The association between HTR1B gene rs13212041 polymorphism and onset of alcohol abuse.

BACKGROUND: Alcohol dependence displays a wide variety of clinical phenotypes. Various typology classifications of alcoholism include age of onset of alcohol abuse as one of the major phenotypic features. Serotonergic changes have been associated with alcoholism, while serotonin receptors type 1B (5-HT1B) play an important role in regulating serotonergic neurotransmission. The rs13212041 polymorphism modulates the expression of HTR1B gene coding for 5-HT1B receptor. This study examined the association of platelet serotonin (5-HT) and HTR1B gene with the onset of alcohol abuse in alcohol-dependent subjects. MATERIALS AND METHODS: Determination of platelet 5-HT concentration and genotyping of rs13212041 HTR1B gene polymorphism were performed in 613 alcohol-dependent patients, subdivided according to early/late onset (before/after 25 years of age) of alcohol abuse. RESULTS: Alcohol-dependent individuals with CC genotype were more frequent in the group with early onset of alcohol abuse compared to carriers of T allele. Besides HTR1B genotype, age and gender, but not platelet 5-HT, were major variables associated with the onset of alcohol abuse. Platelet 5-HT concentration was not significantly different between patients with early and late onset of alcohol abuse, or patients carrying various HTR1B genotypes. Although we observed no influence of co-variables such as age, gender, or somatic and psychiatric comorbidities, platelet 5-HT concentration was significantly affected by smoking. CONCLUSION: These findings support potential involvement of 5-HT1B receptors in the onset of alcohol abuse and development of alcohol dependence. Additionally, the results of our study emphasize the importance of controlling for smoking status, as one of the significant confounding factors influencing platelet 5-HT concentration.

Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes.

The present study aimed to evaluate the association of alcohol dependence and alcohol dependence-related phenotypes with platelet monoamine oxidase type B (MAO-B) activity, Val108/158Met of catechol-o-methyltransferase (COMT), variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene, VNTR in the 3'-untranslated region of dopamine transporter (DAT) gene, -1021C/T of dopamine beta-hydroxylase (DBH) and MAO-B intron 13 polymorphisms. The study included 1270 Caucasian men and women of Croatian origin: 690 patients with alcohol dependence and 580 healthy controls. Patients with alcohol dependence were subdivided according to the presence or absence of withdrawal symptoms, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, suicidal behavior, lifetime suicide attempt and early/late onset of alcohol abuse. The results, corrected for multiple testing, revealed increased platelet MAO-B activity in patients with alcohol dependence, subdivided into those with or without alcohol-related liver diseases, compared to control subjects (P<0.001). In addition, we found an increased frequency of the COMT Met/Met genotype among suicidal (P=0.002) and patients who attempted suicide (P<0.001) and an increased frequency of COMT Val/Val genotype in patients with an early onset of alcohol dependence (P=0.004). This study provides data from a sample of ethnically homogeneous unrelated Caucasian subjects for future meta-analyses and suggests that the increased platelet MAO-B activity might be used as independent peripheral indicator of alcohol dependence, while COMT Val108/158Met polymorphism is associated with increased suicidality and early onset of alcohol dependence.

Insomnia, platelet serotonin and platelet monoamine oxidase in chronic alcoholism.

Insomnia is a common sleep disorder frequently occurring in chronic alcoholic patients. Neurobiological basis of insomnia, as well as of alcoholism, is associated with disrupted functions of the main neurotransmitter systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Blood platelets are considered a limited peripheral model for the central 5-HT neurons, since both platelets and central 5-HT synaptosomes have similar dynamics of 5-HT. Platelet 5-HT concentration and platelet monoamine oxidase type B (MAO-B) are assumed to represent biomarkers for particular symptoms and behaviors in psychiatric disorders. The hypothesis of this study was that platelet 5-HT concentration and platelet MAO-B activity will be altered in chronic alcoholic patients with insomnia compared to comparable values in patients without insomnia. The study included 498 subjects: 395 male and 103 female medication-free patients with alcohol dependence and 502 healthy control subjects: 325 men and 177 women. The effects of early, middle and late insomnia (evaluated using the Hamilton Depression Rating Scale), as well as sex, age and smoking on platelet 5-HT concentration and platelet MAO-B activity were evaluated using one-way ANOVA and multiple regression analysis by the stepwise method. Platelet 5-HT concentration, but not platelet MAO-B activity, was significantly reduced in alcoholic patients with insomnia compared to patients without insomnia. Multiple regression analysis revealed that platelet 5-HT concentration was affected by middle insomnia, smoking and sex, while platelet MAO activity was affected only by sex and age. The present and previous data suggest that platelet 5-HT concentration might be used, after controlling for sex and smoking, as a biomarker for insomnia in alcoholism, PTSD and in rotating shift workers.

Suicide attempt, smoking, comorbid depression, and platelet serotonin in alcohol dependence.

The risk of suicide in patients with alcoholism increases if alcoholism is related to comorbid depression. Both alcoholism and suicidal behavior are associated with reduced serotonin (5-hydroxytryptamine [5-HT]) function. Because suicide is enormous public health problem worldwide, to prevent suicide attempts, it is important to find peripheral marker of suicidal behavior. The aim of this study was to assess whether platelet 5-HT concentration is altered in alcoholic patients with or without suicide attempt. Platelet 5-HT concentration was evaluated in 397 male and 108 female ethnically homogenous medication-free patients with alcoholism, subdivided according to smoking status, comorbid depression, and a history of suicide attempt and in 450 male and 139 female healthy control (nonsuicidal) subjects. Suicide attempt was assessed by two measures: according to the score 4 on the item 3 from the Hamilton Rating Scale for Depression and according to the Structured Clinical Interview regarding suicidal attempt during lifetime. Both male and female patients with alcoholism who were nonsmokers had significantly lower platelet 5-HT concentration than the corresponding healthy subjects. Multifactor analyses of variance revealed the significant effects of alcoholism and smoking, but the lack of significant effects of suicide attempt, sex, or comorbid depression, and no interactions between variables, on platelet 5-HT concentration. Platelet 5-HT concentration did not differ significantly between suicidal patients compared with nonsuicidal patients with alcoholism. Because the results from the present study showed similar platelet 5-HT values between patients with or without a history of suicide attempt, our data did not support the hypothesis that platelet 5-HT concentration might be used as a peripheral marker of the pronounced suicidal behavior in alcoholism.

Platelet serotonin concentration in alcoholic subjects.

Serotonin (5-hydroxytryptamine, 5-HT) is assumed to play a role in the pathophysiology of different psychiatric disorders including alcoholism. Since platelets and central serotonergic synaptosomes share similar pharmacodynamics of 5-HT, this study determined platelet 5-HT concentration in 148 male and 42 female drug-free subjects with alcohol dependency, according to the DSM-IV criteria, and in sex-and age-matched controls. Male and female alcoholics had significantly lower platelet 5-HT concentration than 110 male and 123 female healthy controls. Sex differences, i.e. higher platelet 5-HT concentration in men than in women, were found both in healthy and alcoholic subjects. Platelet 5-HT concentration differed significantly in male and female alcoholic subjects with or without different psychiatric comorbidities. Platelet 5-HT concentration was higher in male alcoholics with comorbid posttraumatic stress disorder (PTSD) than in male alcoholics with comorbid anxious-depressive disorder, or depression, or male alcoholics without any psychiatric comorbidities. Comorbid depression in female alcoholics slightly elevated platelet 5-HT levels but these values were still reduced compared to values in healthy women. Smoking status did not affect platelet 5-HT concentration either in healthy or in alcoholic subjects. The data from our study show sex differences, and reduced platelet 5-HT values, regardless of the nicotine dependence, in the large groups of male and female alcoholic subjects. Among male alcoholics the presence of comorbid PTSD partly normalized the decreased platelet 5-HT values. The results of the present study support the hypothesis that alterations in 5-HT system might be related to alcoholism.