Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polymorphisms in the serotonin transporter gene (5HTT) have been reported to be associated with neuroticism (emotionality) and with depression. A recent report of an association between 5HTT and neuroticism involved unselected samples and self-report questionnaires. We attempted to extend these findings using a selected extremes design and peer ratings. From a sample of 2085 individuals, each assessed on neuroticism by two independent peers, we selected 52 individuals from the top 5% and 54 individuals from the bottom 5%. No association was found for either a functional 44 bp insertion/deletion polymorphism in 5HTT regulatory sequence (5HTTLPR) or for a non-functional variable number tandem repeat 5HTT polymorphism.
 ...
PMID:The serotonin transporter gene and peer-rated neuroticism. 917 33

Transcriptional activity of the human serotonin transporter gene (5HTT) is modulated by complex interaction of multiple genomic and cellular factors. Variability of a polymorphic repetitive element (5HTTLPR) is associated with anxiety, depression, and aggression-related traits and may influence the risk to develop affective spectrum disorders. 5HTTLPR variants display a unique DNA secondary structure that has the potential to regulate the transcriptional activity of the associated 5HTT promoter. The structure of the 5HTTLPR is also likely to precipitate a 381-bp somatic deletion in the 5HTT's promoter region [del(17)(q11.2)] that is observed in 20-60% of genomic DNA isolated from mononuclear blood cells and postmortem brain. The localization of the deletion breakpoints adjacent to identical putative signal sequences (CAGCC) suggests a V(D)J recombinase-like rearrangement event. In comparison with healthy controls, del(17)(q11.2)/wildtype sequence ratios showed a decrease of the deleted variant in recurrent unipolar depression. Our results also suggest that mosaicism of del(17)(q11.2) is likely to be regulated by tissue-specific as well as 5HTTLPR-dependent mechanisms. The findings confirm that the pericentric region of human chromosome 17 is highly unstable and furnishs additional evidence for intricate complexity of 5HTT regulation under physiological condition and in disease.
 ...
PMID:Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression. 1065 Nov 16

The etiology of late-onset Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) is not known. In both disorders there is an extensive degeneration of serotonergic neurons, with corresponding losses of the serotonin (5HT) transporter (5HTT), which is responsible for the reuptake of 5HT from the synaptic cleft. An increasing body of evidence indicates that allelic variation of the 5HTT gene promoter (5HTT gene-linked polymorphic region, 5HTTLPR) determines high or low 5HT uptake in normal human brain. Association studies show that the low-activity allele of the 5HTTLPR is a risk factor for late-onset AD. In PD, the 5HTTLPR influences the risk of developing depression, a common symptom in PD patients. A compromised serotonergic system thus plays an important role in the pathophysiology of both AD and PD.
 ...
PMID:The serotonin transporter in Alzheimer's and Parkinson's disease. 1120 52

The human serotonin transporter is the molecular target for selective serotonin reuptake inhibitor drugs which are being used for treatment of depression. A three-dimensional model of the membrane spanning parts of the transporter was constructed. The transporter was assumed to consist of 12 transmembrane alpha-helices. The model was based on published experimental data of cocaine binding to mutant transporters, amino acid sequence analysis, and interactive molecular graphics. The model suggests that a high affinity cocaine binding site is situated in a region of the model where Asp98 acts like an anchor, while a putative low affinity site is situated in another region with Glu508 as the anchoring amino acid. A series of docking experiments with various reuptake inhibitors were conducted, using interactive molecular graphics techniques combined with energy calculations and analysis of the transporter-ligand complexes. Experiments involving molecular mapping of ligand binding areas may benefit from using the current model in experimental design. From the current model, several amino acids were proposed as prime candidates for mutagenesis and subsequent ligand binding studies. Also for evaluation of results from site directed mutagenesis experiments with SERT and similar transporters we assume the model will be helpful.
 ...
PMID:A putative three-dimensional arrangement of the human serotonin transporter transmembrane helices: a tool to aid experimental studies. 1177

Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter (5HTT), may mediate central effects of cocaine and may also be involved in impulsive and aggressive behavior. We investigated whether polymorphisms in the 5HTT gene were related to traits of impulsivity, sensation seeking, and aggression among cocaine abusers. Standardized measures of these personality traits were obtained in a sample of 105 severely affected cocaine-dependent African-American subjects and 44 African-American controls. Two polymorphisms of the 5HTT gene were examined involving the 5' promoter (5HTTLPR) region and a 17 base pair variable-number-tandem-repeat (VNTR) marker among cocaine patients. No significant relationships were observed between polymorphic variants of the 5HTTLPR and VNTR regions and scores on any of the trait measures. Similarly, demographic variables and measures of severity of substance use and depression were unrelated to allele frequencies or genotype distributions of the variants among cocaine patients. As expected, cocaine patients scored significantly higher on total scores of impulsivity, aggression, and sensation seeking compared to controls. The findings do not seem to support an association between these polymorphisms in the 5HTT gene and impulsive-aggressive traits among cocaine-dependent African-American individuals.
 ...
PMID:Serotonin transporter polymorphisms and measures of impulsivity, aggression, and sensation seeking among African-American cocaine-dependent individuals. 1205 23

A series of novel N- and 3alpha-modified piperidine-based analogues of cocaine were synthesized and tested for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. N-Demethylation of trans-(+)-3alpha-piperidine-based ligands leads to improved activity at the SERT and NET and modest changes at the DAT. Replacement of the N-methyl group in trans-(+)-ester 1a with phenylalkyl groups leads to a modest 2.3-fold improvement in activity at the SERT (K(i) < or = 3.27 microM), insignificant changes at the NET, and a 3.5-fold loss in activity at the DAT (K(i) > or = 810 nM); however, such replacement in cis-(-)-ester 4, the more potent isomer of 1a, leads, in general, to a significant decrease in activity at all monoamine transporters (K(i) > 1 microM). Other N-modified ligands, including the ligands with polar groups incorporated in the N-alkyl substituent (3e-g) and ligands lacking the basic nitrogen (3i and 6d), show decreased activity at all monoamine transporters, though ligands 3e-g are similar in potency at the NET to 1a. N-Norester 2a, a possible metabolite of the lead compound 1a, and alcohol 1c, a compound with a 3alpha-substituent that is more stable to metabolism than 1a, were selected for further behavioral tests in animals. Alcohol 1c and ester 2a are similar in potency at the DAT to cocaine, ester 1a, and oxadiazole 1b, and both fully substitute for cocaine and have potency similar to that of cocaine in drug discrimination tests. Like cocaine, 1c increased locomotor activity (LMA) monotonically with time, whereas 2a produces biphasic effects consisting of initial locomotor depression followed by delayed locomotor stimulation. An interesting difference between cocaine, ester 1a, alcohol 1c, and N-norester 2a is that 1c and 2a are significantly longer acting in LMA tests. Although this result was anticipated for alcohol 1c, it is rather surprising for 2a which has an ester function susceptible to hydrolysis, a pathway of in vivo deactivation of cocaine and its ester analogues. The present results may have important implications for our understanding of the pharmacological mechanisms underlying the behavioral actions of cocaine and of the structural features needed for the design of the new leads in the discovery of a cocaine abuse medication.
 ...
PMID:SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement. 1210 1

The serotonin transporter (5HTT) plays a central role in serotonin neurotransmission. Abnormalities of 5HTT function have been implicated in depression, anxiety and alcohol intake. To better understand the functional role of this important molecule, we have utilized a viral vector approach to overexpress the 5HTT in regions of the rat brain. We have constructed a bicistronic defective herpes virus (HSV-1) vector that expresses both an epitope-tagged 5HTT as well as beta-galactosidase (beta-GAL) as a marker for infected cells. The vector was capable of conferring serotonin uptake activity to Vero cells in culture, indicating transfer of a functional 5HTT. Injection of the 5HTT virus into the rat brain resulted in a dense focus of specific 125I RTI-55 binding at the injection site, indicating that the virally expressed 5HTT can also bind ligand when expressed in the brain. We were also able to overexpress an epitope tagged 5HTT in serotonergic neurons in the dorsal raphe nucleus (DRN) using this approach. These data demonstrate that the levels of the 5HTT in 5HT neurons can be manipulated in the adult rodent brain using an HSV-1 vector.
 ...
PMID:Overexpression of an epitope-tagged serotonin transporter in serotonin neurons of the dorsal raphe nucleus using a defective HSV-1 vector. 1252 44

In epileptic patients, neurobehavioral problems such as cognitive impairment, depression, and psychosocial impairments have been described, which may have a pathological and/or iatrogenic basis. For this reason additional treatment is required, beside antiepileptic drug (AED) therapy, to correct the accompanying neurological deficits. However, the rationale behind use of antidepressants along with antiepileptics has been questioned due to proconvulsant effects of the former. In the present study, the effect of gabapentin (GBP) on seizure score and memory is evaluated when it is given alone and in combination with some antidepressants, such as sertraline (SERTR) and alprazolam (ALP). Pentetrazole (PTZ)-induced convulsion and spontaneous alternation behavior (SAB) models were used to study the anticonvulsant effect and effect on memory, respectively. Results showed that addition of SERT to GBP or ALP resulted in reduction of anticonvulsant efficacy of these drugs. However, the combination of GBP + SERT + ALP was superior as far as effect on seizure severity and memory was concerned.
 ...
PMID:Effects of gabapentin and antidepressant drug combinations on convulsions and memory in mice. 1473 90

A qualitative model for the binding pocket proximal to the 3alpha-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3alpha-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3alpha-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3alpha-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.
 ...
PMID:Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring. 1516 83

We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.
 ...
PMID:Gene-environment interaction analysis of serotonin system markers with adolescent depression. 1524 35


1 2 3 4 5 6 7 8 9 10 Next >>