D- and L-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

Invernizzi, Roberto William; Berettera, C.; Garattini, Silvio; Samanin, R.

doi:10.1016/0014-2999(86)90633-3

Cited by 145 publications

(23 citation statements)

References 23 publications

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“…Animal studies suggest different properties and potencies, within serotonergic and dopaminergic systems with regard to these two isomers. Specifically, the d-isomer is more potent at 5-HT release and uptake inhibition compared with the l-isomer (Invernizzi et al, 1986). In addition, the l-isomer has clear effects on the central dopaminergic system as evidenced by its ability to increase brain levels of homovanillic acid (HVA), a major metabolite of dopamine (DA) (Crunelli et al, 1980).…”

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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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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“…Responses to fenfluramine have therefore been used as a measure of net serotonin function. Nevertheless, the specificity of this racemic agent may be questioned in light of increased striatal levels of the dopamine metabolite homovanillic acid after high-dose (5-10 mg/kg) 1-fenfluramine in rat studies (Invernizzi et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Effects of fenfluramine on plasma homovanillic acid in healthy subjects

Hollander

Stein

Saoud³

et al. 1992

J. Neural Transmission

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The specificity of fenfluramine as a pharmacological probe of the serotonin system has been questioned, since animal studies with high dose l-fenfluramine show increases in striatal levels of the dopamine metabolite homovanillic acid. To test the specificity of fenfluramine in humans with clinical doses, we compared plasma homovanillic acid (pHVA) concentration in healthy volunteers after administration of fenfluramine (60 mg) and placebo. There were no significant effects on pHVA, which supports previous findings that at doses used in pharmacological challenge paradigms, the effect of fenfluramine on the dopamine system is insufficient to alter measures of its change.

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“…For example, fenfluramine's effect on food intake has been blocked by non-selective 5-HT receptor antagonists, methysergide, metergoline, cyproheptadine and cinanserin (Jespersen and Scheel-Krfiger 1973 ;Clineschmidt et al 1974;Barrett and McSharry 1975;Blundell and Latham 1980). In addition, more recent studies using d-fenfluramine, which interacts more selectively with 5-HT mechanisms than/-fenfluramine (Garattini et al 1986a;Invernizzi et al 1986), have shown that its effect on food intake could be blocked by the centrally-active antagonist metergoline, but not by the peripheral 5-HT receptor antagonist xylamidine (Borsini et al 1982(Borsini et al , 1985.…”

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confidence: 95%

Evidence that d-fenfluramine anorexia is mediated by 5-HT1 receptors

1989

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The effects of eight serotonin (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine (3.0 mg/kg, IP) were examined in a test of sweet mash consumption, using non-deprived male rats. d-Fenfluramine's effect was attenuated by the mixed 5-HT1/5-HT2 receptor antagonists, methiothepin and metergoline; by the 5-HT2 receptor antagonist ritanserin; and by (+/-)cyanopindolol, a mixed 5-HT1A/5-HT1B receptor antagonist. In contrast, d-fenfluramine's effect was not antagonised by the 5-HT2 receptor antagonists ketanserin and ICI 169 369; the 5-HT3 receptor antagonist ICS 205 930; or by xylamidine, a peripheral 5-HT receptor antagonist. In this feeding model, none of the 5-HT antagonists, when tested alone, had any effect to increase palatable food consumption. The pattern of results obtained strongly suggest that central 5-HT1 receptors play an important role in the mediation of d-fenfluramine-induced anorexia.

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D- and L-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

Cited by 145 publications

References 23 publications

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

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

Effects of fenfluramine on plasma homovanillic acid in healthy subjects

Evidence that d-fenfluramine anorexia is mediated by 5-HT1 receptors

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