Biomedical subjects

A Heils

Publications and source records attributed to A Heils.

At least 37 records · Page 2Linked to original sources

PubMed1999

Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice.

The aim of the present study was to determine whether alterations in 5-hydroxytryptamine (5-HT)(1A) receptors would be found in knockout mice lacking the serotonin transporter (5-HTT). Hypothermic and neuroendocrine responses to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) were used to examine the function of 5-HT(1A) receptors. Initial studies evaluated the dose-response and time course of 8-OH-DPAT-induced hypothermia and hormone secretion in normal CD-1 mice (the background strain of the 5-HTT knockout mice). 8-OH-DPAT dose-dependently produced hypothermic responses that peaked at 20 min postinjection. 8-OH-DPAT-induced hypothermia was blocked by the 5-HT(1A) antagonist WAY-100635. 8-OH-DPAT dose-dependently increased the concentrations of plasma oxytocin, corticotropin, and corticosterone. In the 5-HTT knockout (-/-) mice, the hypothermic response to 8-OH-DPAT (0.1 mg/kg s.c.) was completely abolished. Furthermore, 5-HTT-/- mice had significantly attenuated plasma oxytocin and corticosterone responses to 8-OH-DPAT. No significant changes in the hypothermic or hormonal responses to 8-OH-DPAT were observed in heterozygous (5-HTT+/-) mice. [(3)H]8-OH-DPAT- and [(125)I]MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-iodobenzamido]ethyl] pip erazine]-binding sites in the hypothalamus and [(125)I]MPPI-binding sites in the dorsal raphe were significantly decreased in 5-HTT-/- mice. The results indicate that lack of the 5-HTT is associated with a functional desensitization of 5-HT(1A) receptor responses to 8-OH-DPAT, which may be a consequence, at least in part, of the decrease in density of 5-HT(1A) receptors in the hypothalamus and dorsal raphe of 5-HTT-/- mice.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

The appetite suppressant d-fenfluramine induces apoptosis in human serotonergic cells.

Fenfluramine is an amphetamine analogue which has been widely used in the treatment of obesity. In rodents, non-human primates, and humans, fenfluramine is associated with some indices of neurotoxicity, as well as pulmonary hypertension and cardiac valve pathology. In the present study, d-fenfluramine was found to be cytotoxic to the serotonin (5-HT) transporter (5-HTT) expressing human placental choriocarcinoma cells. d-Fenfluramine caused DNA fragmentation and apoptosis. Apoptosis was not observed after the 5-HTT had been blocked by fluoxetine, indicating that intact 5-HTT function is required for d-fenfluramine to induce programmed cell death. These observations in a human cell line may reflect a possible mechanism associated with the risks of fenfluramine administration in several species, including humans.

Apoptosis↗

PubMed1998

Distribution of the B33 CTG repeat polymorphism in a subtype of schizophrenia.

Clinical evidence for a dominant mode of inheritance and anticipation in periodic catatonia, a distinct subtype of schizophrenia, suggests that trinucleotide repeat expansions may be involved in the aetiology of this disorder. Since genes with triplet repeats are putative canditates for causing schizophrenia, we have analysed the polymorphic B33 CTG repeat locus on chromosome 3 in 45 patients with periodic catatonia and 43 control subjects. The B33 CTG repeat locus was highly polymorphic, but all alleles in both the patient and control groups had repeat lengths within the normal range. We conclude that susceptibility to periodic catatonia is not influenced by variation at the B33 CTG repeat locus. Nevertheless, that periodic catatonia displays dominant inheritance and anticipation, characteristic of genetic disorders involving trinucleotide repeats, justifies further screening for triplet repeat expansions in this illness.

Adult↗

PubMed1998

Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene.

A possible dysregulation of serotonergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses. In the present study we analysed allelic and genotypic variations of a recently described functional polymorphic region in the promoter of the human serotonin transporter gene (5-HTTLPR) and a variable tandem repeat (VNTR) in intron 2 of the 5-HTT gene. We investigated 413 unrelated individuals, 180 schizophrenic patients and 233 blood donors as controls. With regard to the 5-HTTLPR, both the schizophrenic and the control group did not significantly differ between genotype frequencies (chi2, p = 0.920) and allele frequencies (chi2, p = 0.836). The odds ratio for subjects with schizophrenia who were homozygous for the short allele was 1.04 (95% CI 0.59-1.84). No evidence of allelic association to specific schizophrenia subtypes was found. The 5-HTT associated VNTR also showed no significant differences between either the allelic or the genotypic distributions. Haplotype analysis revealed a significant overall linkage disequilibrium at a level of p = 0.00004. Our findings indicate that both polymorphisms are unlikely to play a substantial role in the genetic predisposition to schizophrenic disorders.

Adolescent↗

PubMed1998

Insertion/deletion variant (-141C Ins/Del) in the 5' regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder. Short communication.

A possible dysregulation of dopaminergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses, in particular of paranoid-hallucinatory states, and of the manic episodes of bipolar affective disorder. In the present study we analysed allelic and genotypic variations of a recently described functional deletion/insertion variant (-141C Ins/Del) in the 5' flanking region of the human dopamine D2 receptor gene. We investigated a total of 620 unrelated individuals, comprising 260 schizophrenic patients, 70 patients with bipolar affective disorder, and 290 population controls. Analysis of the -141C Ins/Del variant revealed that the schizophrenic, bipolar affective and control groups did not differ significantly regarding genotype frequencies and allele frequencies. No evidence of an allelic association with either a family history of schizophrenic psychosis or a diagnosis of schizophrenia of the paranoid type (according to ICD 10) was found. Our findings indicate that the -141C Del variant in the 5' flanking region of the human dopamine D2 receptor gene is unlikely to play a substantial role in genetic predisposition to major psychiatric disorders in Caucasians.

Adult↗

PubMed1998

Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6.

Serotonin (5-HT) is a prime candidate for studies of the interaction between the nervous and immune systems, since it is both an important neurotransmitter and released at high concentrations at sites of inflammation. Serotonergic neurotransmission is regulated by the 5-HT transporter (5-HTT), which determines the magnitude and duration of serotonergic responses. Since tumor necrosis factor alpha (TNF-alpha) and interleukin-6 are two inflammatory mediators that are central to the initiation of inflammation, we studied the impact of these cytokines on the 5-HTT. As model system we used a cell line which constitutively expresses the 5-HTT, namely the choriocarcinoma cell line JAR. We found that TNF-alpha enhances 5-HT uptake, with a doubling of the maximal velocity of uptake. Interleukin-6, on the other hand, had no effect. We thus show for the first time that the cytokine TNF-alpha modulates 5-HTT function. Furthermore, we propose a molecular mechanism for this effect. Since both 5-HT and TNF-alpha are elevated at sites of inflammation, TNF-alpha may act to renormalize 5-HT levels by way of its effect on the 5-HTT. This is especially important for the central nervous system, where the TNF-alpha effect shown here can aid in preventing disturbances of serotonergic neurotransmission.

Carrier Proteins↗

PubMed1998

A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter.

Several studies have shown an association between schizophrenia and the C allele of a T-C polymorphism at nucleotide 102 and the 5HT2A receptor gene. In the present study we observed this association in a sample of 63 parent/offspring trios where the proband received a diagnosis of DSM-III-R schizophrenia using TDT analysis (chi2 = 6.26, P= 0.006, chi2 = 9.00, P=0.001 when one affected offspring was selected at random from each family, suggesting that the results are due to association rather than linkage). There was no significant difference between the transmission of C102 from heterozygous fathers and mothers, which fails to support a role for genomic imprinting in this effect. T102C does not result in an alteration of the amino acid sequence of the protein. We therefore screened the promoter of 5HT2A for polymorphisms using single-strand confirmation polymorphism analysis. An A-G polymorphism at -1438 that creates an HpaII restriction site was identified. This was found to be in complete linkage disequilibrium with T102C and is hence a candidate for the pathogenic variant in schizophrenia. Functional analysis of A-1438G using luciferase assay demonstrated significant basal promoter activity in 5HT2A expressing HeLa cells by both the A and G variants. However, comparison of the A and G variants showed no significant differences in basal activity nor when promoter activity was induced by cAMP and protein kinase C-dependent mechanisms.

Adult↗

PubMed1998

Functional characterization of the murine serotonin transporter gene promoter in serotonergic raphe neurons.

We have isolated and characterized the 5'-flanking regulatory region of the murine serotonin 5-HT transporter (5-HTT) gene. A TATA-like motif and several potential binding sites for transcription factors, including two AP1, several AP2 and AP4 binding sites, CCAAT and GC boxes (SP1 binding sites), a nuclear factor-kappaB, and a cyclic AMP response element-like motif, are present in the 5'-flanking region. A approximately 2.2-kb fragment (-2,143 to +51 with respect to the transcription start site), which had been fused to the luciferase reporter gene and transiently expressed in a 5-HTT-expressing cell line and in serotonergic raphe neurons derived from embryonic rat brainstem, displayed both constitutive and inducible promoter activity. Functional promoter mapping revealed two clusters of activating elements from bp -82 to -527 and bp -1,001 to -1,937. A cell/neuron-selective silencer element(s) is contained between bp -294 and -527. Our findings suggest that (1) the murine 5-HTT gene promoter is active in serotonergic raphe neurons but significantly repressed in neuronal cells from frontal cortex that do not express 5-HTT, (2) the information contained within approximately 0.5 kb of the 5'-flanking sequence is sufficient to confer its cell-selective expression, (3) the promoter responds to cyclic AMP- and protein kinase C-dependent induction, and (4) the expression of the 5-HTT is regulated by a combination of positive and negative cis-acting elements operating through a basal promoter unit defined by a TATA-like motif. Fusion of the 5-HTT gene promoter unit to a gene of choice may aid its cell-selective expression in transgenic strategies.

Animals↗

PubMed1998

Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice.

The sodium-dependent, high affinity serotonin [5-hydroxytryptamine (5-HT)] transporter (5-HTT) provides the primary mechanism for inactivation of 5-HT after its release into the synaptic cleft. To further evaluate the function of the 5-HTT, the murine gene was disrupted by homologous recombination. Despite evidence that excess extracellular 5-HT during embryonic development, including that produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT-/- mice. High affinity [3H]5-HT uptake was completely absent in 5-HTT-/- mice, confirming a physiologically effective knockout of the 5-HTT gene. 5-HTT binding sites labeled with [125I] 3 beta-(4'-iodophenyl)tropan-2 beta-carboxylic acid methyl ester were reduced in a gene dose-dependent manner, with no demonstrable binding in 5-HTT-/- mutants. In adult 5-HTT-/- mice, marked reductions (60-80%) in 5-HT concentrations were measured in several brain regions. While (+)-amphetamine-induced hyperactivity did not differ across genotypes, the locomotor enhancing effects of (+)-3, 4-methylenedioxymethamphetamine, a substituted amphetamine that releases 5-HT via a transporter-dependent mechanism, was completely absent in 5-HTT-/- mutants. Together, these data suggest that the presence of a functional 5-HTT is essential for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity.

Animals↗

PubMed1997

Cellular localization and expression of the serotonin transporter in mouse brain.

The high-affinity serotonin (5-HT) transporter (5-HTT) plays an important role in the removal of extracellular serotonin, thereby modulating and terminating the action of this neurotransmitter at various pre- and post-synaptic serotonergic receptors and heteroreceptors. In order to characterize the anatomical distribution of the 5-HTT in mouse brain, in situ hybridization histochemistry using 35S-labeled riboprobes was performed. These results were compared with 5-HTT binding site distribution as evaluated by [125I]RTI-55 autoradiography. High levels of 5-HTT mRNA were detected in all brain stem raphe nuclei, with variations in labeling among the various subnuclei. Those brain areas known to possess serotonergic cell bodies stained intensely for both 5-HTT mRNA and 5-HTT binding sites. In contrast to previous findings in rat brain, the highest densities of 5-HTT sites were found in areas outside the raphe complex, particularly in the substantia nigra, globus pallidus, and superior colliculi.

Animals↗

PubMed1997

Molecular heterogeneity of neurotransporters: implications for neurodegeneration.

Neurotransporters are high-affinity transport proteins located in the plasma membrane of both presynaptic nerve and glial cells that mediate the removal of neurotransmitters from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles. They comprise three subgroups, Na+/Cl(-)- or Na+/K(+)-dependent cell surface transporters and H(+)-dependent transporters associated with synaptic vesicles. The new insights into neurotransporter diversity provide the means for novel approaches of studying neurotransmitter uptake processes at the molecular level, such as substrate translocation and antagonist binding as well as regulation of gene expression, of intracellular trafficking, and of posttranslational modification. Moreover, modeling neurotransporter-related disorders and therapeutic strategies in genetically engineered animals are now feasible research strategies. Through an improved understanding of the modulation of neurotransporter function in the brain, it may be possible to identify the molecular factors underlying the etiopathogenesis and pathophysiology of neurodegenerative disorders. Due to their specificity for distinct neuronal systems, neurotransporters and their genes are potential targets for novel therapeutic strategies.

Animals↗

PubMed1997

The human serotonin transporter gene polymorphism--basic research and clinical implications.

Mood, emotion, and cognition are modulated by the serotonergic midbrain raphe system, which seems to be involved in the pathogenesis of psychiatric disorders like those of the affective spectrum. Since a dysregulation of serotonin transporter expression might be important in the course of those disorders, we isolated and cloned the 5'-regulatory region of the serotonin transporter gene, which is inducible by cAMP- and PKC-depended signal transduction pathways. Systematic screening for length variations and functional promoter analyses revealed a genetic polymorphism with allelic variation in transcriptional activity and protein expression. This 5-HTT gene polymorphism comprises a tandemly repeated sequence in the 5'-regulatory promoter region of the serotonin transporter gene. Recent population association studies demonstrated the 5-HTT gene promoter polymorphism accounting for 4-5% of population variation of anxiety-related behavioral traits.

B-Lymphocytes↗

PubMed1997

The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication.

By conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter gene's 5'-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio, years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and non-human primate populations.

Alleles↗

PubMed1997

Serotonin transporter gene-linked polymorphic region: allele distributions in relationship to body weight and in anorexia nervosa.

Several lines of evidence implicate a role for the serotonergic system in body weight regulation and eating disorders. The magnitude and duration of postsynaptic responses to serotonin (5-HT) is directed by the transport into and release from the presynaptic neuron. Recently, a common polymorphism of a repetitive element in the region of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) was identified that results in a system of two common alleles. The activity of the 5-HTT, as measured in in vitro assays and in human lymphoblastoid cell lines, is dependent on the respective genotype. We thus hypothesized that this polymorphism is relevant for weight regulation in general and is possibly involved in the etiology of anorexia nervosa (AN). Allele frequencies and genotypes were determined in a total of 385 unrelated obese children, adolescents and adults, 112 underweight subjects and 96 patients with AN. Furthermore, both parents of 98 obese children and adolescents and of 55 patients with AN, respectively, were genotyped, thus allowing to test for both association and linkage. The comparison of allele frequencies between obese and underweight probands provided no evidence for a major role of the 5-HTTLPR in weight regulation. Patients with AN had allele frequencies not significantly different to those observed for obese and underweight individuals.

Adolescent↗

PubMed1997

Gene structure and 5'-flanking regulatory region of the murine serotonin transporter.

By modulating the magnitude and duration of postsynaptic responses, carrier-facilitated serotonin (5-HT) transport into and release from the presynaptic neuron is central to the fine tuning of serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the prime target for widely used antidepressants, psychostimulants, drugs of abuse and neurotoxins. We have isolated the gene encoding the murine 5-HTT and determined the sequence of all exons including adjacent intronic regions and approximately 3.6 kb of the 5'-flanking regulatory region. The murine 5-HTT gene is composed of 14 exons spanning approximately 34 kb. The single gene transcript after splicing is 2744 bp in length and it contains 186 bp of 5' untranslated region (5'-UTR) and 668 bp of 3'-UTR. A TATA-like motif and several potential binding sites for transcription factors including AP1, AP2, AP4, SP1 as well as CRE- and GRE-like motifs are present in the GC-rich 5'-flanking region. The characterization of murine 5-HTT cDNA and genomic organization will facilitate studies of 5-HT uptake function with molecular pharmacologic and transgenic strategies as well as investigations of its role in quantitative traits and psychiatric disorders.

Amino Acid Sequence↗

PubMed1997

Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene.

Obsessive compulsive disorder (OCD) is a common illness, characterized by anxiety-provoking thoughts and the need to perform rituals. OCD is most commonly treated with a class of pharmacological agents known as serotonin reuptake inhibitors (SRIs). SRIs block the reuptake of serotonin (5-HT) into the presynaptic neuron, a process mediated by the serotonin transporter (5-HTT). The successful use of SRIs in OCD has led to the hypothesis that 5-HTT may play a pivotal role in the pathogenesis of OCD. We decided to study this hypothesis from a genetic perspective, because family and twin studies suggest that there is a strong genetic component to OCD. In addition, the sequence of the gene for 5-HTT is available, and a 44-bp insertion/deletion polymorphism has been detected in the promoter region of the gene. There is evidence that this polymorphism alters expression of the transporter protein. We typed 72 OCD patients and 72 matched controls, and found no statistically significant difference between the two groups (chi 2 = 4.319, P = 0.115, 2 d.f.). We observed however a trend towards increased homozygosity in the patient group. We also rated (retrospectively) the patients' clinical responses to SRIs. No association was observed between these ratings and the promoter region polymorphism in the serotonin transporter gene. Given the pharmacological evidence favoring a role for 5-HTT in OCD and SRI response, further genetic evaluation of the serotonin transporter in OCD is indicated.

Adult↗

PubMed1997

Functional promoter polymorphism of the human serotonin transporter: lack of association with panic disorder.

To probe the hypothesis of a role for a functionally relevant 44 bp insertion/deletion of the serotonin transporter promoter in the aetiopathogenesis of panic disorder, we determined the allele frequency of the variant in two samples (combined n = 158) of panic disorder patients (DSMIII-R) and compared it with its allele frequency in two ethnically matched control samples (combined n = 169). The fact that no difference could be observed (x 2 analysis) argues against a major role for this serotonin transporter promoter polymorphism in the aetiopathogenesis of panic disorder.

Alleles↗

PubMed1997

[Neuroleptic malignant syndrome and acute life-threatening catatonia--two contrasting disease entities?].

They are rare but dangerous complications in the course of acute psychotic diseases. A differential diagnose between these units, based on clinical symptoms, is impossible. Moreover the literature of the last years reveals, that the Malignant Neuroleptic Syndrome and Lethal Catatonia are identical complications in functional psychoses. This is also supported by the evidence of therapeutical consequences. In each case neuroleptics appear generally inadequate, and the interruption of neuroleptic medication is necessary, otherwise they would aggravate the disorder. An efficient supplementary treatment is the ECT.

Antipsychotic Agents↗