Carlos A. Hernandez-Avila

Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the μ‐opioid receptor locus (OPRM1)

This study examined whether a reportedly functional polymorphism in the gene encoding the μ‐opioid receptor protein (A118G, which causes an Asn40Asp substitution in the receptors extracellular domain), modifies the cortisol response to the opioid antagonist naloxone. The polymorphism occurs commonly in European Americans and some other population groups, underscoring its potential phenotypic significance. Methods: Using a balanced, within‐subject design involving two test sessions over a period of 3–7 days, we examined ACTH and cortisol responses to intravenous naloxone (125 μg/kg) or placebo in 30 healthy subjects (21 males, mean age = 24.4 years). Plasma ACTH and cortisol concentrations were measured over 120 min post infusion. DNA isolated from whole blood was PCR amplified and genotyped via restriction enzyme digestion, with genotypes assigned based on agarose gel size fractionation. Results: Subjects with one or more Asp40 alleles (n = 6; 5 heterozygotes and 1 homozygote) had significantly higher cortisol concentrations at baseline and at 15, 60, and 90 min after naloxone infusion than subjects homozygous for the Asn40 allele (n = 24). Subjects with the Asp40 allele also had a greater peak cortisol response and a greater area under the cortisol time curve than those homozygous for the Asn40 allele. There were no effects of the Asn40Asp polymorphism on plasma ACTH concentration or on self‐reported anxiety or distress. Conclusions: These findings are consistent with recent reports showing an enhanced cortisol response to naloxone and a reduced agonist effect of morphine‐6‐glucuronide among subjects with the Asp40 variant. Given evidence of its pharmacological significance, the clinical relevance of this polymorphism warrants further investigation.

GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride

GABAA receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABAA receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABAA receptor α-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-α steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n=7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n=20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

Effects of Ondansetron in Early‐ Versus Late‐Onset Alcoholics: A Prospective, Open‐Label Study

BACKGROUND Early-onset alcoholics (EOAs) have a greater familial loading for alcoholism, more severe progression of the disorder, a greater severity of comorbid psychopathology, and a poorer response to treatment than late-onset alcoholics (LOAs). Ondansetron, a 5-hydroxytryptamine-3 antagonist, was found to be superior to placebo in the treatment of EOAs, but not of LOAs. This study compared the tolerability and potential efficacy of an oral solution of ondansetron in EOAs versus LOAs. METHODS Forty outpatients with alcohol dependence (67.5% male; 87.5% European American; 20 EOAs; 20 LOAs) received an oral solution of ondansetron at a dosage of 4 microg/kg twice daily for 8 weeks, together with weekly relapse-prevention therapy. RESULTS EOAs had a significantly greater decrease in drinks per day, drinks per drinking day, and alcohol-related problems than LOAs. Changes in the level of carbohydrate-deficient transferrin were consistent with changes in self-reported drinking behavior. CONCLUSIONS An oral solution of ondansetron seems suitable for the treatment of alcohol dependence, yielding findings consistent with evidence from a placebo-controlled trial that ondansetron, at a dosage of 4 microg/kg twice daily, is of value in the treatment of EOAs.

Polymorphism of the 5-HT1B receptor gene (HTR1B): strong within-locus linkage disequilibrium without association to antisocial substance dependence.

Serotonergic abnormalities may be present in individuals with either substance dependence (SD) or antisocial personality disorder (ASPD), disorders that occur together commonly. Consequently, genes encoding serotonin (5-HT) receptors are candidates for genetic studies of both disorders. Lappalainen et al. (1998) found evidence for linkage of antisocial alcoholism to HTR1B (the locus encoding the 5-HT1B receptor) in both Finns and Southwestern American Indians, and of allelic association of a G861C polymorphism at that locus with antisocial alcoholism in Finns. Unless the G861C polymorphism is found to be functional, it must be in linkage disequilibrium (LD) with a functional variant for it to be of physiological significance. Methods: The present study evaluated LD across three polymorphic systems at HTR1B and haplotype frequencies and allelic association of these systems with both SD generally and alcohol dependence (AD) specifically, with or without a comorbid antisocial diagnosis. Subjects were 370 European Americans (EAs) and 123 African Americans (AAs). Results: Although there was strong evidence for LD across polymorphic systems in both populations, there was no evidence for association to SD or AD, either alone or with a comorbid antisocial diagnosis. Conclusion: Despite no evidence in this study for allelic association of HTR1B to antisocial substance dependence, further evaluation of the hypothesized association is warranted in other population groups.

Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation

Background Studies in European Americans (EAs) have shown that the hypothalamic–pituitary–adrenal (HPA)-axis activation by the opioid blockade is moderated by the single nucleotide polymorphism (SNP) A118G (Asn40Asp) at the μ-opioid receptor locus (OPRM1). We examined the effect of this, and of five intronic OPRM1 SNPs, on adrenocorticotropic hormone and cortisol concentrations, following the placebo-controlled administration of naloxone to healthy individuals who were of EA or Asian ancestry. Methods We used a balanced, within-participant design with two test sessions to examine the hormonal responses to intravenous naloxone (an opioid antagonist) (125 μg/kg) or placebo in 29 healthy participants (62% men, 59% of Asian ancestry). DNA isolated from whole blood was PCR amplified and genotyped using a fluorogenic 5 nuclease assay (TaqMan) method. Results Consistent with earlier reports, participants with one or two Asp40 alleles (n=16) had a significantly greater cortisol response to naloxone than Asn40 homozygotes, but the effect was limited to EAs. Asians with the Asp40 allele did not show a greater increase in cortisol response compared with Asn40 homozygotes. None of the intronic SNPs was associated with cortisol response either directly or via an interaction effect with Asn40Asp. Conclusions Effects of the Asn40Asp polymorphism at OPRM1 on HPA-axis activation seem to be population-specific. The association between the Asn40Asp and the HPA-axis response to naloxone cannot, therefore, be explained with reference only to the amino acid substitution encoded by that polymorphism. Further research to understand the basis for the observed association is warranted.

Adrenocorticotropin and cortisol responses to a naloxone challenge and risk of alcoholism.

BACKGROUND Because abnormalities in opioid neurotransmission appear to underlie some of the inherited risk for alcoholism, we examined the effects of naloxone, an opioid antagonist, on corticotropin and cortisol responses in nonalcoholic subjects differentiated by paternal history of alcoholism. METHODS Placebo-controlled, balanced, within-subject design involving 2 test days over a period of 3 to 7 days. Thirty-six subjects (67% male; 53% paternal-history-positive; mean age = 25.0 years) were screened to exclude substance abuse or dependence. Subjects received intravenous naloxone 125 microg/kg or placebo, with sessions in random order. Plasma corticotropin and cortisol were measured for up to 120 min post infusion. RESULTS Corticotropin responses at baseline and following naloxone did not differ by paternal history of alcoholism; however, paternal-history-positive subjects exhibited greater cortisol concentrations at baseline, and at 15 and 30 min after naloxone administration. Paternal-history-positive subjects also had an earlier and greater peak cortisol response to naloxone and a nonsignificant trend for a greater area under the cortisol time curve than paternal-history-negative subjects. CONCLUSIONS These findings suggest that individuals with greater vulnerability to alcoholism may have altered Hypothalamic-pituitary axis (HPA) dynamics, a finding that is consistent with a growing body of data on the role of opioidergic neurotransmission in the inherited risk of alcoholism.

Nefazodone treatment of comorbid alcohol dependence and Major depression

BACKGROUND Major depression is a common comorbid condition among individuals with alcohol dependence. This study examined the effects of nefazodone, a norepinephrine and serotonin reuptake blocker and 5-hydroxytryptamine-2 receptor antagonist, on mood and anxiety symptoms and drinking behavior in a sample of depressed alcoholics. METHODS This study was a double-blind, placebo-controlled comparison of nefazodone (200-600 mg/day) or placebo in a sample of alcohol-dependent subjects (n = 41; 52% women) with current major depression. After a 1-week placebo lead-in period, subjects were randomly assigned to receive study medication and supportive psychotherapy for 10 weeks. RESULTS Depressive and anxiety symptoms declined significantly over time. Although the nefazodone group showed greater reductions in these symptoms, the effects did not reach statistical significance. Nonetheless, nefazodone-treated subjects showed a significantly greater reduction in heavy drinking days and in total drinks compared with placebo-treated subjects. CONCLUSIONS The lack of significant effects on depression and anxiety symptoms may reflect limited statistical power. Despite the small sample size, nefazodone significantly reduced some measures of alcohol consumption in this sample of depressed alcoholics.

Parental monitoring and alcohol use among Mexican students.

Parental monitoring has been described as a protective factor and useful strategy to prevent substance misuse among youths. The aim of this study was to examine whether perceived parental monitoring influences frequency of alcohol use, age of drinking onset and risky drinking among entering public high school and university students in Mexico City. The study is a cross-sectional survey of entering first year students in the high school and university school system of a large public university in Mexico City conducted during registration at the beginning of the school year. In 2008, of 34,840 students accepted to the affiliated high schools, 28,996 students (51.8% female) completed the alcohol survey and of 37,683 students accepted into university 30,084 students (51.5% female) completed the alcohol survey. The findings suggest that compared to students with higher perceived parental monitoring those reporting lower perceived parental monitoring were more likely to report risky behavior. They were more likely to be ever drinkers, frequent drinkers, have earlier age of onset and high AUDIT scores. Overall, higher parental monitoring was strongly associated with being female and lower parental monitoring with being male. Our findings suggest that more research on parental monitoring as a protective strategy against alcohol misuse is needed. Research focusing on cultural factors including gender and age-related norms and familismo would increase knowledge of the association of parental monitoring and alcohol use among Mexican youths, Mexican American youths and potentially youths from other Hispanic backgrounds.

Self-Efficacy as a Predictor of Relapse During Treatment for Alcohol Dependence

To determine whether different dimensions of self-efficacy predict relapse during treatment of alcohol dependence, data were obtained from three 12-week, placebo-controlled trials of medication combined with coping skills treatment. Hierarchical logistic regression was used to conduct an initial analysis (n = 140) and a replication analysis (n = 181). Controlling for potential confounders, we examined the predictive value of perceived self-efficacy measured prior to treatment and its interaction with sex on relapse risk. Three second-order factors of the Situational Confidence Questionnaire (SCQ), and their interaction with sex, were examined in relation to relapse to Any Drinking (ie, non-abstinence) and relapse to Heavy Drinking. The results underscore the importance of differentiating among the subscales of the SCQ, between different definitions of relapse, and on the basis of the sex of the patient when predicting relapse among alcoholics.

Changes in Alcohol Use Among First Year University Students in Mexico

Background: Alcohol use and misuse is widespread among university students in many countries. Specific cultural factors may impact alcohol use after entering university. Objective: This paper considers changes in alcohol use among first year university students in Mexico. Methods: A qualitative study using ethnographic interviews with 57 female and 60 male student drinkers in Mexico City from March to June 2011. Each interview was evaluated by a set of thematic codes developed inductively from the interviews. Findings from excessive, heavy, regular, occasional drinkers, abstainers, and non-drinkers were analyzed to explore whether or not linkages existed between and/or among particular themes. Results: Students reported factors associated with changes in role and status, friendships, and increased autonomy as reasons for increasing or decreasing their alcohol use after entering university. Conclusions/Importance: Understanding the influence of Mexican cultural norms on alcohol use among Mexican and Mexican Americans can be helpful in informing studies and preventive efforts among both Mexican and Mexican American young people.