John C. Umhau

A genetic determinant of the striatal dopamine response to alcohol in men

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

A replication study of violent and nonviolent subjects: cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids

BACKGROUND Among an independent group of subjects selected for their history of violent, impulsive behaviors and nonviolent control subjects, we attempted to replicate the finding that plasma docosahexaenoic acid concentrations were negatively correlated with cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations. METHODS CSF 5-HIAA and homovanillic acid (HVA), fasting total cholesterol, and plasma fatty acid concentrations were examined in violent and nonviolent subjects matched for their severity of alcohol dependence. RESULTS Violent subjects had significantly higher lifetime violence and hostility ratings and lower concentrations of CSF 5-HIAA than nonviolent subjects. Plasma docosahexaenoic acid was negatively correlated with CSF 5-HIAA only among violent subjects. CONCLUSIONS This observational study suggests that dietary essential fatty acids may change neurotransmitter concentrations. Prospective dietary intervention trials will be required to determine if increasing dietary intake of docosahexaenoic acid will increase or decrease either CSF 5-HIAA concentrations or impulsive and violent behaviors.

Effect of Acamprosate on Magnetic Resonance Spectroscopy Measures of Central Glutamate in Detoxified Alcohol-Dependent Individuals A Randomized Controlled Experimental Medicine Study

CONTEXT Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis 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 using 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 days 4 and 25. SETTING An inpatient research unit at the NIH Clinical Center. Patients Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use. Intervention Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or matched placebo, initiated at the time of admission. MAIN OUTCOME MEASURES The glutamate to creatine ratio as determined using single-voxel ¹H-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability-related measures. RESULTS There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time × treatment interaction: F₁(,)₂₉ = 13.5, P < .001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and unaffected by treatment but were strongly correlated (R² = 0.48, P < .001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone-corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate. CONCLUSION The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00106106.

Reduced cannabinoid CB 1 receptor binding in alcohol dependence measured with positron emission tomography

Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and [18F]FMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3–7 days of admission from ongoing drinking, and after 2–4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20–30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2–4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2–4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.

Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate

Modulation of alcohol craving induced by challenge stimuli may predict the efficacy of new pharmacotherapies for alcoholism. We evaluated two pharmacological challenges, the α2-adrenergic antagonist yohimbine, which reinstates alcohol seeking in rats, and the serotonergic compound meta-chlorophenylpiperazine (mCPP), previously reported to increase alcohol craving in alcoholics. To assess the predictive validity of this approach, the approved alcoholism medication acamprosate was evaluated for its ability to modulate challenge-induced cravings. A total of 35 treatment seeking alcohol dependent inpatients in early abstinence were randomized to placebo or acamprosate (2997 mg daily). Following two weeks of medication, subjects underwent three challenge sessions with yohimbine, mCPP or saline infusion under double blind conditions, carried out in counterbalanced order, and separated by at least 5 days. Ratings of cravings and anxiety, as well as biochemical measures were obtained. In all, 25 subjects completed all three sessions and were included in the analysis. Cravings were modestly, but significantly higher following both yohimbine and mCPP challenge compared with saline infusion. The mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. There was a significant correlation between craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. Both yohimbine and mCPP challenges lead to elevated alcohol craving in a clinical population of alcoholics, and these cravings correlate with alcoholism severity. Under the experimental conditions used, alcohol cravings induced by these two stimuli are not sensitive to acamprosate at clinically used doses.

A select group of perpetrators of domestic violence: evidence of decreased metabolism in the right hypothalamus and reduced relationships between cortical/subcortical brain structures in position emission tomography

In an earlier study, we reported that some perpetrators of domestic violence evidenced exaggerated fear-related responses to the panicogenic agent sodium lactate. In the current study, we employed positron emission tomography (PET) to investigate our hypothesis that there are differences in the neural structures and/or pathways that mediate and control the expression of fear-induced aggression in perpetrators of domestic violence. Regional cerebral glucose metabolism was measured in eight male perpetrators of domestic violence who fulfilled DSM-III-R criteria for alcohol dependence (DV-ALC), 11 male participants who fulfilled DSM-III-R criteria for alcohol dependence and had no history of interpersonal aggression (ALC) and 10 healthy male participants who did not fulfill criteria for any DSM-III-R axis I diagnosis and had no history of interpersonal aggression (HCS). DV-ALC had a significantly lower mean glucose uptake in the right hypothalamus compared to ALC and HCS. Correlations were performed between measures of glucose utilization in the brain structures involved in fear-induced aggression. The comparison of DV-ALC to HCS and to ALC differed in six and seven comparisons, respectively, involving various cortical and subcortical structures. HCS and ALC differed between the left thalamus and the left posterior orbitofrontal cortex. These PET findings show that some perpetrators of domestic violence differ from control participants in showing lower metabolism in the right hypothalamus and decreased correlations between cortical and subcortical brain structures. A possible psychological covariate of these changes in regional activity might be fear-induced aggression, but this hypothesis should be examined in larger study groups that undergo provocation during imaging.

Omega-3 status and cerebrospinal fluid corticotrophin releasing hormone in perpetrators of domestic violence

BACKGROUND Elevated levels of corticotrophin-releasing hormone in the cortical-hippocampal-amygdala pathway increase fear and anxiety, which are components of defensive and violent behaviors. Prostaglandins E2 and F2alpha, which increase corticotrophin-releasing hormone RNA expression in this pathway, are reduced by dietary intakes of omega-3 fats. METHODS Among 21 perpetrators of domestic violence, cerebrospinal fluid and plasma were assessed for corticotrophin-releasing hormone and fatty acid compositions, respectively. RESULTS Lower plasma docosahexaenoic acid (wt% fatty acids) alone predicted greater cerebrospinal fluid corticotrophin-releasing hormone (pg/mL), in exponential (r = -.67, p < .006) and linear regressions (r = -0.68, p < .003 excluding four subjects with the highest docosahexaenate levels). CONCLUSIONS In this small observational study, low plasma docosahexaenoic acid levels were correlated to higher cerebrospinal fluid corticotrophin-releasing hormone levels. Placebo controlled trials can determine if dietary omega-3 fatty acids can reduce excessive corticotrophin-releasing hormone levels in psychiatric illnesses.

Serotonin, testosterone and alcohol in the etiology of domestic violence

In a previous study we administered the panicogenic agent sodium lactate to a select group of perpetrators of domestic violence and comparison groups. Results of that study showed that perpetrators exhibited exaggerated lactate-induced fear, panic and rage. In this current study, we compared the cerebral spinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and testosterone obtained from perpetrators of domestic violence and a group of healthy comparison subjects. All subjects were assessed for DSM-III-R diagnoses. Perpetrators with alcohol dependence (DV-ALC) (n=13), perpetrators without alcohol dependence (DV-NALC) (n=10) and healthy comparison subjects (HCS) (n=20) were clinically assessed using the Spielberger Trait Anxiety, Brown-Goodwin Aggression Scale, Buss Durkee Hostility Inventory and Straus Conflict Tactics. Following an overnight fast and bed rest, subjects received a lumbar puncture to obtain CSF concentrations of 5-HIAA and testosterone. Perpetrators scored significantly higher on measures of aggression than HCS. DV-NALC had significantly lower concentrations of CSF 5-HIAA and higher Straus Conflict Tactics (CT) physical violence scores than DV-ALC and HCS. DV-ALC had significantly higher concentrations of CSF testosterone than DV-NALC. DV-ALC also had significantly higher Straus CT physical violence scores than HCS. DV-NALC and DV-ALC differed on 5-HIAA concentrations, testosterone concentrations, Straus CT physical violence scores and alcohol dependence. These results suggest that DV-NALC and DV-ALC groups could have different biological mechanisms mediating domestic violence.

Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of highly unsaturated fatty acids

Low concentrations of a metabolite of serotonin found in cerebrospinal fluid (CSF), 5-hydroxyindolacetic acid (5-HIAA), are strongly associated with suicidal and violent behaviors. Although lowering of plasma total cholesterol has been suggested to increase mortality from suicide and violence by decreasing concentrations of CSF 5-HIAA via changes in membrane biophysical properties, highly unsaturated fatty acids may play a more important role. Violent and nonviolent comparison groups, early- and late-onset alcoholics, and healthy comparison subjects were studied to control for alcohol use and predisposition to violence. Fasting plasma total cholesterol and CSF were assayed under stringently controlled conditions. When all groups were combined (n = 234), plasma cholesterol concentrations had a weak positive correlation with CSF 5-HIAA (r = 0.18, P < 0.01). However, age correlated with both plasma total cholesterol and CSF 5-HIAA concentrations. When age was included in multiple regression models, the correlation between cholesterol and CSF 5-HIAA concentrations was not significant. Cholesterol correlated weakly with CSF 5-HIAA concentrations only in late-onset alcoholics after age was controlled for, but the relation was not significant after correction for multiple testing. CSF homovanillic acid did not correlate with plasma total cholesterol in any group. Plasma total cholesterol had no apparent relation to CSF neurotransmitter metabolites in any group of subjects. Highly unsaturated essential fatty acids, which are also critical determinants of membrane biophysical properties and may be linked to brain serotonin concentrations, should also be considered in studies examining the effect of lowering fat intake on the incidence of suicide and violence.

The relationship between folate and docosahexaenoic acid in men

Objective:Docosahexaenoic acid (DHA, 22:6n-3), an essential omega 3 fatty acid, may protect against disorders of emotional regulation as well as cardiovascular disease. Animal studies demonstrate that dietary folate can increase tissue concentrations of DHA, although the literature, to date, includes no human studies examining the possibility that folate status may affect plasma DHA concentrations. The objective of this study is to determine if the blood concentrations of folate and DHA are correlated in humans.Design:Retrospective study.Setting:An American research hospital.Subjects:A total of 15 normal and 22 hostile and aggressive subjects, with a mean age of 38 years.Methods:Concentrations of plasma polyunsaturated essential fatty acids and red blood cell folate (RBC folate) were obtained prior to 1996, before American flour was enriched with folate.Results:RBC folate was significantly correlated with plasma DHA, r=0.57, P=0.005 in the aggressive group. Age, smoking and alcohol consumption did not alter the results. No other essential fatty acids were significantly associated with RBC folate in either group.Conclusions:The positive relationship between plasma DHA and RBC folate concentrations suggests that these two nutrients should be examined together in order to make the most accurate inferences about their relative contributions to disease pathogenesis. Our findings present one explanation why some conditions associated with hostility and low DHA status, such as cardiovascular disease and emotional disorders, are also associated with low folate status.Sponsorship:National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism.