Fractionation studies on the absorption of labelled immunoglobulin G by the gut of young rats

1. Centrifugation in density gradients was used to study the fragments produced during intraluminal and intracellular digestion, after the injection of 125I-labelled immunoglobulin G (IgG) into different regions of the small intestine of 14 to 15-day-old (pre-closure) and 24-day-old (post-closure/ rats. 2. After injection into the proximal small intestine and into the ileum of pre-closure animals, the bulk of the radioactivity recorded for gut washes and gut homogenates was located at 4S-7S. The serum from animals which had received injections into the proximal small intestine had high radioactivity and one peak at 7S; the serum from animals which had received injections into the ileum had low radioactivity and no activity in the 7S region. 3. After injection into the proximal small intestine of post-closure animals, the bulk of the radioactivity recorded for gut wash samples was located at 3-5S--5S. Gut homogenates had peak activity at 2-5S--4S. Thus large molecular weight products can be absorbed by the proximal enterocytes of post-closure rats and degraded. The sera of these animals had low radioactivity. 4. After injection into the distal small intestine of post-closure animals, the bulk of the radioactivity recorded for gut wash and gut homogenate samples was located at 4S-7S and in this respect the radioactivity plots resembled those for (2) above. Serum radioactivity was low. 5. The effect of precipitation with trichloroacetic acid and incubation with specific antiserum upon the radioactivity of gut washes, gut homogenates and serum samples was recorded. 6. The relevance of these findings to studies on the transmission of protein by the rat small intestine is discussed.     

Variation in the serotonin transporter gene modulates selective attention to threat.

The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Determination of external loop topology in the serotonin transporter by site-directed chemical labeling

The transmembrane topology of the serotonin transporter (SERT) has been examined by measuring the reactivity of selected lysine and cysteine residues with extracellular reagents. An impermeant biotinylating reagent, sulfosuccinimidyl 2-(biotinamido)ethyl-1, 3-dithiopropionate (NHS-SS-biotin), was shown to label SERT transiently expressed in cultured cells. Replacement of four lysine residues that were predicted to lie in external hydrophilic loops (eK-less) largely prevented the biotinylation reaction. Likewise, the cysteine-specific biotinylation reagent N-biotinylaminoethylmethanethiosulfonate (MTSEA-biotin) labeled wild type SERT but not a mutant in which Cys-109, predicted to lie in the first external loop, was replaced with alanine. These two mutant transporters reacted with the biotinylating reagents in digitonin-permeabilized cells, demonstrating that the abundant lysine and cysteine residues predicted to lie in intracellular hydrophilic domains were reactive but not accessible in intact cells. Mutants containing a single external lysine at positions 111, 194, 243, 319, 399, 490, and 571 reacted more readily with NHS-SS-biotin than did the eK-less mutant. Similarly, mutants with a single cysteine at positions 109, 310, 406, 489, and 564 reacted more readily with MTSEA-biotin than did the C109A mutant. All of these mutants were active and therefore likely to be folded correctly. These results support the original transmembrane topology and argue against an alternative topology proposed recently for the related glycine and gamma-aminobutyric acid transporters.     

Effect of propofol on affective state as assessed by place conditioning paradigm in rats

BACKGROUND: Whether propofol produces a pleasant affective state remains unclear from clinical studies. In the current study, the effect on affective state of subanesthetic and anesthetic doses of propofol was assessed at a preclinical level with rats in a place conditioning paradigm. Propofol was compared with methohexital. METHODS: In the place conditioning paradigm, propofol-induced effect was repeatedly paired with one of two distinguishable compartments of the apparatus, whereas the vehicle-induced effect was repeatedly paired with the other compartment. During a subsequent free-choice test, a preference for the drug-paired compartment over the vehicle-paired compartment would be indicative of pleasant state induced by the drug. For all experiments, the conditioning session lasted 8 days and consisted of four pairings of the drug with one compartment and four pairings of the equivalent volume of vehicle with the other compartment. In experiment 1A, four groups of rats were designated according to the dose of propofol that they received intraperitoneally: 0,30,60, or 90 mg/kg. In experiment 1B, the same procedure was used with subanesthetic doses of intraperitoneal methohexital: 0,10,20, or 30 mg/kg. In experiment 2, the rats were conditioned during the recovery period from short-term anesthesia. For one group, anesthesia was induced by propofol (100 mg/kg) whereas for the other group, anesthesia was induced by an equivalent anesthetic dose of methohexital (40 mg/kg). RESULTS: In experiment 1A, the 30-mg/kg, 60-mg/kg, and 90-mg/kg groups showed a place preference for the drug-paired compartment, but only the group conditioned with 60 mg/kg propofol significantly differed from the 0-mg/kg group. In experiment 1B, the groups conditioned with methohexital showed no place preference for the drug-paired compartment. In experiment 2, the rats showed a place preference for the compartment in which they recovered from propofol-induced anesthesia but no place preference for the compartment in which they recovered from methohexital-induced anesthesia. CONCLUSIONS: Propofol, but not methohexital, induced a pleasant affective state in rats at subanesthetic doses as well as during recovery from an anesthetic dose.     

Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.     

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

The aim of our randomized controlled study was to compare the neuromuscular characteristics of mivacurium and atracurium by evaluating the intubation conditions, intubation times, onset times and the duration of action of these two muscle relaxants using two different dosing principles. Forty-eight patients were included in this study. All patients were premedicated orally with 0.2 mg/kg diazepam. Anaesthesia was induced with 2.0 mg/kg propofol and 0.02 mg/kg alfentanil and maintained with 6 mg/kg/h propofol and 60% nitrous oxide in oxygen. Neuromuscular monitoring was carried out with supramaximal TOF-stimulation (2 HZ) of the ulnar nerve every 10 seconds and recording of the mechanomyogram (MMG) (Myograph 2000, Biometer) at the adductor pollicis muscle. The patients of group 1 (n = 12) received an intubation dose of 0.15 mg/kg mivacurium (2 x ED95) and the patients of group 2 (n = 12) received a priming dose of 0.015 mg/kg mivacurium (20% of ED95) followed by an intubation dose of only 0.07 mg/kg mivacurium (ED95) two minutes later. The patients of group 3 (n = 12) were intubated with 0.46 mg/kg atracurium (2 x ED95) and the patients of group 4 (n = 12) received a priming dose of 0.046 mg/kg atracurium (20% of ED95) and an intubation dose of 0.23 mg/kg atracurium (ED95) four minutes later. The patients were intubated under normocapnic conditions and following stabilisation of the palmar skin temperature after a 90% neuromuscular block (T1) had occurred. The intubation conditions were measured semiquantitatively using an intubation score.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo voltammetric studies of the effects of intrathecal morphine on noxious heat stimuli-induced serotonin release in the nucleus raphe magnus of anesthetized rats

MOTIVATION: The principal motivation was to design an environment for the development of image-analysis applications which would allow the integration of independent modules into one frame and make available tools for their build-up, running, management and mutual communication. RESULTS: The system was designed as modular, consisting of the core and work modules. The system core focuses on overall management and provides a library of classes for build-up of the work modules, their user interface and data communication. The work modules carry practical implementation of algorithms and data structures for the solution of a particular problem, and were implemented as dynamic-link libraries. They are mutually independent and run as individual threads, communicating with each other via a unified mechanism. The environment was designed to simplify the development and testing of new algorithms or applications. An example of implementation for the particular problem of the analysis of two-dimensional (2D) gel electrophoretograms is presented. The environment was designed for the Windows NT operating system with the use of Microsoft Foundation Class Library employing the possibilities of C++ programming language. AVAILABILITY: Available on request from the authors.     

In vitro and in vivo studies of benzisoquinoline ligands for the brain synaptic vesicle monoamine transporter

Tetrabenazine is a high-affinity inhibitor of the vesicular monoamine transporter in mammalian brain. As part of a program to develop in vivo imaging agents for these transporters in human brain, a series of 2-alkylated dihydrotetrabenazine ligands was synthesized and evaluated in vitro and in vivo for binding to the brain vesicular monoamine transporter. Additions of organometallic reagents to tetrabenazine produced 2-methyl, 2-ethyl, 2-n-propyl, 2-isopropyl, and 2-isobutyl derivatives of dihydrotetrabenazine. The stereochemistry and conformation of the addition products were thoroughly verified by two-dimensional NMR techniques. All of these alkyl derivatives displayed in vitro affinity for the vesicular monoamine transporter binding site in rat brain using competitive assays with the radioligand [3H]methoxytetrabenazine. Except for the isopropyl derivative, all compounds when tested at 10 mg/kg iv showed an ability to inhibit in vivo accumulation of the radioligand [11C]methoxytetrabenazine in the mouse brain striatum. Derivatives with small alkyl groups (methyl, ethyl) were more effective than those with large groups (propyl, isobutyl). These studies suggest that large groups in the 2-position of the benzisoquinoline structure will significantly diminish both in vitro and in vivo binding of these compounds to the vesicular monoamine transporter.     

Assessment of glucosylifosfamide mustard biodistribution in rats with prostate adenocarcinomas by means of in vivo 31P NMR and in vitro uptake experiments

A combined in vitro/in vivo study was performed to evaluate the possible application of phosphorus (31P) NMR spectroscopy for therapy monitoring and to investigate glucosylifosfamide mustard (Glc-IPM) transport and biodistribution by radiotracer techniques. Dynamic in vivo 31P NMR measurements were performed in rats with prostate adenocarcinoma after i.v. injection of 1 mmol/kg body weight (bw) of ifosfamide (IFO) (n = 4) and 1 mmol/kg bw (n = 4) or 2.15 mmol/kg bw (n = 9) of Glc-IPM. In a biodistribution study with 14C-labeled Glc-IPM and a final dose of 0.8 mmol Glc-IPM/kg bw, the animals were killed 5, 30, 60, and 120 min after drug administration, an ethanol extraction was performed from several tissues, and the dose per g tissue was calculated. The same tumor cell line was used in saturation and competition experiments to further elucidate the transport mechanism. The 31P NMR signals of IFO and Glc-IPM showed no overlap with the endogenous phosphorus peaks. A rapid washout with a half-life between 25.9 +/- 5.6 min for the lower dose and 34.3 +/- 4.2 min for the higher dose of Glc-IPM was observed in the tumor. No statistically significant change of the pH value was observed during the examination period. The beta-nucleoside 5'-triphosphate (NTP)/inorganic phosphate (Pi) signal intensity ratio showed a tendency to decrease but without statistical significance. A rapid elimination was demonstrated by both the noninvasive NMR technique and the biodistribution study. No saturation was found in vitro for the Glc-IPM uptake, even at the concentration of 5 mM. Furthermore, the Glc-IPM uptake was not inhibited by the presence of 2-deoxyglucose and vice versa. The data show that the pharmacokinetics of Glc-IPM in the tumor can be followed in vivo by 31P NMR. The results presented are evidence for diffusion as the transport mechanism for Glc-IPM in this tumor model. However, the better visualization of Glc-IPM as compared to ifosfamide may be due to metabolic trapping of a negatively charged metabolite after deglycosylation.     

Effects of chronic administration of benfluorex on the pharmacokinetics of iodine 123 labelled insulin in Zucker obese rats (fa/fa)]

Zucker obese rats (fa/fa), aged 8 to 10 weeks, were treated orally by benfluorex (2 x 25 mg.kg-1, day-1) for 2 weeks and were compared with a control group of the same age treated with placebo. Benfluorex induced a break in the weight curve, a significant fall in serum triglycerides, blood glucose and plasma insulin and in the insulin content of the pancreas. Following intrajugular injection of iodine 123 labelled insulin, the liver of the treated animals bound 25 percent more insulin than the liver of control animals. Conversely, the renal clearance of insulin of the treated animals was reduced in comparison to the placebo group. These studies confirm that, in an animal model of obesity associated with insulin resistance, benfluorex exerts a marked hypolipidemic effect and improves insulin resistance. They also demonstrate an increased targeting of insulin towards hepatic receptors either due to an increase in the hepatic blood flow or to an increase in the number of hepatic receptors or to an increase in the affinity of these receptors. However, speculative considerations make this last mechanistic hypothesis somewhat improbable.     

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.     

Methacholine induces wheal-and-flare reactions in human skin but does not release histamine in vivo as assessed by the skin microdialysis technique

A number of investigations have indicated that cholinergic agonists release histamine from isolated mast cells and suggested that cholinergic stimulation releases histamine in vivo. The purpose of this study was to investigate whether the cutaneous wheal-and-flare reaction induced by methacholine challenge in human skin involves histamine release as measured by the skin microdialysis technique. Five hollow dialysis fibers were inserted intradermally in forearm skin in eight healthy subjects. Each fiber was perfused with Kreb's-Ringer bicarbonate at a rate of 3 microliters/min. Dialysates were collected in 2-min fractions before skin challenge and for 20 min after intradermal injection of methacholine 10(-3)-10(-1) M, the vehicle, and a positive control, codeine phosphate 0.3 mg/ml. Histamine was assayed spectrofluorometrically. Methacholine caused a statistically significant dose-related wheal-and-flare reaction, the flare reaction to methacholine 10(-1) M being comparable with that seen with codeine 0.3 mg/ml. No significant histamine release was observed with methacholine, cumulative histamine release of 16 +/- 8 nM by methacholine 10(-1) M being similar to vehicle responses of 15 +/- 9 nM. Histamine release by codeine was 2524 +/- 435 nM. In conclusion, methacholine-induced wheal-and-flare reactions in human skin appeared not to involve histamine release from skin mast cells.     

Critical amino acid residues in transmembrane span 7 of the serotonin transporter identified by random mutagenesis

Transmembrane span 7 of the rat brain serotonin transporter was subjected to random mutagenesis. Of the 27 amino acid residues mutated, six were identified as functionally important by their sensitivity to nonconservative mutations. These residues were Asn-368 and Tyr-385, where substitutions that retained hydrogen-bonding ability were preferred; Gly-376 and Gly-384, where only glycine was accepted; Phe-380, where a phenyl ring was preferred; and Met-386, where hydrophobic substitutions were preferred. Mutations that did not preserve these structural characteristics were highly detrimental to serotonin transport activity. These six residues form a stripe that runs at an angle down the side of the putative alpha-helix, lending support to this structural prediction. Mutations at some of these positions also specifically impaired transport activity under low Na+ conditions. Other mutations at nearby positions in transmembrane span 7 also impaired activity in low Na+, although the activity of the mutants in high Na+ was similar to wild type. These results suggest that at least some of the six critical residues play a role in Na+ binding or perhaps in the coupling of Na+ binding to later steps in the transport cycle. These residues may be important in other aspects of the transporter's function as well.     

Modulation of in vivo neuronal sprouting by serotonin in the adult CNS of the snail

1. During in situ recovery from a lesion to the cerebrobuccal connective (CBC) in the snail Achatina fulica, neurons of the buccal ganglia undergo extensive regeneration and sprouting as assessed by axonal dye-fillings of the CBC. 2. These changes are preceded by the distal degeneration of severed fibres from the serotonergic metacerebral giant neuron (MCG), which results in the depletion of serotonin (5-HT) in the ipsilateral buccal ganglion. We have investigated the potential role of this depletion in causing some of the ensuing neuroplastic events. 3. Pharmacological depletion of 5-HT using either 5,7-dihydroxtryptamine or p-chlorophenylalanine in normal, unlesioned animals was found to produce supernumerary neuronal labelling similar to that seen following a lesion. 4. Systemic daily injections of 5-HT were found to partly suppress the sprouting response following the CBC lesion. For example, the contralateral, uninjured MCG which is normally induced by the lesion to sprout novel projections into the denervated ganglion, is suppressed from doing so by the 5-HT treatment. 5. These growth inhibiting effects of 5-HT upon the contralateral MCG could be antagonized by the prior administration of the 5-HT receptor blocker cyproheptadine, suggesting a specific receptor mediated action. 6. We suggest that 5-HT may play a role in governing the state of neuronal outgrowth in vivo in the CNS of the adult snail, as has been suggested by early development and neuronal cultural studies.     

Primary structure of the serotonin transporter in unipolar depression and bipolar disorder

Genetic factors have been implicated in the etiology of affective disorders but due to the complex inheritance patterns of these disorders, identification of the responsible gene(s) has so far been unsuccessful. Decreased platelet serotonin (5-HT) transport and reduced binding of imipramine or paroxetine to brain and platelet 5-HT uptake sites/transporters in patients with depression and suicide victims define the 5-HT transporter (5-HTT) as a candidate gene. The primary structure of the 5-HTT was analyzed in 17 patients meeting DSM-III-R diagnostic criteria for major depressive or bipolar disorder and in 4 healthy controls using polymerase chain reaction (PCR-) amplification and sequencing of complementary deoxyribose nucleic acid (cDNA) synthesized from platelet 5-HTT messenger ribose nucleic acid (mRNA). Direct PCR sequencing of the protein coding region failed to reveal changes in the deduced amino acid sequence of the platelet/brain 5-HTT (40,000 base pairs sequence screened), although a conservative single-base substitution representing a silent polymorphism was found. The results provide preliminary evidence that alterations in the primary structure of 5-HTT are not generally involved in the pathogenesis of unipolar depression and manic-depressive illness.     

Prostaglandin E1 increases binding of 123I-low-density lipoprotein to the human liver in vivo

Twenty-seven German shepherd dogs with perianal fistulas and histological evidence of colitis were entered in a prospective clinical study to investigate the association between perianal fistula and colitis. Additionally, the response of perianal fistula disease to immunosuppressive doses of prednisone and an alternative protein diet was evaluated. All 27 cases completed the treatment protocol, and perianal fistulas completely resolved in nine (33.3%) cases, improved in nine cases, and remained unchanged in nine cases.     

Changes in the enzymatic activities of beagle liver during maturation as assessed both in vitro and in vivo

1. We have examined changes in caffeine and trimethadione (TMO) metabolism in vivo, agents which are used as probe drugs. In this study the total body clearance (Cl) of caffeine and TMO was low 1 week after birth (week 1), increased rapidly from week 3, peaked and then decreased gradually until reaching the level for the mature, adult dog. The elimination half-life (t1/2) of caffeine and TMO was prolonged during week 1; however, it then gradually became shorter. Gradually it became longer and reached the level for the adult dog. The apparent volume of distribution (Vd) of caffeine did not change throughout the study. However, the Vd of TMO was only high during week 1. 2. The in vitro changes in a variety of typical substrates for seven different cytochrome P450 (CYP) isozymes were examined. In this study three different patterns of metabolism can be identified: (1) activity is low immediately after birth, increases, peaks and then decreases to the adult dog level (p-nitroanisole; CYP1A1, caffeine; CYP1A2, benzphetamine; CYP3A/2B(?), aniline; 2E1 and TMO; CYP2C9/2E1/3A4); (2) activity generally increases rapidly soon after birth, continues to increase, peaks and then gradually decreases to the adult level (phenytoin; CYP2C9); and (3) activity is high (about the same level as the adult) immediately after birth, decreases and then gradually increases to the adult level (erythromycin; CYP3A4/5). 3. The results of these in vivo and in vitro studies suggest that changes in enzyme activity are due to differences in P450 isoenzymes during development.     

Characterization of [11C]tetrabenazine as an in vivo radioligand for the vesicular monoamine transporter

The erythrocytes of paroxysmal nocturnal hemoglobinuria are abnormally sensitive to complement-mediated lysis because they are deficient in membrane proteins that regulate the functional activity of complement. All the deficient proteins in paroxysmal nocturnal hemoglobinuria share the common structural feature of being anchored to the cell surface by a glycosyl phosphatidylinositol moiety. Recent studies showed that the first intermediate in the pathway of the glycosyl phosphatidylinositol anchor synthesis is not formed in paroxysmal nocturnal hemoglobinuria cells. This observation suggests that the molecular basis of paroxysmal nocturnal hemoglobinuria is due to an abnormality involving a gene that encodes a protein essential for the normal biosynthesis of the first intermediate. By using expression cloning, the complementary DNA (called phosphatidylinositol glycan class A [PIG-A]) that corrects the abnormality in glycosyl phosphatidylinositol-anchor synthesis in paroxysmal nocturnal hemoglobinuria cells was identified. Subsequent studies showed that the PIG-A gene is located on the X chromosome. Together, these studies provided a molecular explanation for paroxysmal nocturnal hemoglobinuria.     

Enhanced endocytosis in cultured human breast carcinoma cells and in vivo biodistribution in rats of a humanized monoclonal antibody after cationization of the protein

For monoclonal antibody therapeutics to access target antigen in extravascular compartments, an antibody drug delivery technology is required that has the dual properties of 1) transendothelial migration of the antibody and 2) endocytosis of the antibody into the target cell. These two objectives may be achieved with antibody cationization, and the present studies examine the feasibility of cationizing the humanized 4D5 monoclonal antibody directed against the p185HER2 oncogenic protein. The cationized antibody binds to the p185HER2 extracellular domain with an ED50 of 35 micrograms/ml and inhibits SK-BR3 cell proliferation similar to the native antibody. Confocal microscopy showed that although there was binding of the native 4D5 antibody to the plasma membrane of SK-BR3 cells, this antibody was confined to the periplasma membrane space with minimal endocytosis into the cell. In contrast, robust internalization of the cationized 4D5 antibody by the SK-BR3 cells was demonstrated by confocal microscopy. The systemic volume of distribution of the cationized 4D5 antibody was 11-fold greater than that of the native antibody. In summary, these studies show that a humanized monoclonal antibody may be cationized with retention of antibody affinity for the target antigen and biological activity, yet with a marked alteration in the cellular distribution and pharmacokinetics in vivo.     

A functional variant of the serotonin transporter gene in families with bipolar affective disorder

BACKGROUND: The serotonin transporter protein (SERT) reuptakes serotonin from synapses and has been implied as the site of therapeutic action of many antidepressant drugs. SERT is one of the most relevant candidate genes for bipolar affective disorder. Recently a functionally important 44 basepair deletion in the regulatory region of the SERT gene was described. Association between this variant and affective disorder has been suggested. METHODS: The present study analysed this variation and another variation in the SERT gene and nearby DNA markers in order to test for linkage between SERT and bipolar affective disorder in two Danish families. RESULTS AND CONCLUSION: There was no evidence that variants in the SERT gene were a stronger dominant disease gene for the development of affective disorder in the families. The possibility of a recessive disease gene at or near SERT could not be excluded. LIMITATIONS: The present study cannot exclude if variations at or near the SERT gene were weak susceptibility genes or determine if they are important for other characteristics than presence or absence of disease. CLINICAL RELEVANCE: Further studies of the SERT gene in affective and other disorders, as well as in relation to treatment response to antidepressants are needed.