A Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette's Syndrome Patient

Lam, Susanna; Shen, Yang; Nguyen, Tuan; Messier, Terri L.; Brann, Mark R.; Comings, David E.; George, Susan R.; O’Dowd, Brian F.

doi:10.1006/bbrc.1996.0322

Cited by 47 publications

(20 citation statements)

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“…The assays were conducted with R-SAT kits (Receptor Technologies, Winooski, VT) containing NIH 3T3 cells expressing the rat 5-HT 2A receptor (20,21) or RAT-1 cells expressing the human 5-HT 1A receptor (22,23) cotransfected with the ␤-galactosidase gene and were performed according to the procedures provided (24,25). The cells in DMEM containing serotonin (100 nM) and the analogs (500 nM) were incubated in a humidified 5% CO 2 incubator at 37°C for 4 or 5 days for the 5-HT 2A and 5-HT 1A transfected cells, respectively.…”

Section: Methodsmentioning

confidence: 99%

Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide

Boger

Patterson

Jin

1998

Proc. Natl. Acad. Sci. U.S.A.

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Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT 1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT 2A and 5-HT 1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT 2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the ⌬ 9 -cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT 1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT 2A , but not the 5-HT 1A , receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.Oleamide (1) is an endogenous fatty acid primary amide that accumulates in the cerebrospinal fluid under conditions of sleep deprivation (1-3) and induces physiological sleep in animals (1).Consistent with its role as a prototypical member of a new class of biological signaling molecules, enzymatic regulation of the endogenous concentrations of oleamide has been described (1, 4-7) or proposed (8). Fatty acid amide hydrolase (FAAH) is an integral membrane protein that degrades 1 to oleic acid, and potent inhibitors of the enzyme have been detailed (4, 9-11). The characterization and neuronal distribution of FAAH have been disclosed (5-7), and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide, which serves as an endogenous ligand for the cannabinoid receptor (12, 13). Unlike anandamide, an appealing feature of this new class of biological signaling agents is the primary amide, suggesting that their storage and release may be controlled in a manner analogous to that of peptide hormones terminating in a primary amide (8).Recent studies have shown the oleamide modulates serotonergic neurotransmission (14,15). In the first disclosure of such effects, oleamide was shown to potentiate 5-HT 2C and 5-HT 2A receptor-mediated chloride currents in transfected frog oocytes but not those elicited by the 5-HT 3 ion-gated channel recepto...

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Section: Methodsmentioning

confidence: 99%

Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide

Boger

Patterson

Jin

1998

Proc. Natl. Acad. Sci. U.S.A.

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“…The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n ‫ס‬ 352) and controls (n ‫ס‬ 210) but was found in similar frequencies in all groups [Erdmann et al, 1995]. Further studies suggested that this mutation is unlikely to play a significant role in the genetic predisposition to schizophrenia, mood disorders, obsessive-compulsive, Tourette's syndrome, or neuroleptic malignant syndrome [Brett et al, 1995;Erdmann et al, 1995;Kawanishi et al, 1998a;Lam et al, 1996;Xie et al, 1995;Zhang et al, 1997]. Other silent or rare variants have been reported [Erdmann et al, 1995;Kawanishi et al, 1998b;Lam et al, 1996;Xie et al, 1995].…”

Section: Introductionmentioning

confidence: 98%

Serotonin-2C and serotonin-1A receptor genes are not associated with psychotic symptomatology of mood disorders

et al. 2000

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The serotonergic system is involved in both pathophysiology and treatment of mood disorders. In the present study we investigated the possible influence of the polymorphisms of the serotonin-1A and 2C receptor genes on the symptomatology of mood disorders. Eighty-four inpatients affected by mood disorders (72 bipolar and 12 major depressive disorder) were assessed by the Operational Criteria Checklist for Psychotic Illness to score their lifetime psychotic symptomatology. The subjects were also typed for 5HT1A and 5HT2C variants using polymerase chain reaction techniques. No association was found between 5HT2C and psychopathology as defined by the four symptomatologic factors used as phenotype definition (mania, depression, delusion, and disorganization) even when bipolar subjects were analyzed separately. Only one subject with the 5HT1A variant was observed. Genetic variation at the 5HT1A and 5HT2C receptor genes does not, therefore, play a major role in the pathogenesis of mood disorders symptomatology. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:161-166, 2000.

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“…Preliminary evidence suggests that 5-HT 1A receptor gene variation contributes a small but significant amount of variance to symptom scores for attention-deficit hyperactivity disorder (Comings et al, 2000); a variant in the 5-HT 1A receptor (due to a missense nucleotide change) has been isolated in a patient with Tourette's syndrome (Lam et al, 1996); and selective 5-HT 1A receptor agonists can reduce alcohol intake in dependent animals (De Vry, 1995). However, other investigators have found no association of the 5-HT 1A receptor gene with Tourette's syndrome (Brett et al, 1995), and increased cortisol response to ipsapirone in active mania (Yatham et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Blunted Hormone Responses to Ipsapirone are Associated with Trait Impulsivity in Personality Disorder Patients

Minzenberg

Grossman

New

et al. 2005

Neuropsychopharmacol

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Impulsive aggression is associated with central serotonergic dysfunction. Animal models particularly implicate the 5-HT 1A receptor in this behavior. We tested the hypothesis that central 5-HT 1A receptor function is impaired in impulsive aggressive personality disorder patients. A total of 52 individuals with DSM-III-R personality disorders, all medically healthy adult outpatients without concurrent psychiatric medication treatment, underwent serial plasma cortisol, prolactin, and temperature measurements before and after ipsapirone 20 mg oral administration. Subjects completed self-report measures of impulsivity, hostility, depression and anxiety, and childhood maltreatment. Stepwise regression analysis revealed impulsivity alone among symptom measures to be associated with significantly decreased peak cortisol and prolactin responses. Diagnoses of borderline personality disorder (BPD) and intermittent explosive disorderrevised (IED-R) were associated with significantly increased and decreased cortisol responses, respectively. However, post hoc analyses indicated that impulsivity was significantly negatively correlated with cortisol responses in the BPD group, and may mediate the association of both BPD and IED-R with altered cortisol responses. Temperature response was associated with neither diagnostic nor symptom measures. Neither diagnostic nor dimensional measures of depression or anxiety, nor severity of childhood maltreatment, were significantly associated with cortisol, prolactin, or temperature responses. Impulsivity is related to impaired function at (or downstream to) postsynaptic 5-HT 1A receptors, and this relationship may be partly responsible for the association of impaired serotonergic function with diagnoses such as BPD and IED-R. In addition, D 2 receptor dysfunction may play a role in impulsivity, whereas 5-HT 1A cell-body autoreceptor function may be spared in these disorders.

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A Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette's Syndrome Patient

Cited by 47 publications

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Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide

Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide

Serotonin-2C and serotonin-1A receptor genes are not associated with psychotic symptomatology of mood disorders

Blunted Hormone Responses to Ipsapirone are Associated with Trait Impulsivity in Personality Disorder Patients

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A Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette's Syndrome Patient

Cited by 47 publications

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Structural requirements for 5-HT 2A and 5-HT 1A serotonin receptor potentiation by the biologically active lipid oleamide

Structural requirements for 5-HT 2A and 5-HT 1A serotonin receptor potentiation by the biologically active lipid oleamide

Serotonin-2C and serotonin-1A receptor genes are not associated with psychotic symptomatology of mood disorders

Blunted Hormone Responses to Ipsapirone are Associated with Trait Impulsivity in Personality Disorder Patients

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Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide

Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide