5-HT4 Receptor Agonist Research Articles

Selective Serotonin Reuptake Inhibitors and 5-HT2 Receptor Agonists Have Distinct, Sleep-state Dependent Effects on Postictal Breathing in Amygdala Kindled Mice

Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT2 receptor agonists. SSRIs and 5-HT2 agonists increased postictal breathing frequency (fR), tidal volume (VT), and minute ventilation (VE) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT2 agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT2A antagonist MDL-11939 reduced the effect of citalopram on fR, VT, and VE, and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT2 family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.

Differential engagement of inhibitory and excitatory cardiopulmonary reflexes by capsaicin and phenylbiguanide in C57BL/6 mice.

The Bezold-Jarisch reflex is a powerful inhibitory reflex initiated by activation of cardiopulmonary vagal nerves during myocardial ischemia, hemorrhage, and orthostatic stress leading to bradycardia, vasodilation, hypotension, and vasovagal syncope. This clinically relevant reflex has been studied by measuring heart rate (HR) and mean arterial pressure (MAP) responses to injections of a variety of chemical compounds. We hypothesized that reflex responses to different compounds vary due to differential activation of vagal afferent subtypes and/or variable coactivation of excitatory afferents. HR and MAP responses to intravenous injections of the transient receptor potential vanilloid-1 (TRPV1) agonist capsaicin and the serotonin 5-HT3 receptor agonist phenylbiguanide (PBG) were measured in anesthetized C57BL/6 mice before and after bilateral cervical vagotomy. Capsaicin and PBG evoked rapid dose-dependent decreases in HR and MAP followed by increases in HR and MAP above baseline. Bezold-Jarisch reflex responses were abolished after vagotomy, whereas the delayed tachycardic and pressor responses to capsaicin and PBG were differentially enhanced. The relative magnitude of bradycardic versus depressor responses (↓HR/↓MAP) in vagus-intact mice was greater with capsaicin. In contrast, after vagotomy, the magnitude of excitatory tachycardic versus pressor responses (↑HR/↑MAP) was greater with PBG. Although capsaicin-induced increases in MAP and HR postvagotomy were strongly attenuated or abolished after administration of the ganglionic blocker hexamethonium, PBG-induced increases in MAP and HR were mildly attenuated and unchanged, respectively. We conclude that responses to capsaicin and PBG differ in mice, with implications for delineating the role of endogenous agonists of TRPV1 and 5-HT3 receptors in evoking cardiopulmonary reflexes in pathophysiological states.

Quipazine: Classical hallucinogen? Novel psychedelic?

Quipazine, first identified in the 1960s, has been the topic of >1000 published papers. On the basis of available 5-HT2 serotonin receptor radioligand binding data and various preclinical studies, it might be thought that quipazine bears the hallmarks of a classical hallucinogen or psychedelic agent – agents currently being examined for their potential use in treating certain neuropsychiatric disorders. Nevertheless, by definition, such agents require the availability of human data, which, in the case of quipazine, are lacking. Because quipazine is also a 5-HT3 receptor agonist, future human studies with this agent might prove problematic because 5-HT3 agonists are known to produce emesis. Nevertheless, continued investigation of novel quipazine analogs with modified pharmacological profiles might prove worthwhile.

Molecular Mechanisms of Exercise-induced Hippocampal Neurogenesis and Antidepressant Effects.

It is estimated that approximately 280 million people worldwide suffer from depression. Depression is a common disease to us all, and the socioeconomic loss caused by depression is very large. However, there is currently a problem that many depressed patients do not respond to existing antidepressants, including selective serotonin reuptake inhibitors (SSRIs). Therefore, novel and effective therapeutic agents are highly desirable. It has been reported that exercise has preventive effects on depression (antidepressant effects) and that serotonin, whose release increases in the brain with exercise, is involved in exercise-induced antidepressant effects. We focused on the action of serotonin and investigated its role in the antidepressant effect of exercise using gene knockout mice, and then, we found that serotonin type 3 (5-HT3) receptors play an essential role in the antidepressant effect of exercise. We then further investigated the antidepressant effects mediated by 5-HT3 receptors. Our detailed analyses revealed that neurons expressing 5-HT3 receptors are abundant in the subgranular zone of the hippocampal dentate gyrus and produce insulin-like growth factor-1 (IGF-1). In addition, we newly found that the stimulation of 5-HT3 receptors by agonists promotes IGF-1 release in the hippocampus and increases hippocampal neurogenesis via the IGF-1 signaling pathway, resulting in antidepressant effects. Furthermore, we further showed that a 5-HT3 receptor agonist increases hippocampal neurogenesis and exhibits antidepressant effects in mice with depressive-like behavior. A comparison with the effects of existing antidepressant SSRIs revealed that the 5-HT3 receptor-mediated antidepressant action is a new therapeutic mechanism that differs from existing drugs. Our findings suggest a novel 5-HT3 receptor-IGF-1 mechanism, which could lead to the development of new antidepressant drugs for depression based on the molecular mechanism of exercise-induced antidepressant effects and could bring significant benefits to many depressed patients who do not respond to existing drugs such as SSRIs.

Severe coronary artery spasm after administration of a 5-hydroxytryptamine type 1 receptor agonist in a patient with new-onset Graves’ disease and myocarditis after SARS-CoV2 vaccination

Background Coronary artery spasm is a well-known potential side effect of selective 5-hydroxytryptamine type 1 (5HT1) receptor agonists and, therefore, contraindicated in patients with cardiovascular disease. SARS-CoV-2 vaccination has been associated with myocarditis, mainly in young men. Case summary A 55-year-old man with longstanding cluster headache, treated with the 5HT1-agonist Sumatriptan for ten years, received the mRNA-1273 SARS-CoV-2 booster vaccine. Four days later, he developed severe retrosternal pain several minutes after administering Sumatriptan with electrographic ST-elevation and a raised high-sensitivity cardiac troponin-T (hs-cTnT). Coronary angiogram was normal, but a diagnosis of acute myocarditis and hyperthyroidism secondary to Graves’ disease was made. Discussion We present a case of severe coronary artery spasm induced by a 5HT1-agonist secondary to newly diagnosed Graves’ disease and myocarditis. The mRNA-1273 SARS-CoV-2 booster vaccine administered four days before admission probably triggered both immunoreactions.

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs.

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and β-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson's Disease.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20μmol/L) and palosetron (10μmol/L), but not 5-HT3 receptor agonist m-CPBG (30μmol/L) and SR 57,727 (10μmol/L), 5-HT1A receptor agonist 8-OH DPAT (10μmol/L) and eptapirone (10μmol/L) and 5-HT1A receptor antagonist WAY-100635 (10μmol/L) and p-MPPI (10μmol/L). Intrathecal injection of ondansetron (0.1mg/kg) but not m-CPBG (0.1mg/kg), 8-OH DPAT (0.1mg/kg), and WAY-100635 (0.1mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

5-HT and α-m-5-HT attenuate excitatory synaptic transmissions onto the lateral amygdala principal neurons via presynaptic 5-HT1B receptors

Accumulating evidence suggests that the serotonergic (5-HT) system in the amygdala has significant effects on affective states. Dysregulation of the 5-HT system in the basolateral amygdaloid complex causes affective disorders. To search for therapeutic targets, subtype specification of 5-HT receptors is crucial. The present study was undertaken to identify the 5-HT receptor subtype responsible for the 5-HT-mediated suppression of excitatory transmission to principal neurons (PNs) in the lateral amygdala (LA). Whole-cell recordings were performed to record excitatory post synaptic currents (EPSCs) in acute rat brain slices. We confirmed that 5-HT and α-m-5-HT, a broad 5-HT2 receptor agonist, attenuated EPSCs in LA PNs. The extent of suppressions by 5-HT and α-m-5-HT remained unchanged in the presence of ritanserin, a broad 5-HT2 receptor antagonist. In the presence of NAS-181, a selective 5-HT1B receptor antagonist, the extent of EPSC suppressions by 5-HT and α-m-5-HT was diminished. CP93129, a selective 5-HT1B receptor agonist, attenuated EPSCs in LA PNs, and this effect was abolished in the presence of NAS-181. Additionally, the paired-pulse ratio of EPSCs was increased by CP93129. Thus, our results indicate that 5-HT and α-m-5-HT attenuate excitatory transmissions to LA PNs via presynaptic 5-HT1B receptors.

Participation of Hippocampal 5-HT5A, 5-HT6 and 5-HT7 Serotonin Receptors on the Consolidation of Social Recognition Memory

Social recognition is the ability of animals to identify and recognize a conspecific. The consolidation of social stimuli in long-term memory is crucial for the establishment and maintenance of social groups, reproduction and species survival. Despite its importance, little is known about the circuitry and molecular mechanisms involved in the social recognition memory (SRM). Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator, which plays a key role in learning and memory. Focusing on the more recently described 5-HT receptors, we investigated in the CA1 region of the dorsal hippocampus the participation of 5-HT5A, 5-HT6 and 5-HT7 receptors in the consolidation of SRM. Male Wistar rats cannulated in CA1 were subjected to a social discrimination task. In the sample phase the animals were exposed to a juvenile conspecific for 1 h. Immediately after, they received different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. The animals that received infusions of 5-HT5A receptor antagonist SB-699551 (10 µg/µL), 5-HT6 receptor agonist WAY-208466 (0.63 µg/µL) or 5-HT7 receptor agonist AS-19 (5 µg/µL) intra-CA1 were unable to recognize the familiar juvenile. This effect was blocked by the coinfusion of WAY-208466 plus 5-HT6 receptor antagonist SB-271046 (10 µg/µL) or AS-19 plus 5-HT7 receptor antagonist SB-269970 (5 µg/µL). The present study helps to clarify the neurobiological functions of the 5-HT receptors more recently described and extends our knowledge about mechanisms underlying the SRM.

Prokinetic Agents

Gastrointestinal (GI) prokinetic agents are drugs that increase GI motility and promote the movement of contents in the GI tract by amplifying and controlling the contraction of GI smooth muscle. Currently used prokinetics increase GI motility by acting as a dopamine D2 receptor antagonist (e.g., metoclopramide, domperidone, levosulpiride) and 5-HT4 receptor agonist (e.g., mosapride, prucalopride). Some prokinetics also have a cholinesterase inhibitory property (e.g., itopride), and herb-derived prokinetics (e.g., motilitone) affect multiple receptors. Depending on the type and distribution of receptors on which the prokinetics bind, the effect(s) may be regional or throughout the GI tract. Most prokinetics have been used for functional dyspepsia and gastroparesis because they mainly affect upper GI motility. However, prucalopride, a highly selective 5-HT4 receptor agonist, is used primarily to treat chronic constipation and pseudo-obstruction. Dopamine D2 receptor antagonists also inhibit the D2 receptor in the medulla oblongata chemoreceptor trigger zone; therefore, they can treat nausea and vomiting. However, short term use of dopamine D2 antagonists at an appropriate dose is recommended because of their potential for central nervous system side effects by penetrating the blood-brain barrier. It is necessary to know the mechanism of action, each clinical trial’s characteristics, and the side effects of prokinetics to obtain the best clinical outcomes. This article aims to summarize the results of clinical studies related to the impact of currently available prokinetic agents in Korea on GI motility.

Therapeutic potential of serotoninergic psychedelic substances in the treatment of Obsessive Compulsive Disorder

IntroductionObsessive Compulsive Disorder (OCD) is a psychiatric disorder associated with suffering and disability. The serotoninergic system is implicated in the neurobiological processes of OCD and serotonin reuptake inhibitors (SRIs) are the first-line treatment. However, clinical improvement after starting SRIs can take long and patients may not fully recover. Meanwhile, recent data suggests that activation of 5-HT receptors may exert a therapeutic action in obsessional symptoms. Some psychedelics are strong 5-HT2 receptor agonists and there is a growing research interest as they can be a promising therapeutic approach to OCD.ObjectivesWe aim to provide an overview on the current evidence on the therapeutic potential of serotoninergic psychoactive substances in the treatment of OCD.MethodsNon-systematic review. Literature search in the PubMed database using the terms psychedelics and obsessive-compulsive disorder.ResultsAlthough research is currently limited to a few small studies, the ones conducted so far showed clinically meaningful acute reduction of OCD symptoms after treatment with serotoninergic psychoactive drugs, as well as possible longer-lasting benefits, particularly with psilocybin and lysergic acid diethylamide (LSD). Furthermore, substance-assisted psychotherapy with psychedelics has been showing promising results, being suitable for OCD treatment. It is important to add that, to date, studies have indicated relatively good tolerability to these drugs.ConclusionsThese promising early findings highlight the role of psychedelics in OCD treatment and the need for further research into efficacy, therapeutic mechanisms and safety, in order to determine whether these drugs may be worthy options for OCD treatment in the future.DisclosureNo significant relationships.

Central mechanisms contribute to pro-ejaculatory response induced by the combination of dopamine and 5-HT2 receptor agonist in rats

ABSTRACT Introduction Although we previously demonstrated in rats that combination of a dopamine (DA) receptor agonist and 5-HT2 receptor agonist potently and selectively facilitates the ejaculatory response through the activation of D2-like and 5-HT2C receptors, these central mechanisms are not fully understood. We therefore investigated to clarify the target level of the pro-ejaculatory effects by combination of these agonists. Methods The ejaculatory response was evaluated 30 min after drug administration by the presence of seminal materials on the paper towel as well as that adhering to the shaft of the penis. In addition, we examined isolated rat seminal vesicle contraction. Results Intrathecal administration of 5-HT2 receptor agonist m-CPP (10 μg) but not in intracerebroventricular evoked the synergistic action for ejaculation in the combination with systemic administrated DA receptor agonist apomorphine (0.1 mg/kg, s.c.). Synergy effects of combination were completely inhibited by intrathecal 5-HT2C receptor antagonist SB242084 (10 μg). Intrathecal or intracerebroventricular apomorphine (1-10 μg) evoked the pro-ejaculatory effects in the combination with systemic administrated m-CPP (0.3 mg/kg, i.p.) The selective peripherally acting D2-like receptor agonist carmoxirole did not evoked in the combination with m-CPP. Furthermore, the combination of apomorphine and m-CPP did not produce contraction of rat seminal vesicle. Conclusion These results suggest that this synergistic action for ejaculation induces in the spinal or supraspinal level but not the peripheral sites. Furthermore, the present study suggests that the activation of the spinal ejaculatory pattern generator through 5-HT2C receptors is synergistically potentiated by both spinal and supraspinal DA receptors. Disclosure Work supported by industry: no.

5‐HT7 receptors expressed in the mouse parafacial region are not required for respiratory chemosensitivity

A brainstem homeostatic system senses CO2/H+ to regulate ventilation, blood gases and acid‐base balance. Neurons of the retrotrapezoid nucleus (RTN) and medullary raphe are both implicated in this mechanism as respiratory chemosensors, but recent pharmacological work suggested that the CO2/H+‐sensitivity of RTN neurons is mediated indirectly – by raphe‐derived serotonin acting on 5‐HT7 receptors. To investigate this further, we characterized Htr7 transcript expression in phenotypically identified RTN neurons using multiplex single cell qRT‐PCR and RNAscope. Although present in multiple neurons in the parafacial region of the ventrolateral medulla, Htr7 expression was undetectable in most RTN neurons (Nmb+/Phox2b+) concentrated in the densely packed cell group ventrolateral to the facial nucleus. Where detected, Htr7 expression was modest and often associated with RTN neurons that extend dorsolaterally to partially encircle the facial nucleus. These more dorsolateral Nmb+/Htr7+ neurons tended to express high levels of Nmb and low levels of the intrinsic RTN proton detectors, Gpr4 and Kcnk5. In mouse brainstem slices, CO2‐stimulated firing in RTN neurons was mostly unaffected by a 5‐HT7 receptor antagonist, SB269970 (n=11/12). At the whole animal level, microinjection of SB269970 into the RTN of conscious mice blocked respiratory stimulation by co‐injected LP‐44, a 5‐HT7 receptor agonist, but had no effect on CO2‐stimulated breathing in those same mice. We conclude that Htr7 is expressed by a minor subset of RTN neurons with a molecular profile distinct from the established chemoreceptors and that 5‐HT7 receptors have negligible effects on CO2‐evoked firing activity in RTN neurons or on CO2‐stimulated breathing in mice.

5-HT7 receptors expressed in the mouse parafacial region are not required for respiratory chemosensitivity.

A brainstem homeostatic system senses CO2/H+ to regulate ventilation, blood gases and acid–base balance. Neurons of the retrotrapezoid nucleus (RTN) and medullary raphe are both implicated in this mechanism as respiratory chemosensors, but recent pharmacological work suggested that the CO2/H+ sensitivity of RTN neurons is mediated indirectly, by raphe‐derived serotonin acting on 5‐HT7 receptors. To investigate this further, we characterized Htr7 transcript expression in phenotypically identified RTN neurons using multiplex single cell qRT‐PCR and RNAscope. Although present in multiple neurons in the parafacial region of the ventrolateral medulla, Htr7 expression was undetectable in most RTN neurons (Nmb +/Phox2b+) concentrated in the densely packed cell group ventrolateral to the facial nucleus. Where detected, Htr7 expression was modest and often associated with RTN neurons that extend dorsolaterally to partially encircle the facial nucleus. These dorsolateral Nmb +/Htr7 + neurons tended to express Nmb at high levels and the intrinsic RTN proton detectors Gpr4 and Kcnk5 at low levels. In mouse brainstem slices, CO2‐stimulated firing in RTN neurons was mostly unaffected by a 5‐HT7 receptor antagonist, SB269970 (n = 11/13). At the whole animal level, microinjection of SB269970 into the RTN of conscious mice blocked respiratory stimulation by co‐injected LP‐44, a 5‐HT7 receptor agonist, but had no effect on CO2‐stimulated breathing in those same mice. We conclude that Htr7 is expressed by a minor subset of RTN neurons with a molecular profile distinct from the established chemoreceptors and that 5‐HT7 receptors have negligible effects on CO2‐evoked firing activity in RTN neurons or on CO2‐stimulated breathing in mice.Key points Neurons of the retrotrapezoid nucleus (RTN) are intrinsic CO2/H+ chemosensors and serve as an integrative excitatory hub for control of breathing.Serotonin can activate RTN neurons, in part via 5‐HT7 receptors, and those effects have been implicated in conferring an indirect CO2 sensitivity.Multiple single cell molecular approaches revealed low levels of 5‐HT7 receptor transcript expression restricted to a limited population of RTN neurons.Pharmacological experiments showed that 5‐HT7 receptors in RTN are not required for CO2/H+‐stimulation of RTN neuronal activity or CO2‐stimulated breathing.These data do not support a role for 5‐HT7 receptors in respiratory chemosensitivity mediated by RTN neurons.

Anticonvulsant Effect of Minocycline on Pentylenetetrazole-Induced Seizure in Mice: Involvement of 5-HT3 Receptor.

Minocycline, widely used as an antibiotic, has recently been found to have an anti-inflammatory, neuroprotective and anticonvulsant effects. This study was aimed to investigate the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole (PTZ)-induced seizures considering the possible involvement of 5-HT3 receptor in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Also, 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT3 receptor agonist) and Tropisetron (a 5-HT3 receptor antagonist) were used 45 minutes before minocycline treatment. Our results demonstrate that acute minocycline treatment (80 and 120 mg/kg) increased the seizure threshold. In addition, the 5-HT3 antagonist, tropisetron, at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of minocycline (40 mg/kg), while mCPBG (0.2 mg/kg) blunted the anticonvulsant effect of minocycline (80 mg/kg). In conclusion, our findings revealed that the anticonvulsant effect of minocycline is mediated, at least in part, by inhibition of 5-HT3 receptor.

The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain.

Depression is a common and often recurrent illness with significant negative impact on a global scale. Current antidepressants are ineffective for up to one third of people with depression, many of whom experience persistent symptomatology. 5-HT4 receptor agonists show promise in both animal models of depression and cognitive deficit. We therefore studied the effect of the 5-HT4 partial agonist prucalopride (1 mg daily for 6 days) on the neural processing of emotional faces in 43 healthy participants using a randomised placebo-controlled design. Participants receiving prucalopride were more accurate at identifying the gender of emotional faces. In whole brain analyses, prucalopride was also associated with reduced activation in a network of regions corresponding to the default mode network. However, there was no evidence that prucalopride treatment produced a positive bias in the neural processing of emotional faces. Our study provides further support for a pro-cognitive effect of 5-HT4 receptor agonism in humans. While our current behavioural and neural investigations do not suggest an antidepressant-like profile of prucalopride in humans, it will be important to study a wider dose range in future studies.

Automated Computer Software Assessment of 5-Hydroxytryptamine 2A Receptor-Mediated Head Twitch Responses from Video Recordings of Mice.

Psychedelics are a class of drugs that produce unique subjective effects via agonist actions at the 5-hydroxytryptamine 2A receptor (5-HT2A). The 5-HT2A-mediated head twitch response (HTR) in rodents is used as a reliable proxy for psychedelic drug activity in humans, but existing methods for measuring HTRs require surgery or time-consuming visual scoring. In the present work, we validated a simple noninvasive method for quantitating HTRs using computer-based analysis of experimental video recordings. Male C57BL/6J mice received injections of the 5-HT2 receptor agonist (±)2,5-dimethoxy-4-iodoamphetamine (DOI; 0.03-3 mg/kg, s.c.) and were placed into cylindrical arenas. High frame rate videos were recorded via cameras mounted above the arenas. Antagonist experiments, which entailed pretreatment with the 5-HT2A antagonist M100907 (0.01 or 0.1 mg/kg s.c.) prior to DOI (1 mg/kg s.c.), were also recorded. The experimental videos were analyzed for HTRs using a newly developed feature of a commercial software package and compared to visual scoring carried out by trained observers. As expected, DOI produced dose-related increases in HTRs, which were blocked by M100907. Computer scoring was positively correlated with visual scoring, and no statistical difference between the two methods was found. The software captured nearly all visually observed HTRs, false positives induced by other behaviors (e.g., grooming) were rare and easily identified, and results were improved by optimizing lighting conditions. Our findings demonstrate the utility of combining high frame rate video recordings with commercial software analyses to measure HTRs, validating an additional reliable method to study psychedelic-like drug activity in mice.

Pharmacokinetics of DA-6886, A New 5-HT4 Receptor Agonist, in Rats.

DA-6886 is a novel serotonin (5-hydroxytrypamine [5-HT]) receptor 4 agonist for the potential treatment of constipation-predominant irritable bowel syndrome. The purpose of this study was to validate the quantitative assay of DA-6886 in rat plasma and to evaluate the pharmacokinetics and tissue distribution of DA-6886 in rats. The liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the robust quantification of DA-6886 in rat plasma was successfully validated and applied to the pharmacokinetic studies in rats. The pharmacokinetic parameters of DA-6886 in rats were evaluated following single intravenous or oral administration at three dose levels (2, 10, and 20 mg/kg). DA-6886 exhibited a smaller dose-normalized area under the plasma concentration–time curve (AUC) values and faster clearances in the low-dose group than in the high-dose group following both intravenous and oral administration. The steady-state volume of distribution (Vss) of DA-6886 was relatively large (4.91–7.84 L/kg), which was consistent with its high distribution to the liver, kidney, lung, and digestive tract, and was dose-independent. After oral administration, the extent of absolute bioavailability (F) tended to increase (18.9–55.0%) with an increasing dose. The slope of the log-transformed AUC and/or Cmax values versus log dose was greater than unity and greater for oral administration (~1.9) than for intravenous administration (~1.1). Because the nonlinear pharmacokinetics of DA-6886 was more obviously observed after oral administration, it appears that the saturation of pre-systemic intestinal and/or hepatic first-pass extraction of DA-6886 at high doses occurred.

The role of serotonin neurotransmission in rapid antidepressant actions.

Ketamine has rapid antidepressant effects that represent a significant advance in treating depression, but its poor safety and tolerability limit its clinical utility. Accreting evidence suggests that serotonergic neurotransmission participates in the rapid antidepressant effects of ketamine and hallucinogens. Thus, understanding how serotonin contributes to these effects may allow identification of novel rapid antidepressant mechanisms with improved tolerability. The goal of this paper is to understand how serotonergic mechanisms participate in rapid antidepressant mechanisms. We review the relevance of serotonergic neurotransmission for rapid antidepressant effects and evaluate the role of 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors in synaptic plasticity, BDNF signaling, and GSK-3β activity. Subsequently, we develop hypotheses on the relationship of these receptor systems to rapid antidepressant effects. We found that 5-HT1A and 5-HT1B receptors may participate in ketamine's rapid antidepressant mechanisms, while agonists at 5-HT2A and 5-HT4 receptors may independently behave as rapid antidepressants. 5-HT1A, 5-HT2A, and 5-HT4 receptors increase synaptic plasticity in the cortex or hippocampus but do not consistently increase BDNF signaling. We found that 5-HT1A and 5-HT1B receptors may participate in rapid antidepressant mechanisms as a consequence of increased BDNF signaling, rather than a cause. 5-HT2A and 5-HT4 receptor agonists may increase BDNF signaling, but these relationships are tenuous and need more study. Finally, we found that ketamine and several serotonergic receptor systems may mechanistically converge on reduced GSK-3β activity. We find it plausible that serotonergic neurotransmission participates in rapid antidepressant mechanisms by increasing synaptic plasticity, perhaps through GSK-3β inhibition.

Vestibular migraine (VM) management for an ENT surgeon - an update on diagnostic criteria and current management strategies

Overview: Vestibular migraine is a very common problem needing attention as it’s a diagnosis frequently missed. This article discusses key diagnostic indicators including ID-migraine, motion sickness, phono/photophobia. Key management options including prophylactic and abortive medications are also discussed. Findings: Using of the 3 item ID-Migraine questionnaire increases sensitivity. There is no RCT evidence that Nutraceuticals usage, restriction of MSG Caffeine Chocolates, artificial sweeteners, processed meats, alcohol and aged cheese are useful in management VM. Although beta blockers are used as prophylaxis, metoprolol may not be effective.The mainstay of abortive management is 5HT receptor agonists. Recommendations: It is necessary to raise the awareness of the diagnostic entity and necessary training and education should be given to care givers. Future research is necessary to identify therapeutic agents and lifestyle changes specifically to be effective in this condition.