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Serotonin Transporter (serotonin + transporter)
Terms modified by Serotonin Transporter Selected Abstracts5-HYDROXYTRYPTAMINE IN THE CARDIOVASCULAR SYSTEM: FOCUS ON THE SEROTONIN TRANSPORTER (SERT)CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2006Wei Ni SUMMARY 1The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression. 2The aim of the present review is to discuss our current knowledge of 5-HT and SERT in the cardiovascular (CV) system, as well as their function in physiological and pathophysiological states. 3The SERT protein has been located in multiple CV tissues, including the heart, blood vessels, brain, platelets, adrenal gland and kidney. Modification of SERT function occurs at both transcriptional and translational levels. The functions of SERT in these tissues is largely unexplored, but includes modulation of cardiac and smooth muscle contractility, platelet aggregation, cellular mitogenesis, modulating neuronal activity and urinary excretion. 4Recent studies have uncovered potential relationships between the expression of SERT gene promoter variants (long (l) or short (s)) with CV diseases. Specifically, the risk of myocardial infarction and pulmonary hypertension is increased with expression of the ll promoter, a variant associated with increased expression and function of SERT. The relationship between promoter variants and other CV diseases has not been investigated. 5Newly available experimental tools, such as pharmacological compounds and genetically altered mice, should prove useful in the investigation of the function of SERT in the CV system. 6In summary, the function of SERT in the CV system is just beginning to be revealed. [source] Upregulation of Serotonin Transporter by Alcohol in Human Dendritic Cells: Possible Implication in Neuroimmune DeregulationALCOHOLISM, Issue 10 2009Dakshayani Kadiyala Babu Background:, Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotransmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Methods:, Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24,72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Results:, Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. Conclusions:, Our study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation. [source] Comorbidity of Alcohol Dependence With Attention-Deficit Hyperactivity Disorder: Differences in Phenotype With Increased Severity of the Substance Disorder, but Not in Genotype (Serotonin Transporter and 5-Hydroxytryptamine-2c Receptor)ALCOHOLISM, Issue 10 2003Monika Johann Background: Nearly 50% of subjects with continuing symptoms of attention-deficit hyperactivity disorder (ADHD) in adulthood have been reported to show a comorbid substance use disorder. Both ADHD and alcohol dependence have a high genetic load and might even share overlapping sources of genetic liability. Recently, the functional relevant polymorphism within the promoter region of the serotonin transporter gene (5-HTT) and the 5-hydroxytryptamine-2c (5-HT2c) receptor Cys23Ser have been proposed as candidate genes for both entities. Methods: We investigated phenotype and 5-HTT/5-HT2c genotype characteristics in 314 alcoholics of German descent. Results: There was no significant difference in 5-HTT genotype or 5-HT2c allele distribution between alcoholics and matched controls. Sixty-seven alcoholics fulfilled DSM-IV criteria of ADHD with ongoing symptoms in adulthood and had a Wender Utah Rating Scale score greater than 90. Thirty had ADHD plus antisocial personality disorder. The subgroup of alcoholics with ADHD (ADHD+) showed a significantly higher daily and record ethanol intake per month, an earlier age at onset of alcohol dependence, and a higher frequency of suicidal ideation, court proceedings, and antisocial personality disorder. In our sample, more than 50% of type 2 alcoholics according to Cloninger consist of the ADHD+ and/or antisocial personality disorder-positive subjects. There were no differences in 5-HTT genotype or 5-HT2c allele distribution between the ADHD+ subgroups and alcoholics without comorbidity and matched controls, respectively. Conclusions: Comorbidity of alcoholism and ADHD forms a distinct phenotype that shows an increased severity of the substance disorder. This phenotype contributes substantially to the so-called type 2 alcoholics according to Cloninger. In our sample, the functional relevant 5-HTT promoter and the 5-HT2c receptor Cys23Ser polymorphism do not contribute to the supposed common genetic predisposition of ADHD and alcohol dependence. [source] REVIEW: Cognitive effects of nicotine: genetic moderatorsADDICTION BIOLOGY, Issue 3 2010Aryeh I. Herman ABSTRACT Cigarette smoking is the main preventable cause of death in developed countries, and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive enhancement. Based on knockout mice studies, ,2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. ,7nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine-induced improvement in spatial working memory. Less is known about the contribution of genetic variation in DA transporter and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine. [source] Serotonin transporter, 5-HT1A receptor, and behavior in DBA/2J mice in comparison with four inbred mouse strainsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 16 2009Nina K. Popova Abstract Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5-HT transporter (5-HTT) mRNA level, 5-HT1A receptor mRNA level, and 5-HT1A receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5-HTT mRNA level in the midbrain and a reduced density of 5-HT1A receptors in the frontal cortex without significant changes in 5-HT1A receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light-dark box and elevated plus-maze tests, were found. The results suggested the involvement of decreased 5-HTT gene expression and 5-HT1A receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive-like behaviors. © 2009 Wiley-Liss, Inc. [source] A cocaine insensitive chimeric insect serotonin transporter reveals domains critical for cocaine interactionFEBS JOURNAL, Issue 16 2002Sumandeep K. Sandhu Serotonin transporters are key target sites for clinical drugs and psychostimulants, such as fluoxetine and cocaine. Molecular cloning of a serotonin transporter from the central nervous system of the insect Manduca sexta enabled us to define domains that affect antagonist action, particularly cocaine. This insect serotonin transporter transiently expressed in CV-1 monkey kidney cells exhibits saturable, high affinity Na+ and Cl, dependent serotonin uptake, with estimated Km and Vmax values of 436 ± 19 nm and 3.8 ± 0.6 × 10,18 mol·cell·min,1, respectively. The Manduca high affinity Na+/Cl, dependent transporter shares 53% and 74% amino acid identity with the human and fruit fly serotonin transporters, respectively. However, in contrast to serotonin transporters from these two latter species, the Manduca transporter is inhibited poorly by fluoxetine (IC50 = 1.23 µm) and cocaine (IC50 = 12.89 µm). To delineate domains and residues that could play a role in cocaine interaction, the human serotonin transporter was mutated to incorporate unique amino acid substitutions, detected in the Manduca homologue. We identified a domain in extracellular loop 2 (amino acids 148,152), which, when inserted into the human transporter, results in decreased cocaine sensitivity of the latter (IC50 = 1.54 µm). We also constructed a number of chimeras between the human and Manduca serotonin transporters (hSERT and MasSERT, respectively). The chimera, hSERT1,146/MasSERT106,587, which involved N-terminal swaps including transmembrane domains (TMDs) 1 and 2, was remarkably insensitive to cocaine (IC50 = 180 µm) compared to the human (IC50 = 0.431 µm) and Manduca serotonin transporters. The chimera MasSERT1,67/hSERT109,630, which involved only the TMD1 swap, showed greater sensitivity to cocaine (IC50 = 0.225 µm) than the human transporter. Both chimeras showed twofold higher serotonin transport affinity compared to human and Manduca serotonin transporters. Our results show TMD1 and TMD2 affect the apparent substrate transport and antagonist sensitivity by possibly providing unique conformations to the transporter. The availability of these chimeras facilitates elucidation of specific amino acids involved in interactions with cocaine. [source] Latest news and product developmentsPRESCRIBER, Issue 14 2007Article first published online: 19 OCT 200 Studies suggest risk of bone loss with SSRIs Two cross-sectional studies have suggested the SSRI antidepressants may be associated with an increased risk of bone loss (Arch Intern Med 2007;167:1240,5 &1246,51). In 2722 older women (mean age 79) living in the community who were participating in the Study of Osteoporotic Fractures cohort study, use of SSRIs was associated with a significant increase in the rate of loss of hip bone density compared with nonusers(0.82 vs 0.47 per cent per year). The rate of loss among women taking a tricyclic antidepressant was also 0.47 per cent per year. Excluding women with more severe depression did not alter the findings. In 5995 men aged 65 or older taking an SSRI in another study, mean bone density was 3.9 per cent lower at the hip and 5.9 per cent lower in the lumbar spine compared with no use of antidepressants. Use of a tricyclic antidepressant or trazodone was not associated with increased bone loss. The authors comment that the degree of bone loss is comparable with that associated with corticosteroids. Serotonin transporters have been identified in osteoblasts and osteocytes. Risk of rare birth defects with SSRIs Two US case-control studies have found qualified evidence that use of SSRIs during the first trimester may be associated with a small increase in the risk of rare neonatal defects (N Engl J Med 2007;356:2675,83 & 2684,92). The Slone Epidemiology Center Birth Defects Study identified 9849 infants with birth defects and 5860 without and found no significant association between SSRI use overall and defects previously attributed to SSRIs (craniosynostosis, omphalocele or heart defects). There was some evidence that sertraline and paroxetine may cause specific defects, but this was based on few cases and the absolute risk remained low. The National Birth Defects Prevention Study identified 9622 infants with major birth defects and 4092 controls. There was no significant association with heart defects but the odds of anencephaly, craniosynostosis and omphalocele were each significantly increased by a factor of 2,3. The authors say the absolute risk remains small and their findings require confirmation. UK data do not support MI link with rosiglitazone An interim analysis of a UK clinical trial of rosiglitazone (Avandia) has found no evidence that it is associated with an increased risk of myocardial infarction (N Eng J Med 2007;357:28,38). A US meta-analysis (N Engl J Med 2007;356:2457,71) recently suggested that the odds of an MI or cardiovascular (CV) death in patients taking rosiglitazone were increased by 40,60 per cent compared with controls. The UK analysis of an ongoing nonblinded trial comparing rosiglitazone plus a sulphonylurea or metformin with sulphonylurea/metformin found no significant differences in the risk of MI or CV death. The risk of heart failure was doubled in patients taking rosiglitazone. The authors comment that, with a mean follow-up of 3.75 years, they had too few data to reach a conclusive finding. Switch piroxicam users to another NSAID The European Medicines Agency has advised prescribers to switch patients who are taking oral piroxicam to another NSAID. The advice follows a reappraisal of the safety of piroxicam when the 2006 review of all nonselective NSAIDs suggested it may be associated with increased risks of GI adverse effects and serious skin reactions. The advice does not apply to topical formulations. Piroxicam should not be prescribed for acute conditions and should not be first-choice for osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. The maximum dose should be 20mg per day and treatment should be reviewed after 14 days. The MHRA states there is no need for urgent action; long-term treatment should be reviewed at the next routine appointment. OTC azithromycin? The MHRA is consulting on a request by a pharmaceutical company to reschedule azithromycin to pharmacy-only status for the treatment of known or suspected Chlamydia trachomatis infection in individuals aged 16 years or older. The applicant envisages supplies being made only when a nucleic acid amplification test (NAAT) is positive. Responses should be submitted to the MHRA (www.mhra.gov.uk) by 2 August. Computers can reduce prescribing errors Computerised prescribing reduces by two-thirds the rate of medication errors associated with handwritten prescriptions, a new review has found (Health Services Research 2007; online doi:10.1111/j.1475,6773. 2007.00751.x). There was some evidence that the risk of all errors, dose errors and adverse effects were reduced by computerisation. The greatest impact was seen in settings with very high error rates (>12 per cent) associated with handwritten prescriptions. However, the studies included produced heterogeneous results and the reduction in errors in prescribing for children was not statistically significant. Furthermore, computerisation did not reduce the rate of prescribing the wrong drug. Echinacea works for colds, new study finds The herbal remedy Echinacea does reduce the risk of catching a cold, according to a new metaanalysis (Lancet Infect Dis 2007;7:473,80). In 2006, a Cochrane review found insufficient evidence to support the benefits claimed for Echinacea. The new study, which additionally included experimentally-induced infections among the 14 trials analysed, found that Echinacea reduced the odds of catching a cold by about half and reduced the average duration of a cold by 1.4 days. Though inconclusive, the possibility of publication bias and heterogeneity between the trials could not be excluded. HRT may reduce cardiovascular risk after all A subgroup analysis of the Women's Health Initiative (WHI) suggests that HRT may reduce the risk of coronary heart disease if started soon after the menopause (N Engl J Med 2007;356:2591,602). The main analysis of WHI showed no cardiovascular benefit for HRT, a finding attributed to the relatively old mean age of participants (59). In the new analysis of 1064 women aged 50,59, HRT use was associated with a significant reduction in coronary artery calcification compared with nonuse, with greater effect associated with greater adherence. Reducing BP key to avoiding heart failure An angiotensin,II receptor blocker (ARB) is no better than other antihypertensives at avoiding the development of heart failure in individuals with hypertension, say US investigators (Lancet 2007;369:2079,87). Drugs that affect the renin-angiotensin system can reduce ventricular hypertrophy and may therefore prevent the development of heart failure in patients with hypertension. This study found similar improvements in diastolic function in 384 patients with hypertension and left ventricular dysfunction randomised to valsartan (Diovan) or placebo in addition to standard antihypertensive treatment for 38 weeks. The authors conclude that blood pressure reduction, not choice of drug, is the most important factor. Copyright © 2007 Wiley Interface Ltd [source] Serotonin and dopamine transporter binding in children with autism determined by SPECTDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 8 2008Ismo Makkonen MD Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8y 8mo [SD 3y 10mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9y 10mo [SD 2y 8mo]) using single-photon emission computed tomography (SPECT) with [123I] nor-,-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism. [source] Cell-type-specific limitation on in vivo serotonin storage following ectopic expression of the Drosophila serotonin transporter, dSERTDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2006Sang Ki Park Abstract The synaptic machinery for neurotransmitter storage is cell-type specific. Although most elements of biosynthesis and transport have been identified, it remains unclear whether additional factors may be required to maintain this specificity. The Drosophila serotonin transporter (dSERT) is normally expressed exclusively in serotonin (5-HT) neurons in the CNS. Here we examine the effects of ectopic transcriptional expression of dSERT in the Drosophila larval CNS. We find a surprising limitation on 5-HT storage following ectopic expression of dSERT and green fluorescence protein-tagged dSERT (GFP-dSERT). When dSERT transcription is driven ectopically in the CNS, 5-HT is detectable only in 5-HT, dopamine (DA), and a very limited number of additional neurons. Addition of exogenous 5-HT does not dramatically broaden neuronal storage sites, so this limitation is only partly due to restricted intercellular diffusion of 5-HT. Furthermore, this limitation is not due to gross mislocalization of dSERT, because cells lacking or containing 5-HT show similar levels and subcellular distribution of GFP-dSERT protein, nor is it due to lack of the vesicular transporter, dVMAT. These data suggest that a small number of neurons selectively express factor(s) required for 5-HT storage, and potentially for function of dSERT. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Genetic and non-genetic influences on the development of co-occurring alcohol problem use and internalizing symptomatology in adolescence: a reviewADDICTION, Issue 7 2009Luca Saraceno ABSTRACT Aims Alcohol problem use during adolescence has been linked to a variety of adverse consequences, including cigarette and illicit drug use, delinquency, adverse effects on pubertal brain development and increased risk of morbidity and mortality. In addition, heavy alcohol-drinking adolescents are at increased risk of comorbid psychopathology, including internalizing symptomatology (especially depression and anxiety). A range of genetic and non-genetic factors have been implicated in both alcohol problem use as well as internalizing symptomatology. However, to what extent shared risk factors contribute to their comorbidity in adolescence is poorly understood. Design We conducted a systematic review on Medline, PsycINFO, Embase and Web of Science to identify epidemiological and molecular genetic studies published between November 1997 and November 2007 that examined risk factors that may be shared in common between alcohol problem use and internalizing symptomatology in adolescence. Findings Externalizing disorders, family alcohol problems and stress, as well as the serotonin transporter (5-HTT) S-allele, the monoamine oxidase A (MAOA) low-activity alleles and the dopamine D2 receptor (DDR2) Taq A1 allele have been associated most frequently with both traits. An increasing number of papers are focusing upon the role of gene,gene (epistasis) and gene,environment interactions in the development of comorbid alcohol problem use and internalizing symptomatology. Conclusions Further research in adolescents is warranted; the increasing availability of large longitudinal genetically informative studies will provide the evidence base from which effective prevention and intervention strategies for comorbid alcohol problems and internalizing symptomatology can be developed. [source] PRECLINICAL STUDY: Effect of cannabinoids on platelet serotonin uptakeADDICTION BIOLOGY, Issue 2 2007Marie Velenovská ABSTRACT Serotonin is involved in many of the same processes affected by cannabinoids; therefore, we investigated in vitro and in vivo effects of these drugs on the function of serotonin transporter. The effect of ,9 -tetrahydrocannabinol (,9 -THC), endocannabinoid anandamide and synthetic cannabinoid receptor agonist WIN 55,212-2 on platelet serotonin uptake and membrane microviscosity was examined in 19 marijuana smokers and 20 controls. (1) Serotonin uptake was inhibited at higher doses of ,9 -THC (IC50 = 139 µmol/l), anandamide (IC50 = 201 µmol/l) or WIN 55,212-2 (IC50 = 17.4 µmol/l); the inhibition was found non-competitive. ,9 -THC, anandamide and WIN 55,212-2 produced different effects on the membrane microviscosity. (2) Maximal velocity of platelet serotonin uptake was significantly increased in a group of chronic marijuana smokers suffering impairment of cognitive functions when compared with controls. Opposite effect of marijuana smoking on the serotonin uptake efficiency was observed in males beside females. In summary, this study provides evidence that (1) Activity of serotonin transporter is acutely affected by cannabinoids at relatively high drug concentrations; this effect is indirect and can be partially accounted for the changes in the membrane microviscosity. (2) Increase of maximal velocity of the serotonin uptake could be understood as adaptation change in the serotonergic system induced by chronic cannabis use. A hypothesis was supported that lowered serotonin uptake may reflect a gender-related differences in effects of psychoactive cannabinoids. [source] Serotonin transporter deficiency in rats improves inhibitory control but not behavioural flexibilityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Judith R. Homberg Abstract Impulsivity and aggression have been suggested to inversely correlate with central serotonin (5-HT) levels in a trait-like manner. However, this relationship is far from straightforward. In the present study we addressed the effect of lifelong reduced or absent serotonin transporter (SERT) function, which is associated with constitutively increased extracellular 5-HT levels, on impulsivity and aggression. We used unique SERT knockout rats in a resident,intruder test, five-choice serial reaction time task and serial reversal learning task to assay aggression, inhibitory control and behavioural flexibility, respectively. Homozygous SERT knockout rats (SERT,,/,) displayed reduced aggression and improved inhibitory control, but unchanged behavioural flexibility. The behavioural phenotype of heterozygous SERT knockout rats (SERT,+/,) was not different from that of wild-type controls in any of the behavioural paradigms. We determined monoamine (metabolite) tissue levels in the medial prefrontal cortex, orbitofrontal cortex, lateral hypothalamus, raphe nuclei and cerebrospinal fluid, and found that the 5-HT levels, but not other monoamine tissue levels, were reduced in SERT,,/, rats. In addition, the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in cerebrospinal fluid was increased in these rats. In conclusion, our data show that the absence of the SERT affects aggression and inhibitory control, but not behavioural flexibility, characteristics that may reflect the trait-like consequences of constitutive changes in central 5-HT levels. [source] Rat strain differences in peripheral and central serotonin transporter protein expression and functionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003Francesca Fernandez Abstract Female Fischer 344 (F344) rats have been shown to display increased serotonin transporter (5-HTT) gene expression in the dorsal raphe, compared to female Lewis (LEW) rats. Herein, we explored, by means of synaptosomal preparations and in vivo microdialysis, whether central, but also peripheral, 5-HTT protein expression/function differ between strains. Midbrain and hippocampal [3H]paroxetine binding at the 5-HTT and hippocampal [3H]serotonin (5-HT) reuptake were increased in male and female F344 rats, compared to their LEW counterparts, these strain differences being observed both in rats of commercial origin and in homebred rats. Moreover, in homebred rats, it was found that these strain differences extended to blood platelet 5-HTT protein expression and function. Saturation studies of midbrain and hippocampal [3H]paroxetine binding at the 5-HTT, and hippocampal and blood platelet [3H]5-HT reuptake, also revealed significant strain differences in Bmax and Vmax values. Although F344 and LEW rats differ in the activity of the hypothalamo-pituitary-adrenal (HPA) axis, manipulations of that axis revealed that the strain differences in hippocampal [3H]paroxetine binding at 5-HTTs and [3H]5-HT reuptake were not accounted for by corticosteroids. Hippocampal extracellular 5-HT levels were reduced in F344 rats, compared to LEW rats, with the relative, but not the absolute, increase in extracellular 5-HT elicited by the local administration of citalopram being larger in F344 rats. Because the aforementioned strain differences did not lie in the coding sequences of the 5-HTT gene, our results open the promising hypothesis that F344 and LEW strains model functional polymorphisms in the promoter region of the human 5-HTT gene. [source] A cocaine insensitive chimeric insect serotonin transporter reveals domains critical for cocaine interactionFEBS JOURNAL, Issue 16 2002Sumandeep K. Sandhu Serotonin transporters are key target sites for clinical drugs and psychostimulants, such as fluoxetine and cocaine. Molecular cloning of a serotonin transporter from the central nervous system of the insect Manduca sexta enabled us to define domains that affect antagonist action, particularly cocaine. This insect serotonin transporter transiently expressed in CV-1 monkey kidney cells exhibits saturable, high affinity Na+ and Cl, dependent serotonin uptake, with estimated Km and Vmax values of 436 ± 19 nm and 3.8 ± 0.6 × 10,18 mol·cell·min,1, respectively. The Manduca high affinity Na+/Cl, dependent transporter shares 53% and 74% amino acid identity with the human and fruit fly serotonin transporters, respectively. However, in contrast to serotonin transporters from these two latter species, the Manduca transporter is inhibited poorly by fluoxetine (IC50 = 1.23 µm) and cocaine (IC50 = 12.89 µm). To delineate domains and residues that could play a role in cocaine interaction, the human serotonin transporter was mutated to incorporate unique amino acid substitutions, detected in the Manduca homologue. We identified a domain in extracellular loop 2 (amino acids 148,152), which, when inserted into the human transporter, results in decreased cocaine sensitivity of the latter (IC50 = 1.54 µm). We also constructed a number of chimeras between the human and Manduca serotonin transporters (hSERT and MasSERT, respectively). The chimera, hSERT1,146/MasSERT106,587, which involved N-terminal swaps including transmembrane domains (TMDs) 1 and 2, was remarkably insensitive to cocaine (IC50 = 180 µm) compared to the human (IC50 = 0.431 µm) and Manduca serotonin transporters. The chimera MasSERT1,67/hSERT109,630, which involved only the TMD1 swap, showed greater sensitivity to cocaine (IC50 = 0.225 µm) than the human transporter. Both chimeras showed twofold higher serotonin transport affinity compared to human and Manduca serotonin transporters. Our results show TMD1 and TMD2 affect the apparent substrate transport and antagonist sensitivity by possibly providing unique conformations to the transporter. The availability of these chimeras facilitates elucidation of specific amino acids involved in interactions with cocaine. [source] Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout miceGENES, BRAIN AND BEHAVIOR, Issue 4 2007A. V. Kalueff Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/,) and knockout (,/,) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT ,/, behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT ,/, mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait , a phenotype generally consistent with ,serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT ,/, mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT ,/, mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice. [source] Seasonal variations in [3H]citalopram platelet binding between healthy controls and violent offenders in FinlandHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2005James Callaway Abstract Monthly binding densities (Bmax) of [3H]citalopram to the platelet serotonin transporter (SERT) was measured longitudinally over 1 year in a control group of 18 healthy Finnish male volunteers. Single platelet samples were also analysed from 33 men who were incarcerated for violent crimes during the same calendar year. A statistically significant seasonal variation in SERT Bmax was observed in both data sets, and bi-monthly floating averages for SERT Bmax were calculated and then fit to an annual sinusoidal curve for both groups. The Bmax for platelet [3H]citalopram binding showed a statistically significant (p,=,0.001) seasonal variance between a winter (January,February) maximum of 1590 fmol/mg protein and a summer (July,August) minimum of 1216 fmol/mg protein for the control group, with an R2 of 70% for the annual sinusoidal curve fit. A statistically significant (p,=,0.007) seasonal variance was also observed between a winter (January,February) maximum of 1980 fmol/mg protein and an autumnal (August,September) minimum of 1234 fmol/mg protein for the violent offenders, again with an R2 of 70% for the annual sinusoidal curve fit. This observation lends additional support to the idea that violent human behavior and impulsivity may be directly linked to values of SERT Bmax, which can be affected by various psychoactive drugs and also varies with the natural change of seasons. Copyright © 2005 John Wiley & Sons, Ltd. [source] Association of serotonin transporter gene-linked polymorphic region and variable number of tandem repeat polymorphism of the serotonin transporter gene in lichen simplex chronicus patients with psychiatric statusINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 10 2008Necmettin Kirtak MD Background, The serotonin (5-hydroxytryptamine; 5-HT) is a key neurotransmitter in the central nervous system and a responsible mediator for the itch. Dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex neuropsychiatric diseases. Objectives, The purpose of this study was to evaluate the relationship between lichen simplex chronicus and dysfunction and serotonin transporter (5-HTT) gene polymorphism. Methods, Thirty-nine patients with lichen simplex chronicus and 61 healthy control subjects were examined. Results, The results for the patients and control subjects were not significantly different (P > 0.05) in long/long (L/L) and long/short (L/S) genotypes of 5-HTT gene-linked polymorphic region (HTTLPR) polymorphism, but short/short S/S genotype was lower in lichen simplex chronicus patients (17.9%) than in controls (42.6%). This difference was statistically significant (P = 0.028). The results for the patients and control subjects were not significantly different in 12/12, 10/12 and 10/10 genotypes of variable number of tandem repeat (VNTR) polymorphism (P > 0.05). Beck depression inventory (BDI) scores and symptom checklist-90-revised (SCL-90) psychotic subscale were overrepresented significantly in the 12/12 genotypes than 10/12 genotypes. State and Trait Anxiety Inventory tests (STAI-I and -II) point averages were not statistically significant (P > 0.05) Conclusion, S/S genotypes of HTTLPR polymorphism in the 5-HTT gene may be related to lichen simplex chronicus and that patients who have 12/12 genotypes of VNTR polymorphism may be affected psychiatrically. [source] Plasma serotonin levels and the platelet serotonin transporterJOURNAL OF NEUROCHEMISTRY, Issue 1 2007B. Brenner Abstract Serotonin (5HT) is a platelet-stored vasoconstrictor. Altered concentrations of circulating 5HT are implicated in several pathologic conditions, including hypertension. The actions of 5HT are mediated by different types of receptors and terminated by a single 5HT transporter (SERT). Therefore, SERT is a major mechanism that regulates plasma 5HT levels to prevent vasoconstriction and thereby secure a stable blood flow. In this study, the response of platelet SERT to the plasma 5HT levels was examined within two models: (i) in subjects with chronic hypertension or normotension; (ii) on platelets isolated from normotensive subjects and pretreated with 5HT at various concentrations. The platelet 5HT uptake rates were lower during hypertension due to a decrease in Vmax with a similar Km; also, the decrease in Vmax was primarily due to a decrease in the density of SERT on the platelet membrane, with no change in whole cell expression. Additionally, while the platelet 5HT content decreased 33%, the plasma 5HT content increased 33%. Furthermore, exogenous 5HT altered the 5HT uptake rates by changing the density of SERT molecules on the plasma membrane in a biphasic manner. Therefore, we hypothesize that in a hypertensive state, the elevated plasma 5HT levels induces a loss in 5HT uptake function in platelets via a decrease in the density of SERT molecules on the plasma membrane. Through the feedback effect of this proposed mechanism, plasma 5HT controls its own concentration levels by modulating the uptake properties of platelet SERT. [source] Evidence that serotonin reuptake modulators increase the density of serotonin innervation in the forebrainJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Lijun Zhou Abstract The mechanism of action of commonly used antidepressants remains an issue of debate. In the experiments reported here we studied the effects of three representative compounds, the selective serotonin reuptake inhibitor fluoxetine, the selective serotonin reuptake enhancer tianeptine and the selective norepinephrine reuptake inhibitor desipramine on the structure of central serotonin pathways after a 4-week administration. We found that the serotonin modulators fluoxetine and tianeptine, but not desipramine, increase the density of 5-HT and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and certain forebrain limbic areas, such as piriform cortex and the shell region of nucleus accumbens. These changes were noted in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), i.e. the rate-limiting enzyme for 5-HT biosynthesis and of SERT at the mRNA level. In addition, we found that anterogradely filled terminal axons from injections of biotinylated dextran amine into the dorsal raphe showed significantly more branching in animals treated with fluoxetine compared with animals treated with liposyn vehicle. Our findings suggest that antidepressants may exert very selective structural effects on their cognate monoamine systems in normal animals and raise the possibility that neurotrophic mechanisms may play a role in their clinical efficacy. [source] Effects of oral administration of extracts of Hypericum perforatum (St John's wort) on brain serotonin transporter, serotonin uptake and behaviour in miceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2004Kazufumi Hirano The pharmacological effects of extracts of Hypericum perforatum (St John's wort) were characterized in-vitro and ex-vivo, in relation to its behavioural effects. In in-vitro experiments, St John's wort inhibited brain synaptosomal [3H]serotonin uptake in mice with little effect on specific [3H]paroxetine binding. For selective serotonin-reuptake inhibitors (SSRIs), the IC50 value for [3H]serotonin uptake (molar concentration of unlabelled drug necessary to displace 50% of specific uptake) correlated well with the inhibition constant Ki value for [3H]paroxetine binding in mouse brain. Oral administration of St John's wort (900 mg kg,1), paroxetine (1 mg kg,1) and sertraline (10 mg kg,1) brought about significant increases in the Km value for [3H]serotonin uptake into brain synaptosomes 4 h later, and only SSRIs suppressed specific [3H]paroxetine binding in mouse brain. St John's wort and SSRIs significantly inhibited marble-burying behaviour in mice and the time-course of attenuation of this behaviour by St John's wort was similar to that of [3H]serotonin uptake inhibition. In the forced swimming test, St John's wort, but not SSRIs, suppressed the immobility time of mice after oral administration. These results provide the first in-vivo evidence to suggest that the mode of antidepressant action of St John's wort differs from that of SSRIs. Thus, this study may have a significant impact on phytotherapy with St John's wort. [source] The Interaction of Reward Genes With Environmental Factors in Contribution to Alcoholism in Mexican AmericansALCOHOLISM, Issue 12 2009Yanlei Du Background:, Alcoholism is a polygenic disorder resulting from reward deficiency; polymorphisms in reward genes including serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR), A118G in opioid receptor mu1 (OPRM1), and ,141C Insertion/Deletion (Ins/Del) in dopamine receptor D2 (DRD2) as well as environmental factors (education and marital status) might affect the risk of alcoholism. Objective of the current study was to examine the main and interacting effect of these 3 polymorphisms and 2 environmental factors in contribution to alcoholism in Mexican Americans. Methods:, Genotyping of 5-HTTLPR, OPRM1 A118G, and DRD2-141C Ins/Del was performed in 365 alcoholics and 338 nonalcoholic controls of Mexican Americans who were gender- and age-matched. Alcoholics were stratified according to tertiles of MAXDRINKS, which denotes the largest number of drinks consumed in one 24-hour period. Data analysis was done in the entire data set and in each alcoholic stratum. Multinomial logistic regression was conducted to explore the main effect of 3 polymorphisms and 2 environmental factors (education and marital status); classification tree, generalized multifactor dimensionality reduction (GMDR) analysis, and polymorphism interaction analysis version 2.0 (PIA 2) program were used to study factor interaction. Results:, Main effect of education, OPRM1, and DRD2 was detected in alcoholic stratum of moderate and/or largest MAXDRINKS with education ,12 years, OPRM1 118 A/A, and DRD2 ,141C Ins/Ins being risk factors. Classification tree analysis, GMDR analysis, and PIA 2 program all supported education*OPRM1 interaction in alcoholics of largest MAXDRINKS with education ,12 years coupled with OPRM1 A/A being a high risk factor; dendrogram showed synergistic interaction between these 2 factors; dosage-effect response was also observed for education*OPRM1 interaction. No definite effect of marital status and 5-HTTLPR in pathogenesis of alcoholism was observed. Conclusions:, Our results suggest main effect of education background, OPRM1 A118G, and DRD2 ,141C Ins/Del as well as education*OPRM1 interaction in contribution to moderate and/or severe alcoholism in Mexican Americans. Functional relevance of these findings still needs to be explored. [source] Upregulation of Serotonin Transporter by Alcohol in Human Dendritic Cells: Possible Implication in Neuroimmune DeregulationALCOHOLISM, Issue 10 2009Dakshayani Kadiyala Babu Background:, Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotransmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Methods:, Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24,72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Results:, Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. Conclusions:, Our study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation. [source] Stimulatory effects of the soy phytoestrogen genistein on noradrenaline transporter and serotonin transporter activityMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 4 2010Yumiko Toyohira Abstract We examined the effects of genistein, one of the major soy phytoestrogens, on the activity of noradrenaline transporter (NAT) and serotonin transporter. Treatment with genistein (10,nM,10,,M) for 20,min stimulated [3H]noradrenaline (NA) uptake by SK-N-SH cells. Genistein also stimulated [3H]NA uptake and [3H]serotonin uptake by NAT and serotonin transporter transiently transfected COS-7 cells, respectively. Kinetics analysis of the effect of genistein on NAT activity in NAT-transfected COS-7 cells revealed that genistein significantly increased the maximal velocity of NA transport with little or no change in the affinity. Scatchard analysis of [3H]nisoxetine binding to NAT-transfected COS-7 cells showed that genistein increased the maximal binding without altering the dissociation constant. Although genistein is also known to be an inhibitor of tyrosine kinases, daidzein, another soy phytoestrogen and an inactive genistein analogue against tyrosine kinases, had little effect on [3H]NA uptake by SK-N-SH cells. The stimulatory effects on NAT activity were observed by treatment of tyrphostin 25, an inhibitor of epidermal growth factor receptor tyrosine kinase, whereas orthovanadate, a protein tyrosine phosphatase inhibitor, suppressed [3H]NA uptake by NAT-transfected COS-7 cells. These findings suggest that genistein up-regulates the activity of neuronal monoamine transporters probably through processes involving protein tyrosine phosphorylation. [source] Midbrain SERT in degenerative parkinsonisms: A 123I-FP-CIT SPECT study,MOVEMENT DISORDERS, Issue 12 2010Francesco Roselli MD Abstract SPECT imaging is widely used for the differential diagnosis of degenerative parkinsonisms by exploiting the high affinitiy of the radiotracer 123I-FP-CIT for the dopamine transporter. Reduced levels of DAT are found in Parkinson Disease (PD), Dementia with Lewy Bodies (DLB), and Progressive Supranuclear Palsy (PSP) compared to in Essential Tremor (ET) and Healthy Controls (HC). However, the extent of the neurodegenerative process may extend beyond nigrostriatal system. We have exploited the affinity of the same radiotracer 123I-FP-CIT for the serotonin transporter to investigate SERT levels in the midbrain of patients with PD, DLB, PSP, and ET compared to HC. Using MRI images as anatomical templates for midbrain uptake quantification, we found a mild decrease in SERT levels in PD compared to ET and HC, with marked inter-individual variability; on the other side, PSP and DLB patients displayed markedly reduced to undetectable levels of SERT, respectively. These findings show that the neurodegenerative process affects serotoninergic neurons in parkinsonisms, with much more severe involvement in DLB than in PD patients, despite the comparable loss of striatal DAT. SERT-dependent 123I-FP-CIT uptake may allow a more comprehensive assessment of neurochemical disturbances in degenerative parkinsonisms and may have a value for differential diagnosis. © 2010 Movement Disorder Society [source] Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB,MOVEMENT DISORDERS, Issue 12 2008Isabelle Boileau PhD Abstract This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [11C]DASB. Depressed PD patients displayed a wide-spread increase (8,68%) in [11C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [11C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[11C]DASB findings in major depression, the present preliminary data suggest that increased [11C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease,and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society [source] Distribution of serotonin receptors and interacting proteins in the human sigmoid colonNEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2009N. Chetty Abstract, This study aimed to examine the distribution of 5-HT receptors in the human colon. 5-HT induces desensitization of the circular muscle and as this is facilitated by G-protein coupled receptor kinases (GRKs) and other proteins, we also examined their distribution. Human sigmoid colon samples were dissected into three separate layers (mucosa, taeniae coli and intertaenial strips) and RNA was amplified by RT-PCR. The 5-HT2B receptor and all 5-HT7 receptor splice variants were expressed in all tissues. 5-HT4 a,b,c and n splice variants were also expressed in all tissues and 5-HT4d, 5-HT4g and 5-HT4i were only detected in some samples. The 5-HT2A receptor was seen predominantly in the intertaenial strips of the colon. Only one transcript of the serotonin transporter (SERT) was detected in the muscle layers. Variation was seen in GRK expression with GRK2 and 3 predominantly expressed in the mucosa, while GRK5 and 6 were found more commonly in the taeniae coli. PDZ (named after postsynaptic density protein, Drosophila disc large tumour suppressor and tight junction protein ZO-1) domain containing proteins, which may be involved in 5-HT receptor trafficking, were also detected throughout the sigmoid colon. The 5-HT3A subunit was expressed in all tissues, whereas the 5-HT3E subunit was mainly found in the mucosa layer while the 5-HT3B subunit was more common in the muscle layers. Receptor interacting chaperone (RIC-3), which is involved in transporting 5-HT3 receptor subunits, is expressed less in mucosa compared to muscle layers. In conclusion, these results show that there is variation in distribution of 5-HT receptors and interacting proteins within the sigmoid colon that may contribute to colonic function. [source] Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunctionNEUROGASTROENTEROLOGY & MOTILITY, Issue 6 2005J. Wheatcroft Abstract, Patients with postinfective irritable bowel syndrome and Trichinella spiralis -infected mice share many features including visceral hypersensitivity and disordered motility. We assessed enterochromaffin (EC) numbers and serotonin transporter (SERT) using National Institute of Health (NIH) female mice studied for up to 56 days post- T. spiralis infection. The effects of steroid treatment and the T-cell dependence of the observed responses were assessed by infection of hydrocortisone-treated or T-cell receptor knock out [TCR (,×,) KO] animals. Enterochromaffin cell density in uninfected animals increased from duodenum 10.0 cells mm,2 (5.9,41.0) to colon 61.8. (46.3,162) cells mm,2P < 0.0001. Infection increased duodenal and jejunal counts which rose to 37.3 (22,57.7) cells mm,2 and 50.6 (7,110.8) cells mm,2, respectively, at day 14. Infection significantly reduced jejunal SERT expression, with luminance values falling from 61.0 (45.1,98.3) to a nadir of 11.6 (0,36.0) units at day 9, P < 0.001. Specific deficiencies in all T cells reduced EC hyperplasia and abrogated infection-induced mastocytosis. Thus infection induced inflammation increases EC numbers, as has been reported in PI-IBS, and reduces SERT. This may increase mucosal 5HT availability and contribute to the clinical presentation of PI-IBS. [source] Molecular genetics of bipolar disorder and depressionPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 1 2007TADAFUMI KATO md Abstract, In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene,environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field. [source] The Pharmacology of Citalopram Enantiomers: The Antagonism by R-Citalopram on the Effect of S-Citalopram,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2006Connie Sánchez The exact molecular mechanism by which R-citalopram inhibits the effect of S-citalopram on the serotonin transporter remains to be elucidated. Preliminary evidence indicates an effect of R-citalopram on the association of escitalopram with the high affinity primary site, and on its dissociation from the serotonin transporter, via an allosteric mechanism. Escitalopram can be considered as an allosteric serotonin reuptake inhibitor. This serotonin dual action in binding to two sites on the serotonin transporter (both the primary site and the allosteric site) is hypothesised to be responsible for a longer binding to, and therefore greater inhibition of the serotonin transporter by escitalopram. [source] Behavioral genetics in antisocial spectrum disorders and psychopathy: A review of the recent literatureBEHAVIORAL SCIENCES & THE LAW, Issue 2 2010Tracy D. Gunter M.D. Behavioral geneticists are increasingly using the tools of molecular genetics to extend upon discoveries from twin, family, and adoption studies concerning the heritability of antisocial spectrum disorders and psychopathy. While there is a substantial body of research concerning antisocial spectrum disorders in the behavioral genetics literature, only a few studies could be located using the phenotype of psychopathy. In this report we summarize some of the recent molecular genetics work concerning antisocial spectrum disorders and psychopathy, with a focus on genes involved in the serotonergic and dopaminergic pathways, while also mentioning some of the novel genetic factors being considered. Monoamine oxidase (MAOA) and the serotonin transporter (5HTT) are reviewed at length, as these genes have received significant scientific attention in recent years and are sites of high biological plausibility in antisocial spectrum disorders and psychopathy. Copyright © 2010 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||