Serotonin 1A Receptor Partial Agonist Research Articles

PC-FACS FINAL June 3, 2022

Background: Opioid analgesics, widely used to treat acute, postoperative, and chronic pain, can result in severe respiratory depression.1–3 Can tandospirone, a novel nonbenzodiazepine anxiolytic/antidepressant drug and selective serotonin-1A receptor partial agonist, counter fentanyl-induced respiratory depression?

Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the “TS + fentanyl” and “saline + fentanyl” group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.

Chronic treatment with tandospirone, a serotonin 1A receptor partial agonist, inhibits psychosocial stress-induced changes in hippocampal neurogenesis and behavior

BackgroundThe 5-hydroxytryptamine (5-HT) 1A receptors are considered a potential target for the treatment of mental and neuropsychiatric disorders. Several studies have indicated that 5-HT1A receptor agonists increase hippocampal neurogenesis, which is implicated in the action mechanism of antidepressants. However, these agents have not been applied to humans due to intolerable side effects. We recently showed that chronic administration of tandospirone, a clinically available 5-HT1A receptor partial agonist, increased hippocampal neurogenesis dose-dependently. The present study was done to determine if chronic tandospirone treatment has antidepressant potential from the standpoint of hippocampal neurogenesis and behavior. MethodsMale Sprague-Dawley rats were intraperitoneally administered a vehicle or tandospirone (10mg/kg) once daily for 28 days. Two weeks after starting the injections, animals were exposed to intermittent social defeat (four times over two weeks). The effects of stress and tandospirone on the rodents׳ behavior were evaluated by the Novelty-Suppressed Feeding (NSF) test. The quantification of hippocampal neurogenesis was estimated using immunostaining with Ki-67 and doublecortin (DCX). ResultsChronic tandospirone treatment reversed the psychosocial stress-induced increase in the latency in the NSF test and decrease in the density of DCX-positive cells in the dentate gyrus of the dorsal and ventral hippocampus. However, no difference in the density of Ki-67-positive cells was observed between the vehicle- and tandospirone-administered groups. LimitationsTo clarify the antidepressant potential of TDS, the other behavioral tests for depression will be required. ConclusionsOur findings suggest that tandospirone has antidepressant potential through an inhibiting effect on stress-induced changes in hippocampal neurogenesis.

Vilazodone in the treatment of major depressive disorder: efficacy across symptoms and severity of depression.

Vilazodone is a potent selective serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder in adults. To assess the efficacy of vilazodone across a range of symptoms and severities of depression, data from two phase III, 8-week, randomized, double-blind, placebo-controlled trials were pooled for analysis. Overall improvement in depressive symptoms measured using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Depression Rating Scale was statistically significant (P<0.05) for vilazodone treatment compared with placebo as early as Week 1 and continued throughout double-blind treatment. Vilazodone treatment compared with placebo showed significant improvement on all 10 individual MADRS symptom items at end of treatment (P<0.01). Rates of response and remission were significantly greater in the vilazodone group relative to the placebo group, with numbers needed to treat ranging from eight to nine for response and 12–17 for remission. Between-group treatment differences in MADRS and the other outcome measures were similar among all depression subgroups, with no consistent pattern associated with depression severity. These findings support the efficacy of vilazodone across a broad range of depressive symptoms and severities for the treatment of major depressive disorder.

The efficacy profile of vilazodone, a novel antidepressant for the treatment of major depressive disorder

Objective:Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day.Methods:The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time.Results:Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo-treated patients (least-squares mean [LSM] treatment difference: −3.2 [p = 0.001], RCT-1; −2.5 [p = 0.009], RCT-2). Clinical Global Impressions–Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: −0.4 [p = 0.001], RCT-1; −0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52).Conclusion:Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data.Trial registration:Trial registration: ClinicalTrials.gov identifier: NCT00285376.Trial registration: ClinicalTrials.gov identifier: NCT00683592.Trial registration: ClinicalTrials.gov identifier: NCT00644358.

A Randomized, Double-Blind, Placebo-Controlled, 8-Week Study of Vilazodone, a Serotonergic Agent for the Treatment of Major Depressive Disorder

To evaluate the efficacy, and further establish the safety profile, of oral once-daily vilazodone, a potent and selective serotonin 1A receptor partial agonist and reuptake inhibitor, in the treatment of major depressive disorder (MDD). This phase 3, randomized, double-blind, placebo-controlled, 8-week study (conducted March 2008-February 2009) enrolled 481 adults with DSM-IV-TR-defined MDD. Patients received vilazodone (titrated to 40 mg/d) or placebo. The primary efficacy endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment. Secondary efficacy measures included MADRS and 17-item Hamilton Depression Rating Scale (HDRS-17) response and change in HDRS-17, HDRS-21, Hamilton Anxiety Rating Scale (HARS), Clinical Global Impressions-Severity of Illness (CGI-S), and Clinical Global Impressions-Improvement (CGI-I) scores. The Changes in Sexual Functioning Questionnaire (CSFQ) was administered at baseline and week 8. Vilazodone-treated patients had significantly greater improvement (P = .009) according to the MADRS than placebo patients (intent-to-treat; least-squares mean changes: -13.3, -10.8). MADRS response rates were significantly higher with vilazodone than placebo (44% vs 30%, P = .002). Remission rates for vilazodone were not significantly different based on the MADRS (vilazodone, 27.3% vs placebo, 20.3%; P = .066) or HDRS-17 (vilazodone, 24.2% vs placebo, 17.7%; P = .088). Vilazodone-treated patients had significantly greater improvements from baseline in HDRS-17 (P = .026), HDRS-21 (P = .029), HARS (P = .037), CGI-S (P = .004), and CGI-I (P = .004) scores than placebo patients. Rates of discontinuation due to adverse events were 5.1% (vilazodone) and 1.7% (placebo). The most common adverse events (vilazodone vs placebo) were diarrhea (31% vs 11%), nausea (26% vs 6%), and headache (13% vs 10%). Treatment-related effects on sexual function as measured by the CSFQ were small and similar to placebo. Effects on weight were no different from placebo. Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD. clinicaltrials.gov Identifier: NCT00683592.

Effect of tandospirone, a serotonin-1A receptor partial agonist, on information processing and locomotion in dizocilpine-treated rats

Augmentation therapy with serotonin-1A receptor (5-HT1A) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia. The objective of the present study was to examine the effect of repeated administration of tandospirone (0.05 and 5 mg/kg) on locomotor activity in a novel environment and on sensorimotor gating in rats treated with the N-methyl-D-aspartate receptor antagonist MK-801, which has been used in animal models of schizophrenia. Furthermore, we sought to determine whether the effect of tandospirone on these behavioural measures is blocked by WAY 100635 (0.3 mg/kg), a 5-HT1A receptor antagonist, and whether there is an interaction between haloperidol (0.1 mg/kg; a dopamine-D2 receptor antagonist) and tandospirone. Tandospirone at 5 mg/kg, but not 0.05 mg/kg, decreased locomotor activity in saline or MK-801-treated rats, which were not affected by co-treatment with WAY 100635. Haloperidol decreased locomotion both in saline and MK-801-treated animals, and this effect was not evident in the latter group receiving the higher dose of tandospirone. Tandospirone (5 mg/kg)-induced disruption of sensorimotor gating in saline or MK-801-treated animals was reversed by WAY-100635, but not by haloperidol. These findings suggest that behavioural changes induced by tandospirone are not fully blocked by 5-HT1A antagonists and that tandospirone (5 mg/kg) potentiates the effect of MK-801. Overall, these findings point to an interaction between NMDA and 5-HT(1A) receptors. Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems.

The serotonin1A receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] enhances cholinergic transmission and cognitive function in rodents: a combined neurochemical and behavioral analysis.

These studies examined the influence of the selective 5-hydroxytryptamine (serotonin) (5-HT)(1A) receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] upon cholinergic transmission and cognitive function in rodents. In the absence of acetylcholinesterase inhibitors, S15535 dose-dependently (0.04-5.0 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex and dorsal hippocampus of freely moving rats. In the cortex, the selective 5-HT(1A) receptor antagonist WAY100,635 [(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide) fumarate] dose-dependently (0.0025-0.63) blocked this action of S15535. By contrast, in dorsal hippocampus, WAY100,635 mimicked the induction of acetylcholine release by S15535. In a social recognition paradigm, S15535 dose-dependently (0.16-10.0) improved retention, an action blocked by WAY100,635 (0.16), which was ineffective alone. Furthermore, S15535 dose-dependently (0.04-2.5) and WAY100,635 reversibly abolished amnesic properties of the muscarinic antagonist scopolamine (0.63) in this procedure. Cognitive deficits provoked by scopolamine in autoshaping and Morris water-maze procedures were likewise blocked by S15535 at doses of 0.63 to 10.0 and 0.16 to 2.5, respectively. In a two-platform spatial discrimination task, in which S15535 similarly abrogates cognitive deficits elicited by scopolamine, injection of S15535 (1.0 and 10.0 microg) into dorsal hippocampus blocked amnesic effects of the 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin (0.5 microg). Finally, S15535 (0.16-0.63) improved performance in a spatial, delayed nonmatching to sample model in mice, and in an operant delayed nonmatching to sample model in old rats, S15535 (1.25-5.0 mg/kg p.o.) increased response accuracy and reduced latency to respond. In conclusion, S15535 reinforces frontocortical and hippocampal release of acetylcholine and displays a broad-based pattern of procognitive properties. Its actions involve both blockade of postsynaptic 5-HT(1A) receptors and engagement of 5-HT(1A) autoreceptors.

GABA-A and 5-HT1A receptor agonists block expression of fear-potentiated startle in mice.

The present experiments characterized the acquisition of fear-potentiated startle (FPS) and determined the sensitivity of FPS to anxiolytic compounds in DBA/1J mice. A light (30 s) conditioned stimulus (CS) and mild footshock (0.14 mA, 0.5 s) unconditioned stimulus (US) were used. First, acquisition of FPS was examined by presenting the acoustic startle probe during and after each CS-US pairing trial, allowing for a trial-by-trial measurement of experience-dependent startle plasticity. In this novel protocol, mice showed robust acquisition (larger acoustic startle reflex in the presence of the CS) of FPS after as few as eight CS-US pairings. FPS was significantly greater when the CS and US were paired explicitly (light-paired) as compared to when both the US and CS were presented randomly (unpaired), or when the CS was presented alone (no shock), indicating pairing-dependent learning of the CS. Second, the present study assessed the sensitivity of FPS in mice to anxiolytic drugs. The GABA-A receptor agonists diazepam (3 and 6 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the expression of FPS post-training, as did the serotonin 1A receptor partial agonist buspirone (5 and 10 mg/kg). Furthermore, all three anxiolytic drugs reduced startle responding in a cue-specific manner and without significant changes in baseline responding. These data demonstrate a novel method of studying acquisition of FPS, and support the predictive validity of the FPS model of anxiolytic drug action in mice.

Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin 1A receptors and blockade of α 2-adrenergic receptors underlie its actions

The serotonin 1A receptor partial agonist, buspirone, also displays antagonist properties at D 2 receptors and is metabolized to the α 2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine). Herein, we examined mechanisms underlying the influence of buspirone alone, and in association with the serotonin reuptake inhibitor, fluoxetine, upon extracellular levels of serotonin, dopamine and noradrenaline simultaneously quantified in the frontal cortex of freely moving rats. Buspirone (0.01–2.5 mg/kg, s.c.) dose-dependently decreased dialysate levels of serotonin (−50%), and increased those of dopamine (+100%) and noradrenaline (+140%). The reduction by buspirone of serotonin levels was abolished by the serotonin 1A receptor antagonist, WAY 100,635 (0.16), which did not, however, modify its influence upon dopamine and noradrenaline. In contrast to buspirone, the serotonin reuptake inhibitor, fluoxetine (10.0), increased frontocortical levels of serotonin (+120%), dopamine (+55%) and noradrenaline (+90%). Buspirone dose-dependently (0.01–2.5) decreased the induction by fluoxetine of serotonin levels yet potentiated (three-fold) its elevation of dopamine and noradrenaline levels. The serotonin 1A agonist, 8-hydroxy-2-(di- n-propylamino)-tetralin (0.16), mimicked the action of buspirone in reducing resting levels of serotonin (−60%) and in enhancing those of dopamine (+135%) and noradrenaline (+165%). Like buspirone, it attenuated the influence of fluoxetine upon serotonin levels, yet facilitated its influence upon dopamine and noradrenaline levels. In contrast, WAY 100,635 selectively potentiated the increase in levels of serotonin (two-fold) versus dopamine and noradrenaline elicited by fluoxetine. Further, WAY 100,635 abolished the inhibitory influence of buspirone upon fluoxetine-induced serotonin release, but only partly interfered with its potentiation of fluoxetine-induced increases in dopamine and noradrenaline levels. The D 2/D 3 receptor antagonist, raclopride (0.16), increased basal dopamine (+60%) levels but little influenced those of serotonin and noradrenaline, and failed to modify the action of fluoxetine. The α 2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine) (2.5), which did not modify resting levels of serotonin, markedly increased those of dopamine (+90%) and noradrenaline (+190%) and potentiated (two-fold) the increases in dialysate levels of dopamine, noradrenaline and serotonin provoked by fluoxetine. Further, the α 2-adrenergic receptor agonist, S18616, attenuated the enhancement by buspirone of the fluoxetine-induced increase in levels of dopamine and noradrenaline. In conclusion, the inhibitory influence of buspirone upon resting and fluoxetine-stimulated serotonin levels reflects its agonist properties at serotonin 1A autoreceptors. The facilitatory influence of buspirone upon resting and fluoxetine-stimulated dopamine and noradrenaline levels may also involve its serotonin 1A properties. However, its principal mechanism of action in this respect is probably the α 2-adrenergic antagonist properties of its metabolite, 1-(2-pyrimidinyl-piperazine). The present observations are of significance to experimental and clinical studies of the influence of buspirone upon depressive states, alone and in association with antidepressant agents.

Serotonin 1A receptors, melatonin, and the proportional control thermostat in patients with winter depression.

In patients with seasonal affective disorder, light treatment lowers core temperature during sleep in proportion to its antidepressant efficacy. The regulation of the level of core temperature during sleep is linked with a proportional control thermostat in the central nervous system whose operation appears abnormal in patients with seasonal affective disorder. Because both melatonin and serotonin 1A receptor activation also lower core temperature, we investigated the relationship between (1) endogenous melatonin and core temperature profiles, (2) the proportional control thermostat, and (3) the core hypothermic response to the serotonin 1A receptor partial agonist ipsapirone hydrochloride in patients with seasonal affective disorder and healthy controls. Eighteen patients with seasonal affective disorder and 18 controls first completed a 24-hour study in which their melatonin profiles were characterized. Subjects then returned 3 to 5 days later for the first of 2 drug challenges (ipsapirone hydrochloride, 0.3 mg/kg, or placebo), each separated by 3 to 5 days. Overnight rectal and facial temperatures were recorded before and after each drug challenge. The magnitudes of the core hypothermic responses to ipsapirone were (1) not different between groups and (2) independently correlated with both the levels of the previous nights' core temperature minima (P=.002) and the amounts of nocturnal melatonin secreted (P<.001). The daytime regulation of core temperature by serotonin 1A receptors appears normal in seasonal affective disorder. The magnitude of serotonin 1A receptor-activated hypothermia is governed by a central nervous system proportional control thermostat whose operation appears modulated by both melatonin and the level of the core temperature minimum.

The 5-HT1A receptor: a new effective principle in psychopharmacologic therapy?

The 5-hydroxytryptamine (5-HT)1A receptor has been the focus of considerable research effort over a decade. However, the definitive classification of this receptor and the full characterization of its pharmacology is still in progress. On the one hand, the selective serotonin-1A receptor partial agonist anxiolytics were developed first and represented a new class of pharmacological agents that have demonstrated efficacy in the treatment of generalized anxiety disorder (GAD). These compounds (e.g. buspirone, gepirone, tandospirone or ipsapirone) offered a completely different pharmacologic approach to this disorder from previous medications as benzodiazepines or alcohol. On the other hand, beta-adrenoceptor blockers (e.g. [-]-pindolol, [-]-propranolol) have been shown to have antagonistic properties on the 5-HT1A receptor side. Preliminary results suggest that beta-adrenoceptor blockers may be useful as adjunctive medication in the treatment of depression by augmenting the antidepressant efficacy of selective serotonin reuptake inhibitors. As the beta-adrenoceptor blockers show also affinities to other 5-HT receptors than the 5-HT1A receptor the recently discovered more selective 5-HT1A antagonists became of interest. The pharmacological properties and potential therapeutic utility of these novel compounds will also be discussed.

Serotonin-IA Anxiolytics: An Overview

The selective serotonin-1A receptor partial agonist anxiolytics represent a new class of pharmacologic agents that have demonstrated efficacy in the treatment of generalized anxiety disorder (GAD). These compounds offer a completely different pharmacologic approach to this disorder from previous medications. The selective 5-hydroxytryptamine-1A (5-HT1A) anxiolytics buspirone, gepirone, ipsapirone, and SM-3997 have several important new and unique features that will be reviewed in this paper. These features include no cross-tolerance with alcohol or benzodiazepines, no evidence of abuse or misuse potential, and no withdrawal symptoms or rebound anxiety on cessation of therapy. The 5-HT1A anxiolytics have no muscle relaxant, sedative, or anticonvulsant properties and do not impair psychomotor functioning. They do have a slower onset of effect than standard benzodiazepines-clinical response is usually noted in 1-3 weeks. The side effect profile is quite different from that of the benzodiazepines. It includes gastrointestinal symptoms such as nausea and diarrhea, headache, dizziness, and restlessness. Some patients with GAD who have received chronic (greater than 1 month) benzodiazepine therapy may not respond as well to these compounds initially as will patients with no prior benzodiazepine treatment, especially if the benzodiazepine has been discontinued only recently. These compounds, buspirone in particular, have been shown to have excellent maintenance and prophylactic properties and to be well tolerated with long-term therapy (greater than 3 months). Because of their unique mechanism of action and side effect profile, and no evidence of misuse or abuse potential or interference with mental acuity, these compounds represent a definite advance in the pharmacologic management of GAD.