season of serum collection.
Findings
More than 30% of all subjects had 25(OH)D values below 20 ng/mL. Although mean serum 25(OH)D concentrations did not differ between suicide cases and controls, risk estimates indicated that subjects in the lowest octile of season-adjusted 25(OH)D (<15.5 ng/mL) had the highest risk of suicide, with subjects in the subsequent higher octiles showing approximately the same level of decreased risk (combined odds ratio compared to lowest octile  = 0.49; 95% C.I.: 0.315–0.768).
Conclusions
Low vitamin D status is common in active duty service members. The lowest 25(OH)D levels are associated with an increased risk for suicide. Future studies could determine if additional sunlight exposure and vitamin D supplementation might reduce suicide by increasing 25(OH) D levels.
doi:10.1371/journal.pone.0051543
PMCID: PMC3537724  PMID: 23308099
17.  Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats 
Background
A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.
Methods
We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption.
Results
Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake.
Conclusions
Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.
doi:10.1016/j.pbb.2011.10.016
PMCID: PMC3242882  PMID: 22036774
Intermittent; Alcohol; CRH1R; Intake; Withdrawal; Antalarmin
18.  Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats 
The Journal of Neuroscience  2012;32(22):7563-7571.
Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal [HPA] axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions (i.e., prefrontal cortex, nucleus accumbens [NAc], and bed nucleus of the stria terminalis [BNST]), whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.
doi:10.1523/JNEUROSCI.0069-12.2012
PMCID: PMC3375621  PMID: 22649234
mifepristone (RU38486); corticosterone or glucocorticoid; drug addiction or dependence; anxiety; alcoholism
19.  The serotonin transporter gene linked polymorphic region is associated with the behavioral response to repeated stress exposure in infant rhesus macaques 
Development and psychopathology  2012;24(1):157-165.
The short allele of the serotonin transporter linked polymorphic region (5-HTTLPR) moderates the effects of stress on vulnerability to mood and anxiety disorders. The mechanism by which this occurs may relate to differential sensitivity to stressful life events. Here we explored whether 5-HTTLPR and sex affected behavioral responses to repeated maternal separation in infant rhesus macaques. Behaviors were collected during the acute (Day 1) and the chronic (Days 2–4) phases of the separation, and the effects of duration of separation (acute vs. chronic), genotype (long/long vs. short allele), and sex (male vs. female) on behavioral responses were analyzed across four successive separations. Males increased their levels of locomotion with repeated maternal separation, whereas females exhibited an increase in frequency of self-directed behavior, a measure of “depression-like” behavior. The short-allele predicted increased environmental exploration, particularly during the chronic phase of social separation, indicative of higher arousal. In addition, the short-allele carriers were more likely to increase their levels of self-directed behavior during the chronic phase of separation, as a function of repeated exposures. These findings suggest that the short allele may increase reactivity to repeated, chronic stressors, leaving them more vulnerable to affective psychopathology, with females particularly vulnerable.
doi:10.1017/S0954579411000745
PMCID: PMC3506168  PMID: 22293001
20.  Pharmacological Consequence of the A118G Mu Opioid Receptor Polymorphism on Morphine- and Fentanyl-mediated Modulation of Ca2+ Channels in Humanized Mouse Sensory Neurons 
Anesthesiology  2011;115(5):1054-1062.
Background
The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with inter-individual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of the present study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele.
Methods
The coupling of wild-type and mutant mu opioid receptors to voltage-gated Ca2+ channels after exposure to either ligand was examined by employing the whole-cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele.
Results
The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately 5-fold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared to the 118AA mice.
Conclusions
This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor’s pharmacology in sensory neurons. Additionally, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.
doi:10.1097/ALN.0b013e318231fc11
PMCID: PMC3203255  PMID: 21926562
21.  OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques 
Psychoneuroendocrinology  2011;36(9):1303-1311.
The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: 1) maternal separation in infant subjects at 6 months of age, 2) acute ethanol administration in adolescent subjects at 4 years of age, and 3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 minutes, 10 minutes, and 60 minutes following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 minutes following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele, lending further support to the argument that the rhesus and human allelic variants are functionally similar. Our results also suggest that OPRM1 variation may influence coping style, as well as alcohol-induced and postpartum levels of HPA axis activity and, as such, may modify vulnerability to alcohol use disorders and postpartum depression.
doi:10.1016/j.psyneuen.2011.03.002
PMCID: PMC3131436  PMID: 21459516
Opioids; Hypothalamic-Pituitary-Adrenal (HPA) Axis; Cortisol; Stress; Nonhuman Primate; Separation; Alcohol; Postpartum Depression
22.  The Biometric Measurement of Alcohol Consumption 
Background
Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought.
Methods
Platelet monoamine oxidase B (MAO-B) protein was quantitated in 2 populations of subjects who had histories of different levels of alcohol consumption. Levels were assayed by immunoblotting or by ELISA. The development and evaluation of the new ELISA-based measure of platelet MAO-B protein levels is described.
Results
One subject population constituted a nontreatment-seeking, cross-sectional subject sample, and the other population was a longitudinally followed, hospitalized group of subjects. An algorithm combining measures of platelet MAO-B protein with the plasma levels of carbohydrate-deficient transferrin (CDT) and with liver enzymes (aspartate aminotransferase or γ-glutamyltransferase [GGT]) can detect hazardous/harmful alcohol use (HHAU) with the highest sensitivity and specificity in the cross-sectional nontreatment-seeking population. In the treatment-seeking population, low MAO-B protein levels at admission are associated with heavy drinking prior to admission, and these protein levels increase over a period of abstinence from alcohol.
Conclusions
The platelet MAO-B protein measurement is particularly effective for male alcohol consumers. The combined use of MAO-B protein measures together with measures of CDT and GGT does, however, improve the diagnostic utility of both markers for ascertaining HHAU in women. Furthermore, measurement of changes in platelet MAO-B protein levels during treatment for alcohol dependence may help monitor the success of the treatment program.
doi:10.1111/j.1530-0277.2011.01605.x
PMCID: PMC3461278  PMID: 21895709
Alcohol Consumption; Biomarkers; MAO Protein; Platelets
23.  Pharmacogenetic approaches to the treatment of alcohol addiction 
Nature reviews. Neuroscience  2011;12(11):670-684.
Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.
doi:10.1038/nrn3110
PMCID: PMC3408029  PMID: 22011682
24.  Assessment of Glutamate Transporter GLAST (EAAT1)-Deficient Mice for Phenotypes Relevant to the Negative and Executive/Cognitive Symptoms of Schizophrenia 
Neuropsychopharmacology  2008;34(6):1578-1589.
Glutamatergic dysfunction is increasingly implicated in the pathophysiology of schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlie many of the symptoms in this disease. However, the mechanisms involved are not well understood. Although elucidating the role for glutamate transporters in the disease has been limited by the absence of pharmacological tools that selectively target the transporter, we recently showed that glial glutamate and aspartate transporter (GLAST; excitatory amino-acid transporter 1) mutant mice exhibit abnormalities on behavioral measures thought to model the positive symptoms of schizophrenia, some of which were rescued by treatment with either haloperidol or the mGlu2/3 agonist, LY379268 the mGlu2/3 agonist, LY379268. To further determine the role of GLAST in schizophrenia-related behaviors we tested GLAST mutant mice on a series of behavioral paradigms associated with the negative (social withdrawal, anhedonia), sensorimotor gating (prepulse inhibition of startle), and executive/cognitive (discrimination learning, extinction) symptoms of schizophrenia. GLAST knockout (KO) mice showed poor nesting behavior and abnormal sociability, whereas KO and heterozygous (HET) both demonstrated lesser preference for a novel social stimulus compared to wild-type littermate controls. GLAST KO, but not HET, had a significantly reduced acoustic startle response, but no significant deficit in prepulse inhibition of startle. GLAST KO and HET showed normal sucrose preference. In an instrumental visual discrimination task, KO showed impaired learning. By contrast, acquisition and extinction of a simple instrumental response was normal. The mGlu2/3 agonist, LY379268, failed to rescue the discrimination impairment in KO mice. These findings demonstrate that gene deletion of GLAST produces select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia.
doi:10.1038/npp.2008.215
PMCID: PMC3400972  PMID: 19078949
glutamate; schizophrenia; cognition; prepulse inhibition; social withdrawal; anhedonia
25.  Exposure to Nicotine During Periadolescence or Early Adulthood Alters Aversive and Physiological Effects Induced by Ethanol 
The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4 mg/kg, IP) from postnatal day 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8 g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0 g/kg) and the hypothermic effects of alcohol (1.0 g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8 g/kg) and hypothermic (1.8 g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine can alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed.
doi:10.1016/j.pbb.2011.03.009
PMCID: PMC3250514  PMID: 21420998
Periadolescence; Preexposure; Nicotine; Conditioned taste aversion; Alcohol; Rats

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