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Introduction: Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. Methods: 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. Results: Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L A allele carriers (r² = 34.3 %; p = 0.001), but not in S/L G -allele carriers (p = 0.31) Discussion: In the group of L A allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials. [ABSTRACT FROM AUTHOR]

Besides the ventral tegmental area and the nucleus accumbens as the most investigated brain reward structures, several reports about the relation between volume and activity of the amygdala and drug-seeking behavior have emphasized the central role of the amygdala in the etiology of addiction. Considering its proposed important role and the limited number of human protein expression studies with amygdala in drug addiction, we performed a human postmortem proteomic analysis of amygdala tissue obtained from 8 opiate addicts and 7 control individuals. Results were validated by Western blot in an independent postmortem replication sample from 12 opiate addicts compared to 12 controls and 12 suicide victims, as a second 'control sample'. Applying 2D-electrophoresis and MALDI-TOF-MS analysis, we detected alterations of beta-tubulin expression and decreased levels of the heat-shock protein HSP60 in drug addicts. Western blot analysis in the additional sample demonstrated significantly increased alpha- and beta-tubulin concentrations in the amygdala of drug abusers versus controls ( P = 0.021, 0.029) and to suicide victims ( P = 0.006, 0.002). Our results suggest that cytoskeletal alterations in the amygdala determined by tubulin seem to be involved in the pathophysiology of drug addiction, probably via a relation to neurotransmission and cellular signaling. Moreover, the loss of neuroprotection against stressors by chaperons as HSP60 might also contribute to structural alteration in the brain of drug addicts. Although further studies have to confirm our results, this might be a possible pathway that may increase our understanding of drug addiction. [ABSTRACT FROM AUTHOR]

Objective: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. Methods: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of α2-adrenoceptor (ADRA2A –1291C→G) and the β2-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. Results: Male ADRA2A –1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. Conclusions: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The serotonergic system is involved in the pathophysiology of major depression as well as in the early central nervous system development and adult neuroplasticity. The aim of the study was to examine in 77 patients with major depression and 77 healthy controls the association between the triallelic polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and gray matter (GM) brain volumes measured with 1.5 T magnetic resonance imaging. Voxel-based morphometry were estimated on magnetic resonance images and genotyping was performed. We found that healthy controls have a strong association between the 5-HTTLPR and GM volumes of the dorsolateral prefrontal cortex, left anterior gyrus cinguli, left amygdala as well as right hippocampus, whereas there is no such association in patients with major depression. Healthy subjects carrying the S- or LG-allele have smaller GM volumes than those with the LA-allele, indicating that 5-HTTLPR contributes to the development of brain structures. Patients with depression show reduced GM volumes, particularly when they are homozygous for the LA-allele, suggesting that these patients are more vulnerable for morphological changes during depressive episodes.Molecular Psychiatry (2008) 13, 1093–1101; doi:10.1038/mp.2008.62; published online 1 July 2008 [ABSTRACT FROM AUTHOR]

Alterations of amygdala structure and function have been repeatedly described in patients with borderline personality disorder (BPD). The aim of our study was to determine whether a functional polymorphism of the 5-hydroxytryptamine1A receptor (5-HTR1A) gene C −1019 G (identity number: rs6295 G/C) is associated with structural changes of the amygdala in patients with BPD. Twenty-five right-handed female inpatients with BPD according to DSM IV and 25 healthy controls matched for age, sex, handedness and educational status were enrolled. Brain volumetry of the amygdala was performed with a 1.5-T Magnetom Vision apparatus (Siemens, Erlangen, Germany) and analyzed by the software program ‘brains’. Patients who have the 5-HTR1A gene G allele had significantly smaller amygdala volumes than C/C genotype carriers ( P = 0.02). While no difference of allelic distribution between patients and controls was detected, the described effect of 5-HTR1A genotype on amygdala volume was found for the whole group of patients, as well as in the subgroup of patients with comorbid major depression ( P = 0.004) but not in controls. In contrast to these subgroups of BPD patients who had significant amygdala volume differences, the mean amygdala volume of the whole group of BPD patients was not significantly different from that of controls. In summary, our study provides first evidence that 5-HTR1A gene C −1019 G polymorphism is associated with structural changes in the limbic system of BPD patients, a finding that might be disease related and might contribute to explanation of previous discrepant results regarding amygdala volume changes in BPD. Future research is recommended to clarify possible interactions between this functional polymorphism and symptoms, course and treatment responses in this disorder. [ABSTRACT FROM AUTHOR]

Objective: Low platelet monoaminoxidase B (MAO-B) activity has been associated with various forms of impulsive behaviour and suicidality. The present study investigated the relationship between MAO-B activity in platelets and aspects of suicidality in depressed patients and controls. Method: In 87 patients with affective spectrum disorders (58% suffering from a major depressive episode – MDE) the potential association between platelet MAO-B activity and suicidality was examined. Fifty-nine of the patients had committed suicide attempt recently (SA –‘suicide attempters’), 28 patients were acutely depressed without having shown suicidal thoughts or suicidal behaviour in the past (NA –‘non-suicide attempters’). Results: The SA and NA were comparable as to their diagnoses and general demographic and psychopathological parameters. MAO-B activity did not differ between SA and NA. No systematic correlations existed between MAO-B activity and any dimensions of suicidal behaviour or psychopathology. As a single finding only a weak positive association of higher MAO-B activity in SA with a fatal intention of the SA was observed. Conclusion: Our findings do not support a consistent association of platelet MAO-B activity and suicidal behaviour in general, but specific facts of suicidality might be associated. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol dependence and habitual smoking frequently co-occur and possibly mutually influence each other. Both have been related to alterations of dopaminergic neurotransmission. The aim of this analysis of the Munich Gene Data Bank for Alcoholism(MGBA) was to re-evaluate the potential relation between D2 receptor and dopamine transporter gene haplotypes and quantity-related phenotypes of alcohol consumption (average daily alcohol intake before admission for treatment) and smoking (average units smoked per day). Methods: A total of 333 inpatients (265 males) were enrolled in the study, all of who met the ICD10 diagnosis of alcohol dependence. Mild and strong quantity drinkers and smokers were separated into groups by median split. A number of genetic markers were chosen across D2 dopamine receptor gene (-141 Ins/Del, Taq I B, Taq ID, Ser3 II Cys; rs 1079594 (intron 7); TaqiA) and dopamine transporter (4Obp variable number of tandem repeat; rs2617605 (intron 2); rs37022 (intron 7); rs40l84 (intron 14)). Genotyping was performed using PCR. Results: Strong drinkers reported significantly higher amounts of smoking and vice versa. While no association was detected for dopamine transporter genetic variants, a number of D2 receptor gene single nucleotide polymorphisms were related to both smoking- and drinking-related behaviours. Subsequent analysis of D2 receptor gene haplotypes revealed that two common haplotypes had a significant association with quantitative phenotypes of regular drinking (Ins-C-G-C-A 1) and smoking (Ins-T-G-A-A2). Discussion: The finding of an association between common D2 dopamine receptor gene haplotypes with the quantity of drinking and smoking corroborates with results from previous studies suggesting a relationship between the dopamine system and alcohol and substance use disorders. Furthermore, it makes D2 dopamine receptor a candidate gene significantly influencing both alcohol and nicotine dependence. [ABSTRACT FROM AUTHOR]

The concept that genetic factors contribute to the complex trait of suicidal behaviour has stimulated much work aimed at identifying susceptibility genes. So far molecular genetic studies focused on the serotonergic pathway as the intent to die and the lethality of suicide acts were related to the serotonergic system. Two genes have so far emerged as being involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C) of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal behaviour, but in violent and repeated suicide attempts. The data have further shown that the MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is not related to suicide but might induce violent methods in subjects with other suicide risk factors. Predominantly negative were the findings with any type of the serotonin receptors and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the dopaminergic receptors. This paper reviews the status of current knowledge in this area, points to the weakness of the investigations and presents new approaches beyond the serotonergic system.Molecular Psychiatry (2006) 11, 336–351. doi:10.1038/sj.mp.4001803; published online 7 February 2006 [ABSTRACT FROM AUTHOR]

Upregulation of glutamatergic neurotransmission resulting from chronic ethanol intoxication may cause a hyperexcitable state during alcohol withdrawal, which may lead to seizures and delirium tremens. The aim of our study was to evaluate the association between a history of alcohol withdrawal-induced seizures and delirium tremens, and a functional polymorphism (Ser310Ala) of the GRIK3 gene coding for the glutamatergic kainate receptor subunit GlurR7 in a sample of well-characterized alcoholics compared to controls. In total, 233 patients meeting DSM-IV alcohol dependence criteria and 309 controls, all of German descent, were investigated. GRIK3 functional polymorphism was determined using PCR (polymerase chain reaction) of lymphocyte DNA. History of alcohol withdrawal-induced delirium tremens and seizures were obtained using the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). Data were cross-checked with in-patients’ clinical files. While a significant relationship between history of delirium tremens and the Ser310 allele was detected, no significant results were obtained for alcohol withdrawal-related seizures. Although this result is suggestive for a significant role of this polymorphism in the pathogenesis of delirium tremens in alcohol-dependent individuals, further investigation and confirmation are warranted.The Pharmacogenomics Journal (2006) 6, 34–41. doi:10.1038/sj.tpj.6500343; published online 29 November 2005 [ABSTRACT FROM AUTHOR]

The 5HT1A receptor is one of at least 14 different receptors for serotonin which has a role in moderating several brain functions and may be involved in the aetiology of several psychiatric disorders. The C(-1019)G 5-HT1A promoter polymorphism was reported to be associated with major depression, depression-related personality traits and suicidal behavior in various samples. The G(-1019) allele carriers are prone to depressive personality traits and suicidal behavior, because serotonergic neurotransmission is reduced. The aim of this study is to replicate previous findings in a sample of 185 Alcohol-dependent individuals. Personality traits were evaluated using the NEO FFI and TCI. History of suicidal behavior was assessed by a standardized semistructured interview (SSAGA). No significant differences across C(-1019)G 5-HT1A genotype groups were found for TCI temperament and character traits and for NEO FFI personality scales. No association was detected between this genetic variant and history of suicide attempts. These results neither support a role of C(-1019)G 5-HT1A promoter polymorphism in the disposition of personality traits like harm avoidance or neuroticism, nor confirm previous research reporting an involvement of the G allele in suicidal behavior in alcoholics. Significant associations, however, were detected between Babor's Type B with number of suicide attempts in history, high neuroticism and harm avoidance scores in alcoholics. [ABSTRACT FROM AUTHOR]

A serotonergic dysfunction was suggested to be involved into the biological susceptibility of suicidal behaviour. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is a significant regulating factor in the serotonergic system. Recently the A-6526G, and G-5806T and A-779C polymorphisms of the TPH 1 gene were identified and suggested to be associated with suicidal behaviour, but study results are conflicting. We examined a possible association of the A-6526G, and G-5806T and A-779C polymorphisms with suicide attempts in a sample of 80 alcohol-dependent individuals with a history of at least one suicide attempt. This group was analysed in comparison with 241 alcohol-dependent subjects without such a history. No significant relationship between haplotype and genotype distribution and allele frequencies of these polymorphisms with suicide attempts were detected. Furthermore, no association with number of suicide attempts and TPH haplotypes were found. Our data do not support the hypothesis of A-6526G, G-5806T or A-779C polymorphisms to be associated with suicide attempts in alcohol-dependent individuals. [ABSTRACT FROM AUTHOR]

Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.Molecular Psychiatry (2004) 9, 1030-1036. doi:10.1038/sj.mp.4001525 Published online 4 May 2004 [ABSTRACT FROM AUTHOR]

The serotonin type 3 (5-HT3) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT2) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na+-inward currents through 5-HT3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca2+ influx, measured as a change in intracellular Ca2+ concentrations ([Ca2+]i). All neuroleptic drugs, but not risperidone, antagonized Na+- and Ca2+-inward currents evoked by 5-HT (10?µM for 2?s and 1?µM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na+ and Ca2+ currents. Since 5-HT3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.Molecular Psychiatry (2004) 9, 846-858. doi:10.1038/sj.mp.4001490 Published online 16 March 2004 [ABSTRACT FROM AUTHOR]

Because corticotrophin-releasing hormone (CRH) plays a central role in stress regulation, the possible role of CRH1 polymorphism for anxiety-related personality variables such as harm avoidance possibly associated with alcoholism was studied. The research instruments used to phenotype patients were adopted partly from the US collaborative study of the genetics of alcoholism and include a number of personality inventories such as the temperament and character inventory (TCI). Based on the examination of 170 alcoholic subjects no association was found between CRH1 receptor haplotypes of four single nuclotid polymorphisms (SNPs) and low and high temperament traits of harm avoidance, novelty seeking and reward dependence. The possible implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Summary. The 5-HT1B receptor gene has been postulated to play a modulatory role in alcohol consumption and alcohol dependence, and was considered a candidate gene for alcoholism. More recently, the association of the 5-HT receptor gene polymorphism and antisocial personality traits in alcoholism has been discussed. This possible association was studied using material from our gene bank for alcoholism. The research instruments used to phenotype patients were partly adopted from the US Collaborative Study on the Genetics of Alcoholism (COGA) which include anxiety- and depression-related scales from personality inventories such as the temperament and character inventory (TCI), the NEO-Five-Factor Inventory (NEO-FFI) and the Minnesota Multiphase Personality Inventory (MMPI-2). Based on the examination of 164 alcoholic subjects, an association was found between a lower frequency of the 5-HT 1B 861C allele, antisocial personality traits and conduct disorder in alcohol-dependent subjects. Adult antisocial personality occurred more often in males than females. Possible implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Objective:. Neurotransmitter release of GABAergic and glutamatergic neurons may be significantly influenced by cannabinoid CB1 receptors located at presynaptic nerve terminals. GABA and glutamate have been reported to be involved in the pathogenesis of severe alcohol withdrawal-induced seizures and delirium tremens. The aim of this study is to test the potential influence of a bi-allelic cannabinoid receptor gene (CNR1) polymorphism (G1359A) on severe alcoholwithdrawal syndromes. Methods:. Based upon a sample size estimation, 196 subjects meeting DSM IV and ICD10 criteria for alcohol dependence and 210 non-alcoholic controls were recruited for study. CB1 polymorphisms were determined using polymerase chain reaction (PCR). History of alcohol withdrawal-induced delirium tremens, seizures and other alcohol withdrawal-related phenotypes were obtained using the SSAGA (Semi-Structured Assessment of Genetics in Alcoholism). Data were corroborated with information from the inpatients’ clinical files. Results:. Allele frequencies of the CNR1 G1359A polymorphism were within the range reported by previous studies. After correcting for multiple testing, no association of the A- or G-allele of CNR1 polymorphism with a history of alcohol withdrawal-induced seizures was detected. In addition, no significant relationships with other alcoholism-related phenotypes were found. Conclusion:. This study failed to confirm an earlier report of a potential role of a CNR1 polymorphism in the pathogenesis of delirium tremens. [ABSTRACT FROM AUTHOR]

Antidepressants are commonly supposed to enhance serotonergic and/or noradrenergic neurotransmission by inhibition of neurotransmitter reuptake through binding to the respective neurotransmitter transporters or through inhibition of the monoamine oxidase. Using the concentration-clamp technique and measurements of intracellular Ca2+, we demonstrate that different classes of antidepressants act as functional antagonists at the human 5-HT3A receptor stably expressed in HEK 293 cells and at endogenous 5-HT3 receptors of rat hippocampal neurons and N1E-115 neuroblastoma cells. The tricyclic antidepressants desipramine, imipramine, and trimipramine, the serotonin reuptake inhibitor fluoxetine, the norepinephrine reuptake inhibitor reboxetine, and the noradrenergic and specific serotonergic antidepressant mirtazapine effectively reduced the serotonin-induced Na+- and Ca2+-currents in a dose-dependent fashion. This effect was voltage-independent and, with the exception of mirtazapine, noncompetitive. Desipramine, imipramine, trimipramine, and fluoxetine also accelerated receptor desensitization. Moclobemide and carbamazepine had no effect on the serotonin-induced cation current. By analyzing analogues of desipramine and carbamazepine, we found that a basic propylamine side chain increases the antagonistic potency of tricyclic compounds, whereas it is abolished by an uncharged carboxamide group. The antagonistic effects of antidepressants at the 5-HT3 receptor did not correlate with their effects on membrane fluidity. In conclusion, structurally different types of antidepressants modulate the function of this ligand-gated ion channel. This may represent a yet unrecognized pharmacological principle of antidepressants.Molecular Psychiatry (2003) 8, 994-1007. doi:10.1038/sj.mp.4001314 [ABSTRACT FROM AUTHOR]

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fisher's exact test: genotype distribution: P=0.0038; allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.Molecular Psychiatry (2003) 8, 942-946. doi:10.1038/sj.mp.4001392 [ABSTRACT FROM AUTHOR]

Aims: We analysed the MAOAuVNTR functional polymorphism in the promoter region of the X-chromosomal monoamine oxidase A (MAOA) gene. Genotypes with three-repeat alleles were reported to be associated with antisocial as well as impulsive traits. Methods: The repeat number (3-5) of the MAOA polymorphism was determined in 169 male alcoholic subjects and 72 controls of German descent. Behavioural and personality traits were evaluated using the Brown-Goodwin Assessment for History of Lifetime Aggression, the Buss Durkee Hostility Inventory, as well as the Barrat Impulsiveness Score. A median split in Brown-Goodwin, Buss Durkee Irritability, Buss Durkee Assault and Barrat Impulsiveness Score was conducted. Results: High scores were found, i.e. 47.9% in Brown-Goodwin, 65.7% in Buss Durkee Irritability, 63.3% in Buss Durkee Assault and 59.8% in Barrat Impulsiveness Scale, indicating high impulsiveness, irritability and antisocial behaviour. Based on the results of these questionnaires, we detected no significant differences between the frequency of the three-repeat allele and high or low scores in alcoholics and controls. Conclusions: Taken together, these findings suggest that the three-repeat allele of the MAOAuVNTR 30-bp polymorphism is not associated with impulsive and aggressive personality traits. [ABSTRACT FROM AUTHOR]

Investigates the angiotensin I converting enzyme (ACE) ID and the G-protein beta3-subunit C825T polymorphism in 201 patients with unipolar major depression and 161 ethnically and age-matched controls. Association of the variants with either cardiovascular disease or affective disorders; Increase in the risk for myocardial infarction by the allelic combination of the two genes.

Examines the possible link of A779C and A218C single nucleotide polymorphisms in the tryptophan hydroxylase (TPH) gene with anger-related traits in a sample of community-based healthy volunteers and suicide attempters in Germany. Functions of TPH; Interaction effects for genotype and diagnosis.

— Up-regulation of the glutamatergic neurotransmission from chronic ethanol intoxication may cause a hyperexcitable state during alcohol withdrawal that may lead to seizures and delirium tremens. The aim of our study was to evaluate the association between a history of alcohol withdrawal-induced seizures and delirium tremens and a mGlurR7 (Tyr433Phe); and a mGlurR8 (C2756T) metabotropic glutamate receptor polymorphism in alcoholics compared to controls. A total of 182 patients meeting DSM-IV alcohol dependence criteria and 117 controls, both groups being of German descent, were investigated. mGluR7 and mGluR8 polymorphisms were determined using polymerase chain reaction of lymphocyte DNA. History of alcohol withdrawal-induced delirium tremens and seizures were obtained using the Semi-Structured Assessment of Genetics in Alcoholism (SSAGA). Data were cross-checked with inpatients' clinical files. No significant associations were obtained between both receptor polymorphisms and alcohol withdrawal-induced seizures and delirium tremens. The negative results in this study question the role of these polymorphisms in the pathogenesis of alcohol withdrawal-induced seizures and delirium tremens. [ABSTRACT FROM PUBLISHER]

The serotonergic neurotransmission was suggested to play an important role in the aetiology of alcoholism. This study explores the association between tryptophan hydroxylase (TPH)-alleles and Loudness Dependence of Auditory Evoked N1/P2 Potentials (LDAEP). The TPH is the rate-limiting biosynthetic enzyme in serotonergic pathway. The LDAEP is one of the best validated non-invasive indicators for serotonergic neurotransmission. A sample of 54 alcoholics was recruited. N1/P2 potentials were evoked by five different sound intensities. A dipole source analysis using BESA (brain electric signal topography) was performed and intensity dependence was computed. The TPH intron 7 polymorphism was determined by using PCR in DNA samples. There was a weak but significant association between low LDAEP and the L-TPH allele. No influence from an individual's history of alcohol dependence or a positive family history of alcohol dependence on LDAEP was found. The weak but significant relationship found between L-TPH-allele and high serotonergic neurotransmission may contribute to a more detailed neurobiological characterization of alcohol dependents using functional and genetic parameters. [ABSTRACT FROM AUTHOR]

Summary. Glutamatergic NMDA receptors are believed to play a major role in the pathophysiology of numerous neuropsychiatric disorders including substance use and schizophrenia. Neuropharmacological studies measuring subjective response, psychopathology and biological parameters are helpful in studying pathophysiology of these disorders. We report preliminary data of a placebo-controlled double-blind challenge study in recently detoxified alcoholics (n = 20) and healthy controls (n = 10) using the non-competitive NMDA antagonist dextromethorphan. Findings suggest that dextrometorphan can produce ethanol-like subjective effects in both alcoholics and controls and induce a mild form of craving in alcoholics only. The results of this study give further support to the hypothesis of glutamatergic NMDA receptors mediating much of ethanol's psychotropic effects. Possible clinical implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

In order to investigate the diagnostic value ofH-spiperone binding capacity to lymphocytes in the differential diagnosis of de novo Parkinson's disease (idiopathic Parkinson syndrome, PD), we performed a double blind prospective study of spiperone binding capacity of 123 patients and 23 healthy control persons, belonging to different diagnostic groups (PD, Parkinsonian syndrome due to vascular lesions, multiple system atrophy [MSA], essential tremor). Diagnoses were based on medical history, clinical examination, CT or MRI scan, acute response to dopamimetric drugs, one year follow up, and long term response to L-DOPA treatment. Spiperone binding was assayed using ten different concentrations (0.03-3 nmol) in absence or presence of 1μmol (+)-butaclamol to determine nonsepecific binding. There was no significant difference in spiperone binding between patients with PD not treated with L-DOPA, and patients with other basal ganglia disorders including parkinsonian syndrome due to vascular lesions, multiple system atrophy, or progressive supranuclear palsy, and age matched controls. Binding was significantly higher in parkinsonian patients with PD treated with L-DOPA and patients with essential tremor. It is concluded that at presentH-spiperone binding gives no further information in the differential diagnosis of de novo Parkinson's disease. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest an involvement of adenosine A receptor (AAR) mediated adenosinergic neuromodulation in the etiopathogenesis of schizophrenia. We therefore perfomed a systematic mutation scan of the complete coding region of the human AAR gene in a sample of 42 schizophrenic patients. We detected one rare naturally occurring receptor variant (Gly-340-Ser) and two silent mutations (405C/T and 1083C/T). To our knowledge the Gly-340-Ser substitution is the first naturally occurring molecular variant of the AAR identified. Determining the frequency of the three variants in 42 unrelated healthy controls, we observed a significant trend towards an overrepresentation of the 1083T variant in patients when compared to controls (p=0.041). This trend was followed up in a large independent replication sample. However, we were not able to confirm the original trend in the second sample (p=0.367). The Ser-340 variant was found in a single schizophrenic individual. Investigation of the patient's family revealed independent segregation between the Ser-340 variant and psychiatric illness. Our data suggest that genetically determined structural variation of the AAR does not play a major role in the development of schizophrenia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about the possible impact of the neuroD2 transcription factor on the development of drug abusing behavior.

Examines the significant frequency deviation of the class 1 polymorphism HLA-A10 in schizophrenic patients. Assessment of the bidirectional communication between the central nervous system and the immune system; Evaluation of brain derived neurotrophic factro and dopamine; Elimination of infections.

There is abundant evidence that the serotonin (5-HT) system is modulating mood and several behavioural traits and that disturbances in the regulation of this system can be associated with severe behavioural malfunctions, as aggressive implusive and suicidal behaviour. Recently a functional polymorphism in the promoter region of the serotonin transporter gene (5HTTLPR) was identified and the presence of one or two short alleles was associated with anxiety-related personality traits and several psychiatric disturbances, such as affective disorder or severe alcohol dependence. With respect to the importance of the 5-HT transporter in serotonergic transmission, we have genotyped the DNA of 58 Caucasian suicide victims (with unknown psychiatric diagnoses) and 110 healthy controls for the biallelic functional polymorphism in the 5HTTLPR. We found a highly significant increased frequency of suicide victims being carriers of one or two short alleles (Fisher's Exact Test, two sided, P = 0.0003), which suggests that a genetically altered protein function within the serotonergic pathway might be involved in suicidality, independently from the clinical diagnosis. [ABSTRACT FROM AUTHOR]

Studies the influence of insertion/deletion polymorphism of the angiotensin I-converting enzyme (ACE) on therapeutic outcome in patients with unipolar major depression. Association of ACE allele-D with increased neuropeptide degradation; Effects of variants in the ACE gene on drug response.

The article focuses the antagonistic behavior of antipsychotic drugs with human serotonin type 3 (5-HT3) receptor currents in a noncompetitive manner. It indicates representative recordings of 5-HT-evoked sodium ion currents after application of serotonin and the neuroleptics.