Effect of 5-HT5A antagonists in animal models of schizophrenia, anxiety and depression

Abstract

The few available data on the pharmacological effect of 5-HT5A receptors suggest that antagonists may have anxiolytic, antidepressant and antipsychotic activity. The aim of our study was to verify these suggestions in relevant animal models. Two 5-HT5A antagonist ligands, SB-699551-A (N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride) (3-60 mg/kg, intraperitoneally) and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine) (3-30 mg/kg, intraperitoneally), were examined in the open-field test, in a foot-shock-induced ultrasonic vocalization test, in the forced swim test (FST) and in the amphetamine-induced and phencyclidine-induced hyperlocomotion tests to examine their effect on general behavioural patterns, and their anxiolytic-like, antidepressant-like and antipsychotic-like properties, respectively. In the open-field test, SB-699551-A induced sedation and A-843277 induced writhing. In the ultrasonic vocalization test, SB-699551-A reduced vocalizations, whereas A-843277 was ineffective. In the FST, SB-699551-A was ineffective and A-843277 reduced immobility, but only at the highest dose. In the amphetamine-induced and phencyclidine-induced hyperlocomotion test, both compounds were ineffective. SB-699551-A showed an anxiolytic-like property in the ultrasonic vocalization test; however, this compound has a sedative effect. A-843277 showed an antidepressant-like property in the FST, but its immobility-reducing effect may also be a consequence of abdominal irritation. Consequently, further investigations are required to define the therapeutic potential of 5-HT5A receptor ligands in anxiety, depression and schizophrenia models.

Valerian Root in Treating Sleep Problems and Associated Disorders—A Systematic Review and Meta-Analysis

“…128 In addition, 5-HT 5A is expressed in the brain areas such as the cerebral cortex, hippocampus, amygdala and hypothalamus, 129 suggesting that it is potentially involved in stress reactivity and resilience. Indeed, a study demonstrated that 5-HT 5A antagonists could have different sedative, anxiolytic, and anti-depressant properties 130 (Figure 6). These data suggest that valerian, as a 5-HT 5A partial agonist, may act differently depending on what circumstances the subjects were placed and this could possibly explain the inconsistent outcomes among the trials.…”

Serotonin type 5A receptor antagonists inhibit D-lysergic acid diethylamide discriminatory cue in rats

“…MDL 100907 (Tocris Bioscience, Bristol, UK) was dissolved in a minimal amount of 0.1 N HCl and diluted to the appropriate concentration with sterile water, and SB 699551 (Tocris) was dissolved in sterile water. Their doses were chosen based on previous reports by Marona-Lewicka et al (2005) and Winter et al (2004) for MDL 100907 and by Kassai et al (2012) for SB 699551. ASP 5736 (synthesised at the Department of Medicinal Chemistry) was dissolved in sterile water, and its doses were based on work by Yamazaki et al (2014).…”

“…propanamide dihydrochloride) is the 5-HT 5A receptor antagonist (apparent pK B of 8.0 in 5-CT-induced stimulation of ( 35 S)GTP-gamma-S binding to human 5-HT 5A /HEK 293 cell membranes assay) with a high 5-HT 5A receptor affinity (pK i of 8.5) and at least 30-fold selectivity (except serotonin transporter) for the human 5-HT 5A receptor versus a number of other 5-HT and other CNS receptors (Corbett et al, 2005;Thomas, 2006). The biological activity of SB 699551 has been demonstrated in several in vivo studies (Gonzalez et al, 2013;Kassai et al, 2012), as well as studies from our laboratory (Nikiforuk et al, 2016).…”

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…For example, SB-699551-A had no effect in the forced swim test, but induced sedation in rats (87), and, whereas increased cAMP has been linked to positive effects on memory consolidation (88), an impairment of this trait was reported by other investigators, in mice treated with the same 5HT5A antagonist (89). Furthermore, 5HT5A has been identified as an inhibitory autoreceptor that regulates the release of serotonin, if only in the absence of concurrent signaling through 5HT1A receptors (90).…”