BIMT 17: a putative antidepressant with a fast onset of action?

Borsini, Franco; Cesana, Raffaele; Kelly, John; Leonard, Brian E.; McNamara, Mairéad G.; Richards, Jerry B.; Seiden, Lewis S.

doi:10.1007/s002130050474

Cited by 35 publications

(22 citation statements)

References 39 publications

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“…The present results are not likely to reflect evaluation of an inadequate flibanserin dose range, because flibanserin was tested across a 10-fold dose range from low doses that produced no effect to high doses that only depressed ICSS, and flibanserin doses tested here also produce a range of other behavioral effects in rats (e.g. [43, 44]). Moreover, previous pharmacokinetic studies suggest that the flibanserin doses tested here would be associated with plasma levels spanning levels produced in humans by the recommended therapeutic dose of 100 mg PO [34, 43].…”

Section: Discussionmentioning

confidence: 91%

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Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Lazenka

Blough

Negus

2016

The Journal of Sexual Medicine

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INTRODUCTION Flibanserin is a serotonin receptor subtype 1A (5HT1A) agonist and 2A (5HT2A) antagonist that has been approved by the Food and Drug Administration for treating female sexual interest/arousal disorder. Little is known about the abuse potential of flibanserin. AIM This study examined abuse-related effects of flibanserin in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to evaluate abuse potential of other drugs. METHODS Adult female and male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for electrical brain stimulation under a “frequency-rate” ICSS procedure. In this procedure, increasing frequencies of brain stimulation maintain increasing rates of responding. Drugs of abuse typically increase (or “facilitate”) ICSS rates and produce leftward/upward shifts in ICSS frequency-rate curves, whereas drugs that lack abuse potential typically do not alter or only decrease ICSS rates. Initial studies determined the potency and time course of effects on ICSS produced by acute flibanserin (1.0, 3.2 and 10.0 mg/kg). Subsequent studies determined effects of flibanserin (3.2–18 mg/kg) before and after a regimen of repeated flibanserin administration (5.6 mg/kg/day x 5 days). Effects of the abused stimulant amphetamine (1.0 mg/kg) were examined as a positive control. MAIN OUTCOME MEASURE Flibanserin effects on ICSS frequency-rate curves in female and male rats were examined and compared to effects of amphetamine. RESULTS Baseline ICSS frequency-rate curves were similar in female and male rats. Both acute and repeated administration of flibanserin produced only decreases in ICSS rates, and rate-decreasing effects of the highest flibanserin dose (10 mg/kg) were greater in females than males. In contrast to flibanserin, amphetamine produced an abuse-related increase in ICSS rates that did not differ between females and males. CONCLUSIONS These results suggest that flibanserin has low abuse potential. Additionally, this study suggests that females may be more sensitive than males to rate-decreasing effects of high flibanserin doses.

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Section: Discussionmentioning

confidence: 91%

“…[43, 44]). Moreover, previous pharmacokinetic studies suggest that the flibanserin doses tested here would be associated with plasma levels spanning levels produced in humans by the recommended therapeutic dose of 100 mg PO [34, 43]. The present results also are unlikely to reflect inadequate efficacy of flibanserin at 5HT1A receptors.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Lazenka

Blough

Negus

2016

The Journal of Sexual Medicine

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“…(2) 5-HT 2 receptor antagonists and 5-HT 1A receptor agonists are associated with activity in the DRL 72-s procedure (Marek et al 1989a;Van Hest et al 1992;Richards et al 1994;Borsini et al 1997;Jolly et al 1999;; but see Martin et al 1998). Now, 5-HT 1A agonists, by activating autoreceptors, suppress serotonergic transmission, whereas, in common with 5-HT 2 antagonists, they reinforce (disinhibit) corticolimbic adrenergic transmission (Millan et al 2000b).…”

Section: Actions Of Ssris: Decrease In Efficiencymentioning

confidence: 97%

“…Further, the "atypical" agents mirtazapine and mianserin, which possess 5-HT 2C and α 2 -adrenoceptor (AR) antagonist properties, similarly improve DRL 72-s performance by increasing reinforcement rates and/or decreasing response rates (O'Donnell and Seiden 1983;Marek et al 1989b;Hand et al 1991;Jackson et al 1995;Jones et al 1998). Tricyclic agents, such as clomipramine, amitriptyline and imipramine, are also effective as shown by a decrease in response rates, which may or may not be accompanied by an increase in reinforcement rates Seiden 1980a, 1980b;O'Donnell and Seiden 1983;Howard and Pollard 1984;Danysz et al 1988;Van Hest et al 1992;Olivier et al 1993;Borsini et al 1997).…”

Section: Introductionmentioning

confidence: 96%

Differential modulation of efficiency in a food-rewarded "differential reinforcement of low-rate" 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors

et al. 2002

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The present experimental procedure demonstrates, in analogy to imipramine and mianserin, robust and consistent increases in efficiency with NARIs. Their effects may be distinguished from a decrease in efficiency elicited by SSRIs, and a lack of activity of SNRIs and DARIs. While the reasons underlying the ineffectiveness of SSRIs (in contrast to previous studies) remain to be clarified, these data underline the importance of adrenergic mechanisms in the control of behaviour under conditions of delayed responding. Further, they support the interest of DRL 72-s procedures for the characterisation of diverse classes of antidepressant agent.

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“…Flibanserin was tested in 13 animal models sensitive to antidepressants. It was active in the following 10 models (Table 14): learned helplessness in rats (16), bulbectomized rats (16), chronic mild stress in rats and mice (25), muricidal rats (10), amphetamine withdrawal in rats (31), REM sleep latency reduction (W. Gaida, Boehringer Ingelheim, data on file), forced swimming test in mice (23), distress calls in chicks (10), and fixed ratio (FI) schedule in mice (10). In contrast, flibanserin did not show antidepressant-like behavior in the forced swimming test (10) and differential-reinforcement-of-low rate 72 sec [DRL-72] (16) in rats and tail suspension in mice (10).…”

Section: Animal Models Sensitive To Antidepressantsmentioning

confidence: 99%

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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BIMT 17: a putative antidepressant with a fast onset of action?

Cited by 35 publications

References 39 publications

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Differential modulation of efficiency in a food-rewarded "differential reinforcement of low-rate" 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors

Pharmacology of Flibanserin

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