Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways

Frisch, Amos; Michaelovsky, Elena; Rockah, Rivka; Amir, Ilan; Hermesh, Haggai; Laor, Nathaniel; Fuchs, Camil; Zohar, Joseph; Lerer, Bernard; Buniak, S.F; Landa, Shelby; Poyurovsky, Michael; Shapira, Baruch; Weizman, Ronit

doi:10.1016/s0924-977x(00)00071-7

Cited by 106 publications

(68 citation statements)

References 15 publications

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“…Whereas this SLC6A4 I425V polymorphism was subsequently found in additional probands with a predominantly OCD-like phenotype (Delorme et al, 2005;Wendland et al, in press), data linking OCD with common SLC6A4 variants have been generally inconclusive. Although a few reports found a positive association for the gain-of-function 5-HTTLPR L allele and OCD (Bengel et al, 1999;McDougle et al, 1998), the majority of studies have been negative (Camarena et al, 2001;Cavallini et al, 2002;Chabane et al, 2004;Frisch et al, 2000;Kinnear et al, 2000;Meira-Lima et al, 2004;Walitza et al, 2004). An association between OCD and the STin2 higher-expressing 12-repeat allele was reported in one study (Ohara et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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Both serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) genes have shown positive associations with obsessive-compulsive disorder (OCD) and some other psychiatric disorders, but these results have not been consistently replicated. To explore the hypothesis that this variability might result from the effects of differing combinations of overlooked variants within SLC6A4 together with small OCD and control sample sizes, we studied three common functional polymorphisms (5-HTTLPR, STin2, and the newly discovered SNP, rs25531) in the largest sample size of OCD patients (N ¼ 347) and controls (N ¼ 749) ever investigated. During methods development, we found evidence for potential SLC6A4 genotyping problems with earlier methodology, a third possible contributor to variability in earlier studies. A fourth possible explanation might be SLC6A4 Â BDNF interactions, which prompted us to investigate combined genotypes of BDNF V66M with the three SLC6A4 loci. Except for a nominal association with rs25531 alone, which did not survive correction for multiple comparisons, we found no evidence for any of these other variants being associated alone or together with OCD, and we therefore also examined clinical OCD subtypes within the sample to evaluate clinical heterogeneity. Subgroups based on the age of OCD onset, gender, familiality, factor analysis-derived symptom dimensions, or comorbidity with other psychiatric disorders failed to identify SLC6A4-or BDNF-associated phenotypes, with one exception of overall number of comorbid anxiety disorders being significantly associated with 5-HTTLPR/rs25531. We conclude that despite their attractiveness as candidate genes in OCD, our data provide no support for association in this large OCD patient sample and point toward the need to examine other genes as candidates for risk determinants in OCD.

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Section: Introductionmentioning

confidence: 99%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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“…The HTR 2A A(-1438)G SNP was associated with response inhibition in two specific behavioral tasks in normal subjects (Nomura et al, 2006) and impulsive behavior in bulimia (Bruce et al, 2005).The HTR 2A T10 2C SNP is associated with impulse control in cocaine-dependent subjects (Bjork et al, 2002). A SNP (rs6318) identified in the coding region of the 5-HT 2C R that converts a cysteine (Cys) to a serine (Ser) at amino acid codon 23 in the N-terminal extracellular domain (Ser23 variant) (Lappalainen et al, 1995) has been implicated in the pathogenesis of psychiatric disorders (Burnet et al, 1999;Frisch et al, 2000;Serretti et al, 2000;Lerer et al, 2001). Recently, cocaine-dependent subjects carrying the Ser23 variant were shown to display significantly higher cue reactivity (Anastasio et al, 2014a).…”

Section: Targeted 5-ht 2a/c Receptor Pharmacotherapy For Cocaine mentioning

confidence: 99%

Serotonin 5-HT₂Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

2014

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“…Even though SSRIs supposedly act by blocking the 5-HT transporter, and polymorphisms in the gene for this protein might be related to OCD [5,24], several 5-HT receptor subtypes have also been implicated in OCD. A recent study showed that mice lacking the 5-HT 2C receptor show increased compulsive behavior in several behavioral tests [2].…”

Section: Nih Public Accessmentioning

confidence: 99%

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

Hedlund

Sutcliffe

2007

Neuroscience Letters

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The 5-HT 7 receptor has been suggested as a new putative target for the treatment of neuropsychiatric disorders, especially depression. This hypothesis is based on the finding that antidepressant drugs have relatively high affinity for the 5-HT 7 receptor, and that inactivation or blockade of the receptor leads to an antidepressant-like profile in behavioral models and sleep parameters. Obsessivecompulsive disorder is also believed to involve the serotonergic system and is treated using antidepressants, thus it is of interest to study the possible role of the 5-HT 7 receptor in this disorder. We have evaluated the effect of inactivation or pharmacological blockade of the 5-HT 7 receptor in three mouse behavioral models that are believed to mimic some of the stereotypic aspects of obsessive-compulsive disorder. In the most well established behavioral model, marble burying, both inactivation and blockade of the 5-HT 7 receptor reduced stereotypic behavior in that the number of marbles buried decreased. In two newer, less well characterized models, head dipping and plasticmesh screen chewing, there was no difference between wild-type mice and mice lacking the 5-HT 7 receptor. Taken together the data confirms and expands on previous findings that the 5-HT 7 receptor is of importance for behaviors affected by antidepressants, and suggests that the 5-HT 7 receptor might be of relevance as a target for the treatment of obsessive-compulsive disorder. Keywordsserotonin; marble burying; head dipping; screen chewing; SB-269970The 5-HT 7 receptor, one of the most recently discovered receptors for serotonin [12], has been found to modulate behaviors affected by antidepressant drugs. In both the forced swim test and the tail suspension test, inactivation or blockade of the 5-HT 7 receptor lead to antidepressantlike behavior [7,13,35]. Furthermore, inactivation or pharmacological blockade of the 5-HT 7 receptor lead to changes in rapid eye movement sleep that are opposite to those seen in depression [8,13]. In addition, it has been shown that certain antidepressants might exert some of their effects by acting directly at the 5-HT 7 receptor [26].Obsessive-compulsive disorder (OCD) is a debilitating disease with an overall prevalence of close to 1 % [15]. There is strong evidence in support of a significant role for 5-HT in OCD and antidepressant drugs, mainly selective serotonin reuptake inhibitors (SSRIs), are the pharmacological treatment of choice for OCD [4,15]. However, as many as 40 % of patients do not respond to currently available treatment options [15], so continued research is necessary. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the c...

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Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways

Cited by 106 publications

References 15 publications

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Serotonin 5-HT₂Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

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Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways

Cited by 106 publications

References 15 publications

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

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Serotonin 5-HT₂Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder