Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin synthesis in rat brain

Brambilla, Alessandro; Baschirotto, A.; Grippa, Nicoletta; Borsini, Franco

doi:10.1016/s0924-977x(99)00056-5

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…Autoregulatory negative feedback caused by chronic activity at the 5-HT 1A receptor is thought to decrease serotonergic activity (McDevitt and Neumaier, 2011) and synthesis (Brambilla et al, 1999), ultimately leading to a reduction in sociality. Thus we expected that, like is seen in rodents, 8-OH-DPAT would cause an acute increase in social behavior, followed by decreasing sociality with adaptation to reduced serotonergic activity consequent to negative feedback.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 1A agonism decreases affiliative behavior in pair-bonded titi monkeys

Larke

Maninger

Ragen

et al. 2016

Hormones and Behavior

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Relatively little is known about serotonergic involvement in pair-bonding despite its putative role in regulating social behavior. Here we sought to determine if pharmacological elevation of serotonin 1A (5-HT1A) receptor activity would lead to changes in social behavior in pair-bonded male titi monkeys (Callicebus cupreus). Adult males in established heterosexual pairs were injected daily with the selective 5-HT1A agonist 8-OH-DPAT or saline for 15 days using a within-subjects design. Social behavior with the female pair-mate was quantified, and plasma concentrations of oxytocin, vasopressin, and cortisol were measured. When treated with saline, subjects showed reduced plasma oxytocin concentrations, while 8-OH-DPAT treatment buffered this decrease. Treatment with 8-OH-DPAT also led to decreased plasma cortisol 15 minutes post-injection and decreased social behavior directed toward the pair-mate including approaching, initiating contact, lipsmacking, and grooming. The reduction in affiliative behavior seen with increased activity at 5-HT1A receptors indicates a substantial role of serotonin activity in the expression of social behavior. In addition, results indicate that the effects of 5-HT1A agonism on social behavior in adulthood differ between rodents and primates.

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Section: Discussionmentioning

confidence: 99%

Serotonin 1A agonism decreases affiliative behavior in pair-bonded titi monkeys

Larke

Maninger

Ragen

et al. 2016

Hormones and Behavior

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“…Flibanserin, a 5-HT 1A agonist and 5-HT 2A receptor antagonist, and 8-OH-DPAT, a 5-HT 1A agonist, are thus both unlikely to cause hyperthermic responses. Furthermore, both flibanserin and 8-OH-DPAT administered to rodents selectively decrease 5-HT synthesis in several brain regions (Brambilla et al , 1999), further indicating the unlikelihood of either contributing to 5-HT toxicity.…”

Section: Discussionmentioning

confidence: 99%

Flibanserin and 8‐OH‐DPAT Implicate Serotonin in Association between Female Marmoset Monkey Sexual Behavior and Changes in Pair‐Bond Quality

Aubert

Gustison

Gardner

et al. 2012

The Journal of Sexual Medicine

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Introduction Psychopathological origins of personally distressing, hypoactive sexual desire disorder (HSDD) in women are unknown, but are generally attributed to an inhibitory neural regulator, serotonin (5-HT). Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, shows promise as a treatment for HSDD. Aim To test the hypothesis that female marmoset sexual behavior is enhanced by flibanserin and diminished by 8-OH-DPAT, in order to evaluate the efficacy of serotonergic modulation of female sexual behavior in a pairmate social setting comparable to humans. Methods Sexual and social behavior were examined in 8 female marmoset monkeys receiving daily flibanserin (15mg/kg), 8-OH-DPAT (0.1 mg/kg) or corresponding vehicle for 15–16 weeks in a counterbalanced, within-subject design, while housed in long-term, stable male-female pairs. Main outcome measures Marmoset pairmate interactions, including sexual and social behavior, were scored during weeks 5–6 of daily flibanserin, 8-OH-DPAT or vehicle treatment. 24-h pharmacokinetic profiles of the drugs and their metabolites, as well as drug-induced acute symptoms of the 5-HT behavioral syndrome were also assessed. Results 2-way analysis of variance reveals that flibanserin-treated females attract more male sexual interest (p = .020) and trigger increased grooming (p = .001) between partners. In contrast, 8-OH-DPAT-treated females show increased rejection of male sexual advances (p = .024), a tendency for decreased male sexual interest (p = .080), and increased aggression with their male pairmates (p = .049). Conclusions While 8-OH-DPAT-treated female marmosets display decreased sexual receptivity and increased aggressive interactions with their male pairmates, flibanserin-treated female marmosets demonstrate increased affiliative behavior with their male pairmates. Such pro-affiliation attributes may underly flibanserin’s effectiveness in treating HSDD in women.

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“…Flibanserin exerts a preferential action in the cortex (Table 10). In fact, flibanserin, 2 mg/kg, reduces 5-HT turnover in the cortex without altering it in hippocampus and brainstem (18). This preferential activity on the cortex distinguishes flibanserin from the other 5-HT 1A receptor agonists, buspirone and 8-OH-DPAT, which reduce 5-HT turnover to a similar extent in the cortex, hippocampus, and brainstem (18).…”

Section: Effects On Turnover and Extracellular Levels Of 5-htmentioning

confidence: 91%

“…In fact, flibanserin, 2 mg/kg, reduces 5-HT turnover in the cortex without altering it in hippocampus and brainstem (18). This preferential activity on the cortex distinguishes flibanserin from the other 5-HT 1A receptor agonists, buspirone and 8-OH-DPAT, which reduce 5-HT turnover to a similar extent in the cortex, hippocampus, and brainstem (18). The effect of 8-OH-DPAT and buspirone was interpreted to result from somatic presynaptic 5-HT 1A receptor activation, which inhibits 5-HT turnover in all the 5-HT-containing axons departing from the raphe nuclei.…”

Section: Effects On Turnover and Extracellular Levels Of 5-htmentioning

confidence: 94%

Pharmacology of Flibanserin

et al. 2002

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Flibanserin has preferential affinity for serotonin 5-HT 1A , dopamine D 4 , and serotonin 5-HT 2A receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT 1A agonist, a very weak partial agonist on dopamine D 4 receptors, and a 5-HT 2A antagonist. In vivo flibanserin binds equally to 5-HT 1A and 5-HT 2A receptors. However, under higher levels of brain 5-HT (i.e., under stress), flibanserin may occupy 5-HT 2A receptors in higher proportion than 5-HT 1A receptors. The effects of flibanserin on adenylyl cyclase are different from those of buspirone and 8-OH-DPAT, two other purported 5-HT 1A receptor agonists. Flibanserin reduces neuronal firing rate in cells of the dorsal raphe, hippocampus, and cortex with the CA1 region being the most sensitive in the brain. Flibanserin-induced reduction in firing rate in the cortex seems to be mediated through stimulation of postsynaptic 5-HT 1A receptors, whereas the reduction of the number of active cells seems to be mediated through dopamine D 4 receptor stimulation. Flibanserin quickly desensitizes somatic 5-HT autoreceptors in the dorsal raphe and enhances tonic activation of postsynaptic 5-HT 1A receptors in the CA3 region. Flibanserin preferentially reduces synthesis and extracellular levels of 5-HT in the cortex, where it enhances extracellular levels of NE and DA. Flibanserin displays antidepressant-like activity in most animal models sensitive to antidepressants. Such activity, however, seems qualitatively different from that exerted by other antidepressants. Flibanserin seems to act via direct or indirect stimulation of 5-HT 1A , DA, and opioid receptors in those animal models. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses.Flibanserin behaves as a 5-HT 1A agonist in cloned cells and the cortex and hippocampus of human and rat brain ( Table 2). In the dorsal raphe, flibanserin behaves as an agonist when firing rate was taken as an index of activity in rats (58) but was devoid of agonist activity when forskolin-stimulated cAMP was measured in human tissue (44). In contrast to the dorsal raphe nucleus of rats (24), 5-HT 1A receptors in the dorsal raphe nucleus of humans appears to be linked with adenylyl cyclase (44). In human tissues, the EC 50 of flibanserin in reducing forskolin-stimulated cAMP formation is similar to the affinity values for 5-HT 1A receptors (Table 1 and 2). In contrast, the EC 50 of flibanserin in reducing forskolin-stimulated cAMP formation in cells or rat tissues is different from the affinity values for 5-HT 1A receptors. The coupling system between the receptor and the G-proteins is important to demonstrate activity for agonists (55). Thus, it may be that the relative amount of various G-proteins present in human tissue is different from that present in CHO cells or rat tissue. Flibanserin binds to only one site in human 5-HT 1A ...

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Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin synthesis in rat brain

Cited by 15 publications

References 26 publications

Serotonin 1A agonism decreases affiliative behavior in pair-bonded titi monkeys

Serotonin 1A agonism decreases affiliative behavior in pair-bonded titi monkeys

Flibanserin and 8‐OH‐DPAT Implicate Serotonin in Association between Female Marmoset Monkey Sexual Behavior and Changes in Pair‐Bond Quality

Pharmacology of Flibanserin

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