Biomedical subjects

L G Schmidt

Publications and source records attributed to L G Schmidt.

At least 55 records · Page 3Linked to original sources

PubMed1997

Influence of the dopamine D2 receptor (DRD2) genotype on neuroadaptive effects of alcohol and the clinical outcome of alcoholism.

The present study was performed to test the hypotheses that allelic variants at the human dopamine D2 receptor gene locus (DRD2) confer susceptibility to alcoholism or are associated with clinical subtypes of alcoholism. We investigated an A --> G substitution polymorphism in the 3'-untranslated region of exon 8 (E8) of DRD2 with allele frequencies of f(G) = 0.295 - 0.329. No significant association of the DRD2 genotype or allele frequencies with alcoholism was found in an association study including 283 alcoholics and 146 non-alcoholic controls. However, the frequent homozygous E8 A/A genotype with f(AA) = 0.47 - 0.48 was associated with increased anxiety and depression scores in alcoholics during the follow up after clinical detoxification treatment. In addition, E8 A/A was associated with increased suicide attempts and showed a tendency towards more severe withdrawal symptoms, early relapse and reduced responsiveness to the dopaminergic agonist apomorphine. Regression analysis revealed the DRD2 E8 genotype as the only significant factor determining withdrawal severity in female alcoholics. The findings suggest an influence of the DRD2 genotype on the neuropharmacological effects of chronic alcohol exposure and the clinical course of alcoholism.

Adaptation, Physiological↗

PubMed1997

Superiority of carbohydrate-deficient transferrin to gamma-glutamyltransferase in detecting relapse in alcoholism.

OBJECTIVE: The usefulness of carbohydrate-deficient transferrin is widely accepted in screening (male) population samples for heavy alcohol consumption, but its role in relapse detection is not convincingly established. The authors therefore compared the diagnostic value of carbohydrate-deficient transferrin with the commonly used gamma-glutamyltransferase in identifying relapsed alcoholics during outpatient aftercare. METHOD: The patients were 101 male alcoholics who entered a 6-month rehabilitation program after hospital detoxification. Drinking status was assessed by means of self- and collateral reports obtained during regular contacts with the rehabilitation team; relapse was defined as consumption of any alcohol. Visits occurred weekly during month 1, biweekly during month 2, and every 4 weeks during months 3-6. At every visit a blood sample was taken for measurement of carbohydrate-deficient transferrin and gamma-glutamyltransferase. RESULTS: The proportion of men who reported relapse was 25.6% per scheduled contact on average. Positive predictive values indicated that relapse was identified with a 76.2% probability by carbohydrate-deficient transferrin values above the upper normal limit, in contrast to a 32.9% chance with gamma-glutamyltransferase. Carbohydrate-deficient transferrin was especially useful in detecting early relapses during the initial rehabilitation phase, when gamma-glutamyltransferase values had not normalized. Because of the longer half-life of gamma-glutamyltransferase, it had some value with a 4-week monitoring schedule in detecting new drinking episodes in alcoholics whose previous results had been normal. CONCLUSIONS: Carbohydrate-deficient transferrin proved to be superior to gamma-glutamyltransferase in relapse detection in an outpatient care setting for alcoholics.

Adult↗

PubMed1997

Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence.

The present study tested the hypothesis that the short, low activity variant of a biallelic polymorphism in the 5' regulatory region of the human serotonin transporter (5-HTT) gene confers susceptibility to severe alcohol dependence marked by severe withdrawal symptoms. Applying a phenotype-genotype strategy, our population-based association analysis included 216 German controls and an extreme sample of 103 severely affected alcoholics who were selected from 315 German alcohol-dependent subjects by a history of alcohol withdrawal seizure or delirium. The frequency of the short allele (S) was significantly increased in the severely affected alcoholics, compared with that in the controls (X2 = 3.87, df = 1, nominal p = 0.049). The post-hoc exploration indicated that this allelic association resulted exclusively from a significant excess of the S/S genotype in the severely affected alcoholics (p = 0.035), suggesting a recessively acting effect. Consistently, we found a weak but significant correlation (p = 0.013) between the frequency of the S/S genotype and severity of withdrawal symptoms (WDS): no WDS [18.3%, odds ratio (OR) = 1.16], vegetative WDS only (21.8%, OR = 1.44), and severe WDS with either withdrawal seizure only or delirium only (25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8%, OR = 2.30). Further studies are required to test whether the tentative genotype-phenotype relationship occurred by chance or reflects a real genotypic association between a recessively modifying effect of the short variant of the functional 5-HTT promoter polymorphism and alcohol withdrawal vulnerability.

Adult↗

PubMed1997

Effects of dopaminergic agonists and antagonists on the serum prolactin levels in alcoholized rats.

A single dose of ethanol (1 g/kg p.o.) significantly decreased, whereas higher doses of ethanol (2 or 3 g/kg p.o.) significantly increased the serum prolactin (PRL) concentration. Administration of ethanol at a dose of 2 g/kg p.o. for 4 weeks did not affect this parameter but the ethanol withdrawal syndrome caused a significant rise in the serum PRL level. Chronic studies showed that D1-dopaminergic agonist SKF 38390 (2.5 mg/kg) significantly raised serum PRL levels in rats. This effect was reversed by long-lasting treatment of rats with ethanol and ethanol withdrawal. Pimozide (1 mg/kg), D2 antagonist, increased PRL in those rats. On the other hand, D1-antagonist SCH 23390 (0.5 mg/kg) and D2-agonist PPHT (0.5 mg/kg) were without effect in rats administered ethanol for a long period of time. In rats with ethanol withdrawal syndrome, administration of D1-antagonist SCH 23390 (0.5 mg/kg) also did not affect the serum PRL concentrations. However, D1-agonist SKF 38393 (2.5 mg/kg) and D2-antagonist pimozide (1 mg/kg) increased the serum PRL level in rats with ethanol withdrawal syndrome, whereas D2 agonist PPHT (2 mg/kg) decreased PRL level in serum. Thus, the acute effect of ethanol on PRL level appears to be dose-dependent. It seems that chronic ethanol administration and its withdrawal especially affected D1 receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1996

Long-term changes of markers of alcoholism after orthotopic liver transplantation (OLT).

Both physical rehabilitation and the course of the alcoholism improve after orthotopic liver transplantation (OLT) in patients with end-stage alcoholic liver cirrhosis. In the present study including 17 alcoholics and 14 nonalcoholics, after OLT, three of the alcoholic patients resumed their pre-OLT alcohol drinking habits, 4 consumed alcohol occasionally, 10 remained abstinent over the observation period of 13 to 36 months. The laboratory parameters before OLT did not discriminate alcoholics from nonalcoholic patients. Furthermore, the blood levels of two so-called alcogens (harman and norharman) were determined to investigate whether they discriminate between the two groups. Alcogens are natural compounds that are presumed to induce alcohol abuse in predisposed individuals. Both alcogens measured were elevated in plasma from nonalcoholics and alcoholics before OLT, suggesting a disturbance in inactivation in end-stage liver disease. Following OLT, the alcogens normalized but in the alcoholics this process was slower with respect to harman. The present exploratory study suggests that the normalized metabolic capacity of the liver after OLT causes a normalization of the levels of alcogens, for which harman and norharman are representative. These changes could contribute to the observed benefit to the outcome in alcoholics with respect to the alcohol dependence.

Adult↗

PubMed1996

Dopamine D2 receptor gene (DRD2) haplotypes in Caucasians.

The human dopamine D2 receptor gene (DRD2) is considered a candidate gene for neuro-psychiatric diseases. We typed three new DNA sequence variants in DRD2 intron 4, intron 6 and exon 8, in combination with the known TaqI A restriction fragment length polymorphism (RFLP) and exon 7 311Ser/Cys in 106 unrelated psychiatrically healthy Caucasians. Based on the genotypic data we delineated 10 distinct DRD2 haplotypes and their genetic relationship. Our data provide evidence that the Taq A1 allele and the 311Cys variant are components of different groups of haplotypes though both variants have been speculated to be associated with alcoholism or schizophrenia in recent studies. Therefore we conclude that the prior knowledge of the frequencies and genetic relationships of DRD2 haplotypes will lead to the selection of more suitable intragenic markers for future association studies.

Gene Frequency↗

PubMed1996

Serotonergic ethanol effects and auditory evoked dipole activity in alcoholic and healthy subjects.

Ethanol has central serotonergic effects that may be of pathogenetic importance in a subgroup of alcohol-dependent patients with a central serotonergic hypofunction. Recent results indicate that pronounced amplitude increases of auditory evoked responses (tangential dipoles, N1/P2 component) with increasing stimulus intensity (loudness) may be an indicator of such a low serotonergic neurotransmission. Because of its serotonin-agonistic effects, ethanol can be expected to decrease this intensity dependence. Twenty-eight alcoholic patients were studied both in the intoxication phase and after 1 week of withdrawal. A reduced intensity dependence of the tangential dipole activity was observed in the intoxicated state. Correspondingly, a reduction of this parameter was found in 14 healthy subjects after an ethanol load (1 g/kg, p.o.).

Adult↗

PubMed1996

Reduced dopaminergic function in alcoholics is related to severe dependence.

With a view to the role of dopamine (DA) systems in reward processes and considering recent studies linking specific alleles at the DA-D2 receptor gene locus with alcoholism (especially with severe types) dopaminergic functions were evaluated in 49 alcoholics using growth hormone (GH) response to DA receptor agonist apomorphine (0.01 mg/kg subcutaneously). neuroendocrine testing was performed (during intoxication) at the time of admission to an inpatient alcohol treatment program and was repeated 7 days later (in a postintoxicated state). Patients underwent clinical examination, detoxification treatment and a subsequent rehabilitation program for abstinence including follow-up evaluation of outcome for 6 months. A two-factor analysis of variance (ANOVA) revealed a significant change of GH response (peak values corrected for baseline) over time (between intoxication and postintoxication; p < 0.001) and between abstainers and relapsers (p = 0.032). Relapse was also associated with paternal alcoholism, early onset of disease, and a more complete dependence syndrome and cerebellar atrophy. Standardized canonical discriminant coefficient was highest for reduced GH response compared to other relapse predictors in the model used. It is concluded that reduced GH response to dopaminergic stimulation corresponds to a progressed stage or syndrome of severe alcohol dependence; however, if reduced, dopaminergic function is one cause or consequence of addiction in this particular subgroup of patients that remains to be elucidated.

Adult↗

PubMed1996

Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients.

OBJECTIVES: To explore 2 facets of dopamine receptor sensitivity in alcoholics: (1) whether reduced sensitivity of central dopamine receptors is correlated with anxiety, depression, or novelty seeking and (2) whether this reduction is associated with poor treatment outcome. METHOD: Sixty-four alcohol-dependent patients were assessed according to their clinical outcome, sensitivity of central dopamine receptors (apomorphine-induced growth hormone secretion), mood states, and personality traits before and after detoxification. RESULTS: Patients with poor treatment outcome displayed a blunted growth hormone response before, but not after, detoxification. Growth hormone response was not significantly correlated with novelty seeking. Relapsing patients tended to be less depressed than patients who remained abstinent during observation. CONCLUSION: This study did not support the hypothesis that reduced sensitivity of dopamine receptors is associated with anxiety, depressed mood, or high novelty seeking in alcoholism.

Adult↗

PubMed1996

[Alcohol dependence in homeless men. Incidence, development and determinants].

Against the background of the complex relationship of alcoholism and homelessness, we investigated the question of whether homeless alcoholics and those with homes differed regarding biographical and clinical variables. Therefore, 49 of 72 (68.1%) homeless male visitors to a city kitchen in the center of Berlin, who had fulfilled the ICD-10 criteria for the alcohol-dependence syndrome, were compared with 141 outpatients of the addiction research unit of the Department of Psychiatry of the Free University of Berlin. It was found that homeless alcoholics had more psychosocial disadvantages than other alcoholics. They had been raised more frequently in families with an alcoholic father or mother and a higher number of children. The level of education and job qualification was lower in the homeless alcoholics. Early homelessness was predicted by a lack of sexual behavior (no partnership experienced) and a family history of alcoholism. In the interview, homeless alcoholics reported fewer symptoms of alcohol-dependence syndrome than other alcoholics; however, the first symptoms had been experienced earlier. Alcohol-related somatic and psychological consequences were reported more frequently in alcoholics with homes, whereas social problems were more common in the homeless subjects. The results are discussed in the light of methodological limitations and other reports on the topic.

Adult↗

PubMed1996

Harman and norharman in alcoholism: correlations with psychopathology and long-term changes.

In the search for mechanisms specific for alcoholism, it has become evident that beta-carbolines (BCs; e.g., harman and norharman) are compounds that may act on brain reward systems, thereby mediating an increase in voluntary ethanol (ETOH) drinking in animals. This study was undertaken to analyze relationships between these compounds and clinical variables (e.g., family history, personality data, and affect) in alcoholics and to trace the time course of blood concentrations in subjects abstaining from alcohol for at least 6 months. Nonalcoholics were investigated during sober and ETOH-loading conditions (1 g ETOH/kg body weight). Levels of harman were elevated in the chronically intoxicated alcoholics and correlated with the scores on the self-rating depression (SDS) and the self-rating anxiety (SAS) scales. The group of alcoholics with at least one alcoholic parent had higher levels than the group without such a history. Levels remained elevated for 6 months. Norharman levels were only slightly elevated on the day of admission. They were correlated to high harm avoidance and SDS scores. A family history of alcoholism and the severity of alcoholism as assessed by the number of ICD-10 criteria fulfilled were correlated with norharman levels. Long-term observation revealed elevated levels of norharman after 3 months of abstinence, but not after 6 months. The association of harman levels with anxiety and depression demonstrated in the present study suggests that alcoholics with high harman levels use alcoholic beverages as self-medication in an attempt to overcome possible anxiogenic/depressiogenic actions of harman. Norharman levels are less strongly associated with these mood states, but significantly correlated to harm avoidance tendencies. It has been suggested that the activity of the indolergic neurons is relatively high in individuals with a high harm avoidance score. Biosynthesis of norharman might be stimulated under these conditions (tryptamine serves as precursor).

Adult↗

PubMed1996

No association of the structural dopamine D2 receptor (DRD2) variant 311Cys with alcoholism.

The human dopamine D2 receptor (DRD2) has been implied in the vulnerability for alcoholism and/or the modification of its severity. This is supported through animal experimental and pharmacological data. We analyzed the DRD2 311Ser/Cys polymorphism in 312 German alcoholics and 131 ethnically matched controls to investigate the association of genetic DRD2 variants with alcoholism or clinical characteristics of homogeneous subgroups of alcoholics. We observed no association between the 311Cys variant and alcoholism, and none of the clinical characteristics evaluated was significantly associated with 311Cys. The allele frequencies of the 311Cys variant were 0.026 and 0.031 in the alcoholics and controls, respectively. These are the highest reported 311Cys frequencies in Caucasians. The DRD2 TaqI A1/A2 restriction fragment length polymorphism was analyzed simultaneously in our samples. In most cases, the 311Cys allele is associated with the TaqI A2-allele. Data do not suggest a clinical relevance of the 311Cys variant in alcoholism. However, the relevance of this variant in other diseases or the existence of other DRD2 variants with altered receptor function or expression cannot be excluded.

Adult↗

PubMed1996

Lack of allelic association of dopamine D1 and D2 (TaqIA) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism.

Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA-polymorphisms of the dopamine D1 and D2 receptor (DRD1, DRD2) genes and is associated with poor treatment outcome. Therefore, 97 alcohol-dependent patients were assessed according to their sensitivity of central dopamine receptors (apomorphine-induced secretion of growth hormone), clinical outcome during a 6-month observation period, and genotypic constitution of the TaqIA restriction fragment length polymorphism (RFLP) at the DRD2 locus and of the Bsp1286I RFLP at the DRD1 locus. On the 1st day of detoxification, dopamine receptor hyposensitivity was found in treatment nonresponders, but not in responders. Apomorphine-induced growth hormone release did not differ significantly in alcoholics with different genotypes of the DRD1 and DRD2 RFLPs. Neither did we find a significant allelic association with treatment response. Thus, we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome.

Adult↗

PubMed1996

Long-term observation of the hypothalamic-pituitary-thyroid (HPT) axis in alcohol-dependent patients.

Thyroid hormone levels and thyrotrophin (TSH) were measured in 45 alcohol-dependent patients before detoxification and 8 days, 3 months and 6 months after detoxification, and compared to levels in healthy controls. Before detoxification, levels of thyroxine (T4) and thyroxine-binding globulin (TBG) were significantly reduced in patients compared with healthy controls, while triiodothyronine (T3), reverse T3, and TSH levels did not differ from those in healthy controls. During the entire observation period, free T4 (fT4) and free T3 (fT3) levels were slightly elevated compared with those in healthy controls. T4 and TBG levels increased significantly during the first week of abstinence. Severity of withdrawal symptoms was negatively correlated with the total T4 levels after 8 days of abstinence. Three months after detoxification, relapsers displayed significantly lower T4 and TBG levels compared with abstinent patients. The increase in T3 levels was most pronounced between 8 days and 3 months of abstinence in both relapsing and abstinent patients. Six months after detoxification, only abstinent patients could be assessed, and they displayed increased TBG and T3 levels compared to healthy controls. Our findings suggest a different time-course for T3 and T4 levels after detoxification in alcohol-dependent patients, and indicate that T4 levels after detoxification interact with withdrawal symptoms.

Adult↗

PubMed1996

Influence of dopaminergic transmission on severity of withdrawal syndrome in alcoholism.

OBJECTIVE: Dysfunction of dopaminergic transmission has been suggested as influencing withdrawal syndrome in alcohol-dependent patients. Therefore, dopamine levels and sensitivity of dopamine receptors were correlated with the severity of withdrawal syndrome in 40 alcoholics. METHOD: Dopamine blood plasma levels and apomorphine-induced Growth Hormone (GH) release were measured on the first day of detoxification (Day 1) and after 8 days of abstinence (Day 8). Severity of withdrawal syndrome was assessed daily by the Clinical Institute Withdrawal Assessment (CIWA) score. In the 22 patients (out of the 40) treated by chlormethiazole, severity of withdrawal was measured by the required chlormethiazole dose. RESULTS: A positive correlation was found between dopamine levels on Day 1 and the total CIWA score and necessary chlormethiazole dose, respectively. Correlation with the CIWA score was even stronger when the sensitivity of post-synaptic dopamine receptors was taken into account. No significant correlation between dopamine levels on Day 8 and withdrawal syndrome was found. CONCLUSIONS: Our findings indicate an influence of dopaminergic transmission on withdrawal syndrome during early withdrawal.

Adult↗

PubMed1996

Allele-specific PCR for simultaneous amplification of both alleles of a deletion polymorphism in intron 6 of the human dopamine 2 receptor gene (DRD2).

The human dopamine 2 receptor gene (DRD2) is an important candidate gene for drug addiction and alcoholism. So far, no mutations within the coding region of DRD2 have been found to be associated with addiction disorders. To identify sequence polymorphisms for further haplotype analyses and to analyze the importance of possible intron sequence variations of the human DRD2 gene (>260kb) in greater cohorts and in a routine manner we established an optimized methodological procedure for polymerase chain reaction (PCR) amplification and direct non-radioactive sequencing followed by a bidirectional allele-specific PCR protocol; the latter one allows the simultaneous amplification of several alleles in one reaction tube. Overall, the sequences of the DRD2 introns 3-7 are highly conserved. Nevertheless, in each of the analyzed intron sequences we found substitution variants as well as a one base-pair deletion polymorphism in intron 6. The allele-specific PCR allowed the reliable testing of 95 healthy control individuals and 270 alcoholics for analyzing a possible genetic association of this newly characterized polymorphic DRD2 marker with alcoholism in an ethnically and clinically homogenous group of patients. However, the observed allele frequencies for the 1bp deletion polymorphism were 15.9% for the alcoholics and 15.3% for the controls suggesting no association of the deletion to alcoholism.

Alleles↗

PubMed1995

The Tridimensional Personality Questionnaire and the intensity dependence of auditory evoked dipole source activity.

The relationship between the tridimensional personality questionnaire's (TPQ) dimensions "novelty seeking," "harm avoidance," and "reward dependence" and the intensity dependence of the auditory evoked N1/P2-component was investigated in healthy subjects. Using dipole source analysis, evoked activity of the primary auditory cortex (tangential dipole) could be analyzed at least in part separately from that of secondary auditory areas (radial dipole). It was found that the intensity dependence of the tangential dipole was positively correlated to the TPQ dimension "novelty seeking," but not to "harm avoidance" and "reward dependence." This is in line with findings concerning similar personality traits like "sensation seeking," "impulsivity," or "extraversion." It is therefore concluded that a strong intensity dependence may characterize subjects with an action-oriented and extroverted personality style. The results are discussed within the concept that a low central serotonergic neurotransmission is underlying both an impulsive personality type and a strong intensity dependence of the tangential dipole.

Adult↗

PubMed1995

Dopamine D1, D2 and D3 receptor genes in alcohol dependence.

Hereditary factors play a substantial role in the etiology of alcohol dependence. Alcohol mediates its reinforcing effects by an activation of the mesolimbic dopamine system. These findings suggest that the genes encoding the dopamine receptor (DR) subtypes represent high-ranking candidates for susceptibility genes to addictive disorders. Our present population-based association study investigated whether sequence variants of the dopamine D1, D2 and D3 receptor genes confer susceptibility to alcohol dependence in 278 alcoholics, and clinically more homogeneous subgroups ascertained through positive family history, early age at onset, delirium, withdrawal seizures and antisocial tendencies. No evidence for an allelic association was found for the PCR-based TaqA RFLP fo the DRD2 gene and a Bsp1286I RFLP of the DRD1 gene. Without correction for multiple testing, we found a significantly increased allele frequency of a common DRD3 gene variant expressing a serine at position 9 in the extracellular N-terminal part of the receptor protein in 55 alcohol-dependent individuals with delirium (chi 2 = 4.1, df = 1, p = 0.042). Further studies have to examine whether this amino acid substitution or a nearby mutation confers genetic susceptibility to at least a subgroup of alcohol-dependent individuals with delirium.

Adult↗