5-HT2a/2c receptor blockade by amesergide fully attenuates prolactin response tod-fenfluramine challenge in physically healthy human subjects

Coccaro, Emil F.; Kavoussi, Richard J.; Oakes, Mitchell; Cooper, Thomas B.; Hauger, Richard L.

doi:10.1007/bf02246407

Cited by 65 publications

(20 citation statements)

References 26 publications

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“…At least in part, prolactin response to fenfluramine challenge seems to be mediated by post-synaptic 5-HT2A/2C receptors (Coccaro et al 1996a;Goodall et al 1993). Our findings suggest that depression that is responsive to treatment by an SSRI is not distinguishable from treatment resistant depression by a 5-HT2A/ 2C receptor difference in responsivity as measured by fenfluramine challenge, nor is successful treatment marked by an increase in the functioning of these receptors.…”

Section: Relationship Between Clinical Response and Post-treatment Prmentioning

confidence: 63%

“…A number of studies have investigated the mechanism of fenfluramine effect on prolactin with particular interest in post-synaptic 5-HT receptors (Coccaro et al 1996a(Coccaro et al ,b, 1998Goodall et al 1993;. At least in part, prolactin response to fenfluramine challenge seems to be mediated by post-synaptic 5-HT2A/2C receptors (Coccaro et al 1996a;Goodall et al 1993).…”

Section: Relationship Between Clinical Response and Post-treatment Prmentioning

confidence: 99%

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Prolactin Response to dl-Fenfluramine Challenge before and after Treatment with Paroxetine

Dulchin¹

2001

Neuropsychopharmacology

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Section: Relationship Between Clinical Response and Post-treatment Prmentioning

confidence: 63%

Section: Relationship Between Clinical Response and Post-treatment Prmentioning

confidence: 99%

Prolactin Response to dl-Fenfluramine Challenge before and after Treatment with Paroxetine

Dulchin¹

2001

Neuropsychopharmacology

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“…27 Fenfluramine-induced prolactin release has been shown to be mediated by 5-HT2C receptors. 28 The HT2CR cys23ser polymorphism examined in this study may have functional effects on mCPP binding in vitro. 5 In a study of normal female subjects, Quested et al 29 found a reduced hypophagic response to mCPP in ser23 carriers, but no effect on endocrine or thermic responses.…”

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confidence: 79%

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder

et al. 2001

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Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar. 1 Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs 2 and also in the action of mood stabilizing agents, particularly lithium carbonate. 3 Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain, 4 are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser), 5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this interpopulation variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD ( 2 = 7.34, df 1, P = 0.006) and BP ( 2 = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder. Molecular Psychiatry (2001) 6, 579-585.It is widely accepted that the genetic basis of affective disorders, both unipolar (recurrent major depression) and bipolar (manic depressive illness) is complex and is likely to involve several genes and also environmental factors. 6,7 A principal aim of the European Collaborative Project on Affective Disorders (ECPAD) is to harness the statistical power potentially provided by the large numbers of subjects who can be recruited by the participating centers in order to elucidate the role of candidate genes and environmental factors in the pathogenesis of affective illness. 8 In the course of the project a very large sample has been recruited and clinically evaluated, with blood samples obtained for DNA extraction. The method of recruitment of patients has been described in detail by Souery et al 8 and is summarized below in the Methods section. Subjects were genotyped for the HT2CR cys23ser polymorphism in the participating laboratories according to a standardized protocol (see below). Clinical and genotype data were centralized in the ECPAD database in Brussels and were electronically transferred to BL and FM for statistical analysis. After removal of subjects whose geographical origin was unclear, whose genotype data were ambiguous or contrad...

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“…Second, PRL [d-FEN] responses appear to reflect activation of 5-HT-2c, but not 5-HT-1a or 5-HT-3, receptors. PRL [d-FEN] responses can be completely abolished both in rats (Di Renzo et al, 1989) and humans (Goodall et al, 1993) by ritanserin, and in humans by the 5-HT-2a/2c antagonist, amesergide (Coccaro et al, 1996c). Given the absence of effect of 5-HT-1a (pindolol; Park and Cowen, 1995), 5-HT-2a (amperozide;Albinsson et al, 1994), and 5-HT-3 (ondansetron; Coccaro et al, 1996a) antagonists on PRL [d-FEN] responses, it is likely that the PRL [d-FEN] responses are largely due to activation of 5-HT-2c post-synaptic receptors in the limbic hypothalamus with 5-HT that has been newly synthesized.…”

Section: Discussionmentioning

confidence: 99%

“…The same is true for PD subjects with a history of suicidal, but not self-injurious, behavior and for subjects with a diagnosis of IED by research criteria. On the basis of our knowledge of the neuropsychopharmacology of d-FEN, central 5-HT deficits in impulsive aggressive individuals are likely due to abnormalities involving 5-HT-2c post-synaptic receptors in the limbic hypothalamus (Coccaro et al, 1996c). These data also suggest that the word impulsive, in the term impulsive aggression, describes the form of aggression (ie, as impulsive in nature) associated with central 5-HT deficits demonstrated by a reduction in DPRL[d-FEN]-R responses and not impulsivity in general.…”

Section: Discussionmentioning

confidence: 99%

Aggression, Suicidality, and Intermittent Explosive Disorder: Serotonergic Correlates in Personality Disorder and Healthy Control Subjects

Coccaro

Lee

Kavoussi

2009

Neuropsychopharmacol

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Central serotonergic (5-HT) activity has long been implicated in the regulation of impulsive aggressive behavior. This study was performed to use a highly selective agent for 5-HT (d-Fenfluramine, d-FEN) in a large group of human subjects to further explore this relationship dimensionally and categorically. One hundred and fifty healthy subjects (100 with personality disorder, PD and 50 healthy volunteer controls, HV) underwent d-FEN challenge studies. Residual peak delta prolactin (DPRL[d-FEN]-R; ie, after the removal of potentially confounding variables) was used as the primary 5-HT response variable. Composite measures of aggression and impulsivity were used as dimensional measures, and history of suicidal/self-injurious behavior as well as the presence of intermittent explosive disorder (IED) were used as categorical variables. DPRL[d-FEN]-R responses correlated inversely with composite aggression, but not composite impulsivity, in all subjects and in males and females examined separately. The correlation with composite aggression was strongest in male PD subjects. DPRL [d-FEN]-R values were reduced in PD subjects with a history of suicidal behavior but not, selfinjurious behavior. DPRL [d-FEN]-R values were also reduced in patients meeting Research Criteria for IED. Physiologic responses to 5-HT stimulation are reduced as a function of aggression (but not generalized impulsivity) in human subjects. The same is true for personality disordered subjects with a history of suicidal, but not self-injurious, behavior and for subjects with a diagnosis of IED by research criteria. These data have particular relevance to the notion of impulsive aggression and the biological validity of IED.

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5-HT2a/2c receptor blockade by amesergide fully attenuates prolactin response tod-fenfluramine challenge in physically healthy human subjects

Cited by 65 publications

References 26 publications

Prolactin Response to dl-Fenfluramine Challenge before and after Treatment with Paroxetine

Prolactin Response to dl-Fenfluramine Challenge before and after Treatment with Paroxetine

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder

Aggression, Suicidality, and Intermittent Explosive Disorder: Serotonergic Correlates in Personality Disorder and Healthy Control Subjects

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