Activity of Serotonin 5-HT_1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties

Abstract

Although serotonin 5-HT receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.

Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats

“…F13714, F15599, and S15535 all reduce offensive aggression (de Boer and Newman-Tancredi, 2016). Both F13714 and F15599 induce a serotonergic-5-HT 1A syndrome in rats (Newman-Tancredi et al, 2009;Assié et al, 2010;Jastrzȩbska-Wiȩsek et al, 2018). S15535 does not induce the serotonergic-5-HT 1A syndrome at all (de Boer and Newman-Tancredi, 2016;Jastrzȩbska-Wiȩsek et al, 2018) and also has no sedativelike activity in offensive aggression (de Boer et al, 2000).…”

“…Serotonin is also known to crosstalk with non-serotonergic systems which may exert effects on (sexual) behavior as well (e.g., Blier, 2001). In case of a non-selective 5-HT 1A receptor agonist like 8-OH-DPAT, next to its inhibiting action on the serotonergic neuron, direct 5-HT 1A heteroreceptor stimulation still occurs leading to post-synaptically mediated effects, like the serotonergic-5-HT 1A behavioral syndrome (Berendsen et al, 1990;Jastrzȩbska-Wiȩsek et al, 2018). In the case of F13714, a relatively selective (compared to heteroreceptor) 5-HT 1A auto-receptor agonist (Assié et al, 2006) potently facilitated sexual activity in male SERT +/+ rats suggesting that pro-sexual activity is related to activation of 5-HT 1A auto-receptors.…”

“…The relatively selective 5-HT 1A heteroreceptor agonist F15599 also facilitated male sexual activity in SERT +/+ rats. The difference in potency (factor 256 difference) to obtain the pro-sexual activity (at the lowest effective dose) can possibly be explained by the difference of the in vitro and in vivo affinity and efficacy of both compounds on 5-HT 1A receptors (Assié et al, 2010;Newman-Tancredi, 2011;Jastrzȩbska-Wiȩsek et al, 2018). This might be taken as suggestive that both compounds exert pro-sexual activity via activation of 5-HT 1A auto-receptors.…”

Antidepressants and Sexual Dysfunctions: a Translational Perspective

“…Clinically, the only available (partial) 5-HT 1A -receptor agonist buspirone (also dopamine D 2 -receptor antagonist) is used as an antidepressant and has not been associated with sexual side effects [38,50]. In our rat model, low doses of buspirone that exert an antidepressant effects in animal depression models [79] have mild prosexual activity [16] (Table 1). Our rat data are in line with (limited) human data indicating that buspirone has no sexual side effects, but is also not a strong (add-on) drug in combination with SSRIs.…”

Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

“…In several studies, buspirone displayed antianxiety properties in rats and mice (Pytka et al, 2016). On the contrary, Collinson and Dawson (1997)) as well as Kumar, Rajkumar, Lee, and Dawe (2016) showed the anxiogenic activity of buspirone in elevated plus maze test, but buspirone was also reported to be inactive in that test (Jastrzȩbska-Wiȩsek et al, 2018). Furthermore, one study assigned the anxiolytic effect of buspirone to its metabolite 1-PP, while another revealed no antianxiety activity of 1-PP and idazoxan (α 2 -adrenoreceptor antagonist).…”