5-HT1A Receptor Agonist Research Articles

Влияние перинатального стресса и антидепрессантов на острый и тонический болевой ответ и психоэмоциональное поведение у молодых самцов крыс

In male rats born by females stressed during pregnancy and treated with serotonin reuptake inhibitor fluoxetine or 5-HT1A receptor agonist buspirone, the effects of peripheral inflammatory pain in the first two days of life on pain sensitivity, pain system reactivity in response to the inflammatory agent, depressive-like behavior and cognitive abilities were studied when rats reached adolescence. It was found that pain in prenatally stressed newborns did not cause deterioration of behavior in any of the tests used. Moreover, it prevented the harmful effects of prenatal stress, which was manifested in a decreased level of pain response in the hot plate test and inflammatory pain response in the formalin test compared to the responses in prenatally stressed males not subjected to the pain in the newborn age. Under these conditions, the effect of the drugs did not manifest itself, which indicates that the drugs exert an effect in individuals only with pronounced anxiety-depressive behavior. It is concluded that under certain conditions, stress effects in perinatal age increase the organism's resistance to stressful events in the later life. The results are discussed in the context of the match/mismatch stress hypothesis, according to which stress at critical periods of development can program the adaptive behavior of an organism to subsequent stresses.

Selective 5-HT1A receptor agonists biased to pERK1/2 or β-arrestin activation show differential in vivo behavioral profiles

Selective 5-HT1A receptor agonists biased to pERK1/2 or β-arrestin activation show differential in vivo behavioral profiles

Prenatal Stimulation of 5-HT1A Receptors Improves Adaptive Behavior in Prenatally Stressed Rats.

Various types of adaptive behavior during the prepubertal period were analyzed in the offspring of rats receiving chronic injections of serotonin (5-HT) reuptake inhibitor fluoxetine, 5-HT1A receptor agonist buspirone, or their combination starting from gestation day 9 and subjected to immobilization stress from the 15th day of pregnancy until delivery. Prenatal stress increased pain sensitivity, prolonged inflammatory pain response, and increased the levels of anxiety and depression. Chronic administration of drugs acting through 5-HT1A receptors to pregnant rats improved the studied behavioral parameters in their offspring. Differences in the pain sensitivity were found between the effect of drug combination and each of them separately, and in the level of depression between combined administration and fluoxetine alone.

Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties.

Depression is a neuropsychiatric disorder that affects more than 350 million people all over the world. There are psychological and pharmacological treatments for depression which mainly focus on monoaminergic neurotransmission theory. The main concern regarding available antidepressants is the lag period and other side effects, such as sexual dysfunction. Gepirone is a drug of the azapirone group which is a 5-HT1A receptor agonist belonging to the buspirone family. Gepirone is under clinical development and has been shown to be more effective than selective serotonin reuptake inhibitors (SSRIs), as this drug treats the psychiatric disorders without causing sexual dysfunction, which limits the use of SSRIs. It possesses greater selectivity for the 5-HT1A receptor than SSRIs. Clinical studies have shown that gepirone has differential action at pre- and postsynaptic 5-HT1A receptors. Gepirone extended-release tablets (gepirone ER, Travivo) showed promising effects in adult outpatients for the treatment of major depressive disorder (MDD) in a double-blind, randomized, placebo-controlled clinical study. Gepirone also showed an antianxiety effect in a placebo-controlled trial in generalized anxiety disorder. Absorption of gepirone is increased when administered with food as there is no substantial change in Cmax and half-life but it significantly increases AUC and mean residence time. Gepirone undergoes first-pass metabolism and its major metabolites are 1- (2-pyrimidinyl)-piperazine (1-PP) and 3-OH-gepirone, both of which are pharmacologically active. In addition to its better efficacy, gepirone is well tolerated and the major adverse effects observed have been nausea, dizziness and lightheadedness. Evidence from preclinical and clinical studies revealed that gepirone could be a breakthrough therapeutic agent in the treatment of anxiety and MDD.

Electroanalytical identification of 25I-NBOH and 2C-I via differential pulse voltammetry: a rapid and sensitive screening method to avoid misidentification.

25I-NBOH is a new potent serotonin 5-HT2A receptor agonist recently identified in blotter paper seizures. This compound is a thermolabile molecule that undergoes degradation under routine gas chromatography-mass spectrometry analysis leading to misidentification. In this paper, the voltammetric behavior of 25I-NBOH and 2C-I was investigated and their electroanalytical characteristics were determined. A novel, fast and sensitive electrochemical method for the detection of 25I-NBOH using a SPCE is described and all method characteristics demonstrated the method to be analytically valuable. This method is selective and achieves full differentiation between 25I-NBOH, 2C-I and 25I-NBOMe.

Correction of pain-related and affective behavior by combination of fluoxetine and buspirone in prenatally stressed rats

The inhibitor of serotonin (5-HT) reuptake fluoxetine does not cause any improvement in every patient suffering from depression; moreover, fluoxetine during pregnancy disrupts the normal development of the fetus. Clinical observations in adult patients suggest that treatment of depression with a combination of fluoxetine and 5-HT1A receptor agonists has a higher therapeutic effect than the effect of a single fluoxetine. In the present study, the effect of chronic management of the combination of fluoxetine and a 5-HT1A receptor agonist anxiolytic buspirone was examined in order to correct the adverse effects of prenatal stress on pain and affective behavior in the female offspring during the prepubertal period of development. It was found that the immobilization stress of rat dams in the last third of pregnancy (the stress of rat dams during pregnancy is used as a model of human depression) caused in the offspring the increased functional activity of the pain system, an increase in the level of depressive-like behavior. Chronic administration to pregnant dams of fluoxetine, buspirone, or their combination has improved the characteristics under study in the female offspring. The results indicate that the chronic administration of a combination of fluoxetine and buspirone during the gestation of rat dams neutralized the negative effect of prenatal stress in female offspring. More effective action of the combination of the drugs compared with the action of fluoxetine was revealed in the pain sensitivity to thermal stimulus and in the first acute phase of pain behavior in the formalin test. Undesirable deviations in the investigated types of behavior in female rats subjected to pharmacological effects of each of the drugs during the prenatal period were not revealed.

Activation of somatodendritic 5-HT1A autoreceptors reduces the acquisition and expression of cued fear in the rat fear-potentiated startle test

RationaleFear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT)1A receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT1A autoreceptors and post-synaptic 5-HT1A heteroreceptors in fear conditioning is still unclear.ObjectiveTo determine the role of pre- and post-synaptic 5-HT1A receptors in the acquisition and expression of cued and contextual conditioned fear.MethodsWe studied the acute effects of four 5-HT1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT1A receptors biased agonists F13714 (0–0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT1A autoreceptors, or F15599 (0–0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT1A heteroreceptors, with the prototypical 5-HT1A receptor agonist R(+)8-OH-DPAT (0–0.3 mg/kg, SC) or the 5-HT1A receptor antagonist WAY100,635 (0–1.0 mg/kg, SC).ResultsF13714 (0.16 mg/kg) and R(+)-8-OH-DPAT (0.03 mg/kg) injected before training reduced cued fear acquisition. Pre-treatment with F15599 or WAY100,635 had no effect on fear learning. In the fear-potentiated startle test, F13714 (0.04–0.16 mg/kg) and R(+)-8-OH-DPAT (0.1–0.3 mg/kg) reduced the expression of cued and contextual fear, whereas F15599 had no effect. WAY100,635 (0.03–1.0 mg/kg) reduced the overall startle response.ConclusionsThe current findings indicate that activation of somatodendritic 5-HT1A autoreceptors reduces cued fear learning, whereas 5-HT1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT1A heteroreceptors in the expression of conditioned fear.

5-HT1A Receptor Function Makes Wound Healing a Happier Process.

Skin wound healing is a multistage phenomenon that is regulated by cell–cell interplay and various factors. Endogenous serotonin is an important neurotransmitter and cytokine. Its interaction with the serotonin 1A receptor (5-HTR1A) delivers downstream cellular effects. The role of serotonin (5-hydroxytryptamine, 5-HT) and the 5-HT1A receptor has been established in the regeneration of tissues such as the liver and spinal motor neurons, prompting the investigation of the role of 5-HT1A receptor in skin healing. This study assessed the role of 5-HT1A receptor in excisional wound healing by employing an excisional punch biopsy model on 5-Ht1a receptor knockout mice. Post-harvest analysis revealed 5-Ht1a receptor knockout mice showed impaired skin healing, accompanied by a greater number of F4/80 macrophages, which prolongs the inflammatory phase of wound healing. To further unravel this phenomenon, we employed the 5-HT1A receptor agonist [(R)-(+)-8-Hydroxy-DPAT hydrobromide] as a topical cream treatment in an excisional punch biopsy model. The 5-HT1A receptor agonist treated group showed a smaller wound area, scar size, and improved neovascularization, which contributed to improve healing outcomes as compared to the control. Collectively, these findings revealed that serotonin and 5-HT1A receptor play an important role during the healing process. These findings may open new lines of investigation for the potential treatment alternatives to improve skin healing with minimal scarring.

Evaluation of Isolated Vascular Response to 5HT1A, 5HT1B1D & 5HT2A Receptors Agonist & Antagonist in Chronic Endotoxemic Rats.

The main vascular feature in endotoxemia is impaired contractile responses to vasoactive agents. We study the aortic response to 5HT11 A, 5HT1B1D and 5HT2A receptors agonist and antagonist in chronic endotoxemic rats. Intraperitoneal injection of 1 mg/kg lipopolysaccharide for 5 days induced chronic endotoxemia. Control rats received intraperitoneal injection of 1 ml/kg saline for 5 days. Rats divided into 3 groups. In first, DOI2 hydrochloride used as an agonist and sarpogrelate hydrochloride as an antagonist of 5HT2A receptor. In second, (R)-(+)-8-OH-DPAT3 and WAY1001354 used as an agonist and antagonist of 5HT1A receptor respectively. In third, Zolmitriptan used as an agonist and GR127935 hydrochloride as an antagonist of 5HT1B1D receptor. Aorta Isolated for organ bath study. Real time-PCR5 and histopathological study examined receptors gene expression and protein localization. Cumulative 8-OH-DPAT caused relaxation in control aorta (EC506 7.79±21.35 and 8.53±10.74 with and without antagonist), which was enhanced in endotoxemia (EC50 6.35±8.48 and very wide±17.38 with and without antagonist). Cumulative zolmitriptan caused relaxation in control aorta (EC50 very wide±8.65 and 8.38±8.44 with and without antagonist), which was enhanced in endotoxemia (EC50 very wide±9.53 and 8.37±13.49 with and without antagonist). DOI hydrochloride contracted the control aorta (EC50 6.51±7.14 and 5.98±1.65 with and without antagonist), which was converted to relaxation in endotoxemic group (EC50 infinity±80.43 and 7.37±20.28 with and without antagonist). PCR studies revealed enhanced 5HT1A receptor and diminished 5HT1B1D and 5HT2A receptor genes expression, while histopathological studies showed inflamed, damaged endothelium in endotoxemic aorta. Our data supports enhanced vasodilation and impaired vasoconstriction during endotoxemia.

Vortioxetine: a novel antidepressant for the treatment of major depressive disorder

ABSTRACTIntroduction: Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder (MDD) in adults. It is formulated into tablets and has a dose range of 5–20 mg. The recommended starting dose is 10 mg administered orally once daily without the need for food.Areas covered: This review focuses on the preclinical and clinical discovery of vortioxetine. It analyzes the pharmacological, neurochemical, and behavioral mechanisms of the medication and how these contribute to its potential therapeutic advantages as described in published preclinical and clinical studies and product labels.Expert opinion: Vortioxetine displays high affinity for serotonin transporter (SERT), and serotonin 5-HT3, 5HT1A, 5HT7 receptors. Functional studies show that vortioxetine acts as a SERT blocker, a 5-HT3, 5-HT7 receptor antagonist, and a 5-HT1A receptor agonist. The drug is active in animal models predictive of antipsychotic and antidepressant activities and demonstrates procognitive effects in several animal models that assessed memory, cognition, and executive functions. Short- and long-term clinical trials demonstrated the clinical efficacy of vortioxetine in treating depressive symptoms and cognitive deficits in MDD patients. It also displays fairly benign safety and tolerability profiles. Vortioxetine’s unique psychopharmacological properties might contribute to an improved clinical outcome in MDD patient populations.

Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure.

Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset.

5-HT1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox

Serotonin syndrome is an adverse reaction due to increased serotonin (5-hydroxytryptophan: 5-HT) concentrations in the central nervous system (CNS). The full 5-HT1A receptor (5-HT1AR) agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) has been recognized to elicit traditional serotonergic behaviors. Treatment with 8-OH-DPAT selectively increased PKCδ expression out of PKC isoforms and 5-HT turnover rate in the hypothalamus of wild-type mice. Treatment with 8-OH-DPAT resulted in oxidative burdens, co-immunoprecipitation of 5-HT1AR and PKCδ, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT1AR or PKCδ in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT1AR antagonism (i.e., WAY100635), PKCδ inhibition (i.e., rottlerin and genetic depletion of PKCδ), or NADPH oxidase/p47phox inhibition (i.e., apocynin and genetic depletion of p47phox). However, WAY100635, apocynin, or rottlerin did not exhibit any additive effects against the protective effect by inhibition of PKCδ or p47phox. Furthermore, apocynin, rottlerin, or WAY100635 also significantly protected from pro-inflammatory/pro-apoptotic changes induced by 8-OH-DPAT. Therefore, we suggest that 8-OH-DPAT-induced serotonergic behaviors requires oxidative stress, pro-inflammatory, and pro-apoptotic changes, that PKCδ or p47phox mediates the serotonergic behaviors induced by 8-OH-DPAT, and that the inhibition of PKCδ-dependent p47phox activation is critical for protecting against serotonergic behaviors.

Oncotoxic Properties of Serotonin Transporter Inhibitors and 5-HT1A Receptor Ligands

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.

Sexual Dysfunction: Hypoactive Sexual Desire Disorder

Healthy female sexual functioning is driven by sexual desire. Sexual desire, traditionally defined as sexual thoughts and fantasies, is a natural life force and an art form affecting all aspects of a woman’s interpersonal and professional life. Virtually, all diagnostic categories of female sexual dysfunction, including arousal disorder, anorgasmia, and sexual pain disorder are linked to, caused by, or aggravated by loss of sexual desire. Decreased sexual desire is a diagnosis (hypoactive sexual desire disorder, HSDD) with its own International Classification of Diseases code (F52.0).. Impact is often subtle. HSDD may express as seemingly unrelated emotional disturbances that degrade life quality in family relationships, in the workplace, or both. For some women, it is severely distracting. The diagnosis of HSDD is made when symptoms are sufficient to cause distress. In older women, HSDD is heavily impacted by menopause-associated withdrawal of reproductive hormones, particularly testosterone and estradiol. HSDD greatly improves with transdermal replacement of these steroids. Side effects of transdermal hormones are minimal but response can be gratifying. In premenopausal women, HSDD behaves more as a psychoendocrine disorder that is responsive in some patients to flibanserin, a nonhormonal 5-HT1A receptor agonist. Side effects of flibanserin are significant but manageable. This review contains 12 figures, 6 tables, and references. Key Words: estradiol, flibanserin, hypoactive sexual desire disorder, menopause, selective serotonin reuptake inhibitors, sexual desire, sexuality, testosterone, transdermal, women

Involvement of 5-HT1A and 5-HT2A Receptors but Not α2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Cariprazine, an orally active and potent dopamine D3-preferring D3/D2 receptor partial agonist, is approved to treat adults with schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine also displays partial agonism at serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptors and antagonism at 5-HT2A and 5-HT2B receptors in vitro. The study objective was to determine whether cariprazine leads to functional alterations of monoamine systems in vivo via electrophysiological recordings from anesthetized rats. Dorsal raphe nucleus (DRN), locus coeruleus (LC), and hippocampus pyramidal neurons were recorded, and cariprazine was administered systemically or locally through iontophoresis. In the DRN, cariprazine completely inhibited the firing activity of 5-HT neurons, which was fully reversed by the 5-HT1A receptor antagonist, WAY100635. In the LC, cariprazine reversed the inhibitory effect of the preferential 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine, on norepinephrine (NE) neurons (ED50 = 66 µg/kg) but did not block the inhibitory effect of the α 2-adrenergic receptor agonist, clonidine. Cariprazine, iontophorized into the hippocampus, diminished pyramidal neuronal firing through activation of 5-HT1A receptors, while its concomitant administration did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acted as a 5-HT1A autoreceptor agonist in the DRN, a 5-HT2A receptor antagonist in modulating the firing activity of LC NE neurons, and a full agonist at 5-HT1A receptors mediating the electrophysiological effect of 5-HT on pyramidal neurons. The modulatory actions of cariprazine on these monoaminergic systems may contribute to its therapeutic effectiveness in patients with depressive episodes.

Involvement of 5-HT2A receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats

We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light–dark test. In addition, we examined the rats' 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.

Breathing stimulation mediated by 5-HT1A and 5-HT3 receptors within the preBötzinger complex of the adult rabbit

Serotonin (5-HT) has been reported to play excitatory effects on respiration by acting on preBötzinger complex (preBötC) neurons in neonatal or juvenile rodents. However, whether its action is circumscribed to the preBötC and present in other animal species, particularly in adult preparations, is unknown. We investigated the respiratory role of 5-HT within the preBötC and neighbouring respiration-related regions. Experiments were performed on α-chloralose-urethane anesthetized, vagotomized, paralyzed and artificially ventilated rabbits making use of bilateral microinjections (30–50 nl). 5-HT caused excitatory effects on respiratory activity only when applied to the preBötC. These effects were mediated by 5-HT1A and 5-HT3 receptors as shown by microinjections of specific agonists of the different types of 5-HT receptors. Unexpectedly, the blockade of 5-HT1A receptors by methysergide or the specific antagonist (S)-WAY 100135 induced excitatory respiratory effects. Microinjections of the 5-HT3 receptor antagonist ondansetron did not influence respiration, but prevented (S)-WAY 100135-induced responses. The blockade of GABAA receptors by bicuculline within the preBötC prevented the effects of the 5-HT1A receptor agonist 8-OH-DPAT. The involvement of GABAergic inhibition and 5-HT1A receptor-mediated disinhibition is also corroborated by immunohistochemical data. The results show for the first time in an adult animal preparation that 5-HT plays a pivotal role in the modulation of the preBötC activity probably via both presynaptic and postsynaptic mechanisms and highlight the importance of disinhibition phenomena. Present findings may be relevant to some respiratory disorders in which an impairment of central 5-HT mechanisms has been reported, such as sleep apnoea and sudden infant death syndrome.

Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model.

Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT1A receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) and the β3 subunit of γ-aminobutyric acid type A receptors (GABAAR) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC.

Critical roles of serotonin-oxytocin interaction during the neonatal period in social behavior in 15q dup mice with autistic traits

Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11–13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT1A receptor agonist 8OH-DPAT treatment from postnatal day 7 (PD7) to PD21 ameliorated social abnormality in the three-chamber social interaction test in adult 15q dup mice. The effect of 8OH-DPAT was inhibited by blockade of OXT receptors in 15q dup mice. Thus, serotonin-OXT interaction via 5-HT1A receptors plays a critical role in the normal development of social behavior in 15q dup mice. Therefore, targeting serotonin-OXT interaction may provide a novel therapeutic strategy for treatment of ASD.

Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice.

Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates. Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5mg/kg) or vehicle followed by MK801 (0.5mg/kg), PCP (7.5mg/kg), amphetamine (6mg/kg), scopolamine (2mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated. The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion. These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity.