The effect of 5-HT4 serotonin receptors in the CA3 hippocampal region on D-AP5-induced anxiolytic-like effects: Isobolographic analyses.

Increasing evidence shows the close relationship between hippocampal glutamatergic and serotonergic systems through the modulation of behavioral responses. This study aimed to investigate the possible involvement of 5-HT4 receptors in the CA3 hippocampal region in anxiolytic-like effects induced by D-AP5 (a competitive antagonist of the glutamate NMDA [N-Methyl-D-aspartate] receptor). Male Wistar rats were placed in the elevated plus maze (EPM) apparatus that is used to assess anxiety-related behaviors, and the percentages of open arm time (%OAT) and open arm entries (%OAE) which are associated with anxiety-related behaviors were measured. The close arm entries (CAE) which is correlated with locomotor activity was also evaluated. The results showed that, intra-CA3 injection of D-AP5 (0.4 µg/rat), RS67333 (1.2 µg/rat; a 5-HT4 receptor agonist), and RS23597-190 (1.2 µg/rat; a 5-HT4 receptor antagonist) increased %OAT and %OAE, indicating the anxiolytic-like effect of these drugs. Also, only RS23597-190 (1.2 µg/rat) decreased CAE. Intra-CA3 injection of sub-threshold dose of RS67333 (0.012 µg/rat) or RS23597-190 (0.012 µg/rat), 5 min before the injection of D-AP5 (0.2 µg/rat) increased %OAT, indicating potentiating the anxiolytic-like effect of D-AP5. The isobolographic analyses also showed the additive or synergistic anxiolytic-like effect of intra-CA3 co-administration of D-AP5 with RS67333 or RS23597-190, respectively. In conclusion, CA3 5-HT4 receptors are involved in D-AP5-induced anxiolytic-like behaviors in rats.

Activation and Blockade of Serotonin-4 Receptors in the Lateral Habenula Produce Antidepressant Effects in the Hemiparkinsonian Rat.

BACKGROUND: The 5-hydroxytryptamine (5-HT) neurotransmitter system and lateral habenula (LHb) are involved in the regulation of depression, while the mechanisms remain to be clarified. OBJECTIVES: The effects and possible mecha-nism underlying activation or blockade of 5-HT4 receptors (5-HT4Rs) in the LHb in depression were investigated by behavioral and neurochemical methods based on a Parkinson's disease (PD) rat model. METHOD: 6-Hydroxydopamine (6-OHDA) was injected unilaterally into the substantia nigra pars compacta to establish the PD rat model. The depressive-like behaviors were measured by the forced swimming test (FST) and sucrose preference test (SPT). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by a neurochemical method. RESULTS: The 6-OHDA lesions increased the immobility time in the FST and decreased the sucrose consumption in the SPT, suggesting the induction of depressive-like behaviors. Intra-LHb injection of BIMU-8 (5-HT4R agonist) or GR113808 (5-HT4R antagonist) produced antidepressant effects in the lesioned rats. Intra-LHb injection of BIMU-8 significantly increased the DA levels in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHip), increased the 5-HT level in the mPFC and decreased the NA level in the vHip only in the lesioned rats, while intra-LHb injection of GR113808 changed DA, NA and 5-HT levels in the mPFC, LHb and vHip in both sham and the lesioned rats. CONCLUSIONS: All these results suggest that activation or blockade of the LHb 5-HT4Rs produce antidepressant effects in the 6-OHDA-lesioned rats, which are related to the changes of monoamines in the limbic and limbic-related regions.

The role of 5-HT4 serotonin receptors in the CA1 hippocampal region on memory acquisition impairment induced by total (TSD) and REM sleep deprivation (RSD).

Sleep is a circadian rhythm that is modulated by endogenous circadian clock located in the suprachiasmatic nucleus (SCN). Sleep modulates memory acquisition and promotes memory consolidation. Studies have shown that sleep deprivation (SD) impairs different types of memory including passive avoidance. Furthermore, the hippocampus plays a significant role in modulating passive avoidance memory. On the other hand, 5-HT4 receptors are expressed in the hippocampus and involved in learning and memory processes. In this study, we aimed to investigate the role of CA1 hippocampal 5-HT4 receptors in memory acquisition impairment induced by total sleep deprivation (TSD: 24 h) and REM sleep deprivation (RSD: 24 h). The water box apparatus was used to induce TSD, while multi-platform apparatus was applied to induce RSD. Passive avoidance memory test was also used to evaluate memory acquisition. The results showed that, intra-CA1 pre-training injection of RS67333 (5-HT4 agonist) and RS23597 (5-HT4 antagonist) at the doses of 0.01 and 0.1 µg/rat decreased memory acquisition, but did not alter pain perception and locomotor activity. Furthermore, TSD and RSD decreased memory acquisition; however, only TSD decreased locomotor activity and induced analgesic effect. The sub-threshold doses of RS67333 and RS23597, 0.001 and 0.0001 µg/rat, respectively, reversed the effect of TSD on memory acquisition and locomotor activity. In addition, only RS23597 reversed TSD-induced analgesia. In RSD condition, the subthreshold dose of RS23597 improved RSD-induced memory acquisition deficit. In conclusion, CA1 hippocampal 5-HT4 receptors play an important role in TSD/RSD-induced cognitive alterations.

l-Lysine Acts as a Serotonin Type 4 Receptor Antagonist to Counteract In Vitro and In Vivo the Stimulatory Effect of Serotonergic Agents on Aldosterone Secretion in Man.

In the normal human adrenal gland, serotonin (5-HT) stimulates aldosterone secretion through the 5-HT4 receptor (5-HT4R). However, the physiological role of the serotonergic control of adrenocortical function is not known. In the present study, we have investigated the ability of l-Lysine, which has been shown to act as a 5-HT4 receptor antagonist, to counteract in vitro and in vivo the stimulatory effect of 5-HT4R agonists on aldosterone production. l-Lysine was found to inhibit aldosterone production induced by 5-HT and the 5-HT4R agonists BIMU8 from cultured human adrenocortical cells. The action of l-Lysine (4.95 g/day orally) on the adrenal cortex was also evaluated in 20 healthy volunteers in a double blind, cross-over, placebo controlled study. l-Lysine had no significant influence on basal plasma aldosterone levels and the aldosterone responses to upright posture, tetracosactide, and low sodium diet (10 mmol/day for 3 days). Conversely, l-Lysine significantly reduced the surge of plasma aldosterone induced by metoclopramide indicating that l-Lysine is able to efficiently antagonize the adrenal 5-HT4 receptors in vivo. These results suggest that l-Lysine supplementation may represent a new treatment of primary adrenal diseases in which corticosteroid hypersecretion is driven by overexpressed 5-HT4 receptors.

Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear.

Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist.

5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tert-butyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure.

Optimal dose period for indisetron tablets for preventing chemotherapy-induced nausea and vomiting with modified FOLFOX6: a randomized pilot study.

BACKGROUND: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. We designed a pilot study in order to explore the optimal dosing period for indisetron during modified FOLFOX6 (mFOLFOX6). PATIENTS AND METHODS: Forty-two chemotherapy-naive patients with advanced colorectal cancer scheduled to receive mFOLFOX6 were randomly assigned to either a 1- or 3-day indisetron regimen arm. The primary endpoint was complete protection from vomiting. RESULTS: Proportions of patients with complete protection from vomiting were 85.7% [95% confidence interval (CI) 63.7-97.0] with the 3-day regimen and 81.0% (95% CI 58.1-94.6) with the 1-day regimen. Proportions of patients with complete protection from nausea were 47.6% in each arm (95% CI 25.7-70.2). No rescue therapy rates were 66.7% (95% CI 43.0-85.4) versus 57.1% (95% CI 34.0-78.2). No severe adverse events were observed in either arm. CONCLUSION: Both 1- and 3-day indisetron regimens were feasible for preventing nausea and vomiting induced by mFOLFOX6.