mdl-100907 and Disease-Models--Animal

Agomelatine is a novel antidepressant that acts as a melatonin MT1 and MT2 receptor agonist and serotonin 5-HT2C receptor antagonist, putatively reversing circadian rhythm disruption in major depressive disorder (MDD) and promoting dendritic neurogenesis in animal models of depression. It may be a preferable alternative to antidepressants currently in use due to its improved tolerability profile.. The PubMed database was searched for published randomized controlled trials (RCTs) evaluating the efficacy of agomelatine as well as its tolerability and safety in the treatment of MDD. The key search term used was agomelatine combined with major depressive disorder/depressive disorder/depression and antidepressant. Article selection was based upon sample size and overall methodological quality.. Agomelatine is a multi-modal agent with novel mechanisms of action, having sound evidence supporting its overall statistical efficacy and adequate tolerability profile for MDD treatment. However, the clinical significance of agomelatine has been contested, calling for additional studies in evaluation of its effect size. Of further concern are reported transient elevations in transaminases and severe but rare liver reactions.

Topics: Acetamides; Animals; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Disease Models, Animal; Humans; Neurogenesis; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists

Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.

Topics: Acetamides; Animals; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Disease Models, Animal; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

Repeated administration of psychostimulants in rodents can enhance the stimulating effect on locomotor activity, a phenomenon called behavioral sensitization. This has been widely used as animal models for schizophrenia as well as addiction and psychosis, because of the similarity to its process in acquisition and progression. However, there are no studies demonstrating whether the drugs improve the psychostimulant-induced behavioral sensitization when administered after establishment of the sensitization, while previous studies have mainly focused on the analyses of the development (induction) phase of the sensitization. We demonstrated that the activation of serotonin (5-HT) receptors or blockade of 5-HT2 receptors, given after establishment of the sensitization, attenuates the expression of methamphetamine-induced behavioral sensitization in mice. In addition, we also showed that repeated administration of methamphetamine induces the increased reactivity of prefrontal serotonergic neurons specifically. These observations suggest that the 5-HT system is a neurochemical basis for the behavioral sensitization, and imply that 5-HT1A and 5-HT2 receptors may have potential therapeutic values in the remission of methamphetamine abuse or psychosis. Here, we provide an overview of the roles of serotonergic neurons in the psychostimulant-induced behavioral sensitization.

Topics: Animals; Central Nervous System Stimulants; Disease Models, Animal; Humans; Methamphetamine; Mice; Motor Activity; Neurons; Prefrontal Cortex; Psychoses, Substance-Induced; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Stimulation, Chemical; Substance-Related Disorders

Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT(1A)-receptor agonist, and ritanserin, a 5-HT(2)-receptor antagonist, inhibited the expression and development of both methamphetamine- and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT(3)-receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine- and cocaine-induced behavioral sensitization in mice and imply that 5-HT(1A)-receptor agonists and 5-HT(2)-receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Brain; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Dioxanes; Dioxoles; Disease Models, Animal; Ligands; Methamphetamine; Mice; Motor Activity; Oxazines; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists

The limitations of current antidepressant medications merit the exploration of alternative agents with novel antidepressant mechanisms of action. The established clinical finding that desynchronization of internal rhythms plays an important role in the pathophysiology of depressive disorders has stimulated the idea that resetting normal circadian rhythms may have antidepressant potential. Recent experiments using the novel melatonin receptor agonist and serotonin 2 (5-HT2c) receptor antagonist agomelatine (S20098; N[2-(7-methoxy-1-naphthyl)ethyl]- acetamide) revealed a notable chronobiotic activity and clear antidepressant-like effects in a variety of preclinical models. Binding studies performed in vitro proved that agomelatine is a high-affinity agonist at both the melatonin MT1 and MT2 receptor types. In addition, these studies revealed that agomelatine, in contrast to melatonin, blocks 5-HT2c receptors with significant affinity. Antagonism of 5-HT2c receptors is reported for various established antidepressant compounds. The antidepressant properties of agomelatine are thus based on its melatonergic actions and 5-HT2c receptor antagonism.

Topics: Acetamides; Animals; Antidepressive Agents; Biological Clocks; Brain; Depressive Disorder, Major; Disease Models, Animal; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Tupaiidae

The intimate relationship between depressive disorders and biological rhythm disturbances has long been known. One major component in diurnal rhythm regulation in mammals, like humans, is the melatonin axis and its close connections with serotonergic and noradrenergic structures. In major depression various functional anomalies have been shown in all of these systems. Agomelatine is a novel antidepressant with direct agonist activity at the melatonin MT1 and MT2 receptors, and a selective antagonist action at the serotonin 5HT2C receptor. It has no measurable affinity to any other known receptor. In animal models agomelatine has antidepressant-like and anxiolytic-like properties, it promotes sleep, and is able to resynchronize various experimentally uncoupled or phase-shifted biological rhythms. In randomized and controlled clinical trials agomelatine appears to be an effective antidepressant, comparable to standard SSRI/SNRI drugs, with excellent safety and tolerability profile. It usually produces mild and transient side effects, similar to those seen in patients receiving placebo. Sleep architecture and subjective measures of sleep quality may also respond favorably. Agomelatine causes significantly less sexual dysfunction than a reference SNRI. No discontinuation symptoms have been observed upon abrupt withdrawal. The overall dropout rates in the clinical trials have been remarkably low, suggesting good acceptability and compliance. Even though most current antidepressants are effective, they also have weaknesses; therefore we still need innovative drugs with novel biochemical actions, faster efficacy and/or better tolerability.

Topics: Acetamides; Animals; Anti-Anxiety Agents; Antidepressive Agents; Circadian Rhythm; Depressive Disorder, Major; Disease Models, Animal; Humans; Hypnotics and Sedatives; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Serotonin 5-HT2 Receptor Antagonists; Sleep

Topics: Animals; Antipsychotic Agents; Cholinergic Agonists; Disease Models, Animal; Dopamine Antagonists; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Mice; Mice, Transgenic; Nitric Oxide Synthase; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotensin; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists

Perseveration is a characteristic of patients with obsessive-compulsive disorder (OCD). Clinically, neuronal activity in the lateral orbitofrontal cortex (OFC) is increased in OCD patients. Successful treatment with selective serotonin reuptake inhibitors (SSRIs) reduces activity in the lateral OFC of OCD patients, but the precise mechanisms underlying this effect are unclear. Previously, we reported that repeated injection of the dopamine D

Topics: Animals; Behavior, Animal; Disease Models, Animal; Interneurons; Mice; Obsessive-Compulsive Disorder; Prefrontal Cortex; Pyramidal Cells; Receptor, Serotonin, 5-HT2C; Reversal Learning; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction

Psychedelic drugs acting as 5-hydroxyptryptamine 2A receptor (5-HT

Topics: Aminopyridines; Amphetamines; Animals; Behavior, Animal; Citalopram; Compulsive Behavior; Disease Models, Animal; Female; Fluorobenzenes; Indoles; Mice; Piperidines; Psilocybin; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Agonists; Serotonin Antagonists

Acute intermittent hypoxia (AIH) modifies the functioning of the respiratory network, causing respiratory motor facilitation in anesthetized animals and a compensatory increase in pulmonary ventilation in freely behaving animals. However, it is still unclear whether the ventilatory facilitation induced by AIH in unanesthetized animals is associated with changes in the respiratory pattern. We found that Holtzman male rats (80-150 g) exposed to AIH (10 × 6% O

Topics: Animals; Disease Models, Animal; Hypoxia; Ketanserin; Male; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Serotonin 5-HT2 Receptor Antagonists; Tidal Volume

Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT

Topics: Age Factors; Animals; Animals, Newborn; Antipsychotic Agents; Autoradiography; Behavior, Animal; Disease Models, Animal; Hippocampus; Prefrontal Cortex; Prepulse Inhibition; Rats; Receptor, Serotonin, 5-HT2A; Reflex, Startle; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Sexual Maturation

Cigarette smoke plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Recently, elevated serotonin (5-HT) levels were found in the plasma of COPD patients. The role of 5-HT and its receptors in airway inflammation and remodeling induced by cigarette smoke is unclear.. BALB/c mice received the 5-HTR2A inhibitor ketanserin, the 5-HTR2B inhibitor RS-127445 or the natural 5-HTR2A/2B inhibitor quercetin intraperitoneally, then were exposed to cigarette smoke for 6 or 12 weeks. Control mice received placebo and were exposed to room air or cigarette smoke. Mice were sacrificed and bronchial alveolar lavage fluid (BALF) and lung tissue samples were collected.. Immunohistochemistry and western blot confirmed an increase in both 5-HTR2A and 5-HTR2B expression in mouse lungs after exposure to cigarette smoke for 6 and 12 weeks. Cigarette smoke induced accumulation of macrophages and neutrophils and increased levels of inflammatory cytokines, including IL-1β and TNF-ɑ, in BALF and lung tissue; these effects were inhibited by ketanserin, RS-127445 and quercetin. Pretreatment with 5-HT receptor antagonists suppressed the goblet cell hyperplasia induced by 6- or 12-week exposure to cigarette smoke, based on Alcian blue-periodic acid Schiff staining. After 12 weeks of cigarette smoke exposure, Masson's staining showed fibrosis surrounding the mouse airways, and inhibitor pretreatment significantly attenuated the thickening and collagen deposition around the small airways.. Our results suggest that cigarette smoke-induced airway inflammation and small airway remodeling are partially mediated by 5-HTR2A and 5-HTR2B, which could be a new therapeutic target for airway remodeling in COPD.

Topics: Airway Remodeling; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Humans; Injections, Intraperitoneal; Ketanserin; Lung; Male; Mice; Mucus; Nicotiana; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Quercetin; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Respiratory Mucosa; Serotonin 5-HT2 Receptor Antagonists; Smoke; Specific Pathogen-Free Organisms

Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action.. Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration.. Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA.. Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.

Topics: Animals; Benzazepines; Cocaine; Disease Models, Animal; Dopamine Antagonists; Dopamine Uptake Inhibitors; Haloperidol; Hyperthermia; Ketanserin; Male; Rats; Rats, Wistar; Risperidone; Ritanserin; Serotonin 5-HT2 Receptor Antagonists

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Chronic Pain; Disease Models, Animal; Fluorobenzenes; Male; Mice; Neuralgia; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT

Topics: Amygdala; Animals; Disease Models, Animal; Gene Knockdown Techniques; Male; Neuralgia; Neurons; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Corticotropin-Releasing Hormone; Serotonin 5-HT2 Receptor Antagonists

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.

Topics: Animals; Aorta; Disease Models, Animal; Endotoxemia; Humans; Lipopolysaccharides; Male; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5-HT). Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HT. Compared with NC rats, the SCI rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HT. In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT

Topics: Animals; Chronic Disease; Disease Models, Animal; Female; Injections, Intravenous; Injections, Spinal; Lumbosacral Region; Motor Neurons; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Reference Values; Serotonin 5-HT2 Receptor Antagonists; Spinal Cord Injuries; Up-Regulation; Urination; Urodynamics

Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia.. To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice.. The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT. The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT

Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Drugs, Chinese Herbal; Fear; Fluvoxamine; Male; Mice, Inbred ICR; Motor Activity; Prefrontal Cortex; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction

As a monoamine neurotransmitter, 5-hydroxytryptamine (5-HT) or serotonin modulates mood, appetite, and sleep. Besides, 5-HT also has important peripheral functions. 5-HT receptor 2B (5-HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5-HT2BR in neointimal hyperplasia, a key pathological process in restenosis.. The expression of 5-HT2BR was upregulated in wire-injured mouse femoral arteries. In addition, BW723C86, a selective 5-HT2BR agonist, promoted the injury response during restenosis. 5-HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5-HT-induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5-HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a β-arrestin2-dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5-HT2BR-mediated smooth muscle cell migration. Mice with deficiency of. These results demonstrated that activation of 5-HT2BR and β-arrestin2-biased downstream signaling are key pathological processes in neointimal formation, and 5-HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.

Topics: Animals; beta-Arrestin 2; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Femoral Artery; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Organic Chemicals; Rats; Receptor, Serotonin, 5-HT2B; Ribosomal Protein S6 Kinases, 70-kDa; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Remodeling; Vascular System Injuries

The fruit of Vaccinium bracteatum Thunb. (VBF) is commonly known as the oriental blueberry in Korea. The aim of this study was to evaluate the antidepressant-like effects of water VBF extract (VBFW) in a mouse model of chronic restraint stress (CRS) and to identify the underlying mechanisms of its action. The behavioral effects of VBFW were assessed in the forced swim test (FST) and open field test (OFT). The levels of serum corticosterone (CORT), brain monoamines, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway were evaluated. VBFW treatment significantly reduced the immobility time and increased swimming time in FST without altering the locomotor activity in unstressed mice. Furthermore, CRS mice treated with VBFW exhibited a significantly decreased immobility time in FST and serum CORT, increased locomotor activity in OFT, and enhanced brain monoamine neurotransmitters. Similarly, VBFW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and PFC. In addition, VBFW may reverse CORT-induced cell death by enhancing cyclic AMP-responsive element-binding protein expression through the up-regulation of ERKs/Akt signaling pathways. In addition, VBFW showed the strong antagonistic effect of the 5-HT[Formula: see text] receptor by inhibiting 5-HT-induced intracellular Ca[Formula: see text] and ERK1/2 phosphorylation. Our study provides evidence that antidepressant-like effects of VBFW might be mediated by the regulation of monoaminergic systems and glucocorticoids, which is possibly associated with neuroprotective effects and antagonism of 5-HT[Formula: see text] receptor.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Brain; Cells, Cultured; Chronic Disease; Corticosterone; Depression; Disease Models, Animal; Humans; Male; MAP Kinase Signaling System; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Rats; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological; Vaccinium myrtillus

In Prader-Willi syndrome (PWS), nonprotein coding small nucleolar (sno) RNAs are involved in the paternally deleted region of chromosome 15q11.2-q13, which is believed to cause the hyperphagic phenotype of PWS. Central to this is SnoRNA116. The supplement Caralluma fimbriata extract (CFE) has been shown to decrease appetite behavior in some individuals with PWS. We therefore investigated the mechanism underpinning the effect of CFE on food intake in the Snord116del mouse. Experiments utilized appetite stimulants which included a 5-hydroxytryptamine (5-HT) 2c receptor antagonist (SB242084), as the 5-HT2cR is implicated in central signaling of satiety.. Caralluma fimbriata extract administration decreased food intake more strongly in the SNO100CFE group with significantly stimulated food intake demonstrated during coadministration with SB242084. Though stimulatory deprivation was expected to stimulate food intake, 2DG and MA resulted in lower intake in the snord116del mice compared to the WT animals (p = <0.001). Immunohistochemical mapping of hypothalamic neural activity was consistent with the behavioral studies.. This study identifies a role for the 5-HT2cR in CFE-induced appetite suppression and significant stimulatory feeding disruptions in the snord116del mouse model.

Topics: Aminopyridines; Animals; Apocynaceae; Appetite Depressants; Chromosome Deletion; Disease Models, Animal; Eating; Female; Gene Deletion; Humans; Hypothalamus; Indoles; Male; Mice, Inbred C57BL; Phenotype; Phytotherapy; Plant Extracts; Prader-Willi Syndrome; Random Allocation; Receptor, Serotonin, 5-HT2C; RNA, Small Nucleolar; Serotonin 5-HT2 Receptor Antagonists

Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross-modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury. Serotonin (5-HT) is known to modulate sensory information processing and integration, but its impact on cortical reorganization after sensory loss, remains largely unexplored. To address this issue, we assessed the involvement of 5-HT in ME-induced cross-modal plasticity and the 5-HT receptor (5-HTR) subtype used. We first focused on establishing the impact of ME on the total 5-HT concentration measured in the visual cortex and in the somatosensory barrel field. Next, the changes in expression as a function of post-ME recovery time of the monoamine transporter 2 (vMAT2), which loads 5-HT into presynaptic vesicles, and of the 5-HTR

Topics: Aging; Animals; Disease Models, Animal; Eye Enucleation; Female; Male; Mice, Inbred C57BL; Neuronal Plasticity; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Receptors, Serotonin, 5-HT2; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Signal Transduction; Synapses; Time Factors; Vesicular Monoamine Transport Proteins; Visual Cortex

In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). As ASD is frequently associated with altered response to acute stress and stress may exacerbate repetitive behavior in ASD, we studied the Del mouse behavior in the context of an acute stress using the forced swim test, a paradigm well characterized with respect to serotonin. Del mice perseverated with active coping (swimming) in the forced swim test and failed to adopt passive coping strategies with time as did their wild-type littermates. Analysis of monoamine content by HPLC provided evidence for altered endogenous serotonin neurotransmission in Del mice while there was no effect of genotype on any other monoamine. Moreover, we found that Del mice were highly sensitive to the 5-HT2A antagonists M100907, which at a dose of 0.1 mg/kg normalized their level of active coping and restored the gradual shift to passive coping in the forced swim test. Supporting evidence for altered endogenous serotonin signaling was provided by observations of additional ligand effects including altered forebrain Fos expression. Taken together, these observations indicate notable changes in endogenous serotonin signaling in 16p11.2 deletion mice and support the therapeutic utility of 5-HT2A receptor antagonists.

Topics: Adaptation, Psychological; Animals; Autistic Disorder; Behavior, Animal; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 16; Disease Models, Animal; Fluorobenzenes; Intellectual Disability; Male; Mice; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Exploratory Behavior; Fluorobenzenes; Grooming; Male; Mice; Mice, Inbred Strains; Neostriatum; Piperidines; Prefrontal Cortex; Receptor, Serotonin, 5-HT2A; Reversal Learning; Serotonin 5-HT2 Receptor Antagonists; Stereotyped Behavior

Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon.. Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior.. Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning.. Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD.

Topics: Amygdala; Animals; Association Learning; Conditioning, Psychological; Disease Models, Animal; Dorsal Raphe Nucleus; Electroshock; Fear; Male; Memory Consolidation; Mice, Inbred C57BL; Mice, Transgenic; Models, Neurological; Models, Psychological; Neurons; Optogenetics; Receptor, Serotonin, 5-HT2C; Restraint, Physical; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Stress Disorders, Post-Traumatic; Stress, Psychological

Pulmonary fibrosis is characterized by excessive accumulation of connective tissue, along with activated extracellular matrix (ECM)-producing cells, myofibroblasts. The pathological mechanisms are not well known, however serotonin (5-HT) and 5-HT class 2 (5-HT2) receptors have been associated with fibrosis. The aim of the present study was to investigate the role of 5-HT2B receptors in fibrosis, using small molecular 5-HT2B receptor antagonists EXT5 and EXT9, with slightly different receptor affinity. Myofibroblast differentiation [production of alpha-smooth muscle actin (α-SMA)] and ECM synthesis were quantified in vitro, and the effects of the receptor antagonists were evaluated. Pulmonary fibrosis was also modeled in mice by subcutaneous bleomycin administrations (under light isoflurane anesthesia), and the effects of receptor antagonists on tissue density, collagen-producing cells, myofibroblasts and decorin expression were investigated. In addition, cytokine expression was analyzed in serum. Lung fibroblasts displayed an increased α-SMA (P < 0.05) and total proteoglycan production (P < 0.01) when cultured with TGF-β1 together with 5-HT, which were significantly reduced with both receptor antagonists. Following treatment with EXT5 or EXT9, tissue density, expression of decorin, number of collagen-producing cells, and myofibroblasts were significantly decreased in vivo compared to bleomycin-treated mice. Receptor antagonization also significantly reduced systemic levels of TNF-α and IL-1β, indicating a role in systemic inflammation. In conclusion, 5-HT2B receptor antagonists have potential to prevent myofibroblast differentiation, in vitro and in vivo, with subsequent effect on matrix deposition. The attenuating effects of 5-HT2B receptor antagonists on fibrotic tissue remodeling suggest these receptors as novel targets for the treatment of pulmonary fibrosis.

Topics: Animals; Bleomycin; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Humans; In Vitro Techniques; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Myofibroblasts; Proteoglycans; Pulmonary Fibrosis; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Tumor Necrosis Factor-alpha

There is emerging evidence for a dopamine (DA)-serotonin (5-HT) interaction underlying obsessive-compulsive disorder (OCD). In the quinpirole sensitization rat model of OCD, compulsive checking is induced by chronic treatment with the DA agonist quinpirole, and is attenuated by the 5-HT agonist drug mCPP. However, mCPP has affinity for a number of 5-HT receptor subtypes, and it is unknown by which receptors mCPP exerts its effects on quinpirole-treated animals. The present study tested in rats whether mCPP activity at 5-HT2A/C receptors mediates the attenuation of compulsive checking in quinpirole-treated animals. Rats were chronically treated with quinpirole on the open field for the induction of compulsive checking. Following the induction phase, animals were treated with mCPP (1.25 mg/kg) and the selective 5-HT2A/C receptor antagonist ritanserin (1 mg/kg or 5 mg/kg) to test whether blockade of 5-HT2A/C receptors inhibits attenuation of checking by mCPP. Results showed that as expected, quinpirole induced compulsive checking, and mCPP reduced its performance. However, 5-HT2A/C receptor blockade by ritanserin did not inhibit the attenuation of compulsive checking by mCPP. These results suggest that the reduction in compulsive checking by mCPP is not mediated by activity at 5-HT2A/C receptors, but by another receptor subtype.

Topics: Animals; Compulsive Behavior; Disease Models, Animal; Male; Obsessive-Compulsive Disorder; Piperazines; Quinpirole; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Ritanserin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists

Controlled, interventional, animal study.. To evaluate the effect of a 5-HT2A receptor antagonist on pain-related behavior, endogenous 5-hydroxytryptamine (5-HT) plasma levels, and expression of 5-HT2A receptors in dorsal root ganglia (DRGs) in a rat lumbar disc herniation model.. Application of nucleus pulposus on the nerve root induces immediate peripheral 5-HT production and the expression of 5-HT2A receptors in the adjacent DRG. However, the efficacy of a 5-HT2A receptor antagonist for pain relief in this situation and the mechanism remain unknown.. Autologous nucleus pulposus was applied to the left L5 nerve root of 91 adult female Sprague-Dawley rats. The selective 5-HT2A receptor antagonist sarpogrelate hydrochloride (SPG; 1 mg/kg or 10 mg/kg) or vehicle was administered orally once a day from 1 to 21 days postoperatively. Von Frey tests were used to test pain behavior before and after surgery. To assess the effect of SPG on endogenous 5-HT release surrounding the inflamed nerve root, we measured levels of 5-hydroxyindole acetic acid, a 5-HT metabolite, in plasma. Expression of 5-HT2A receptors in the left L5 DRG was examined with immunoblotting.. The higher dose (10 mg/kg) of SPG significantly improved the mechanical withdrawal thresholds from 5 to 21 days after surgery compared with vehicle treatment. 5-hydroxyindole acetic acid in plasma was not significantly different among any groups at any time points. Both doses of SPG inhibited the expression of 5-HT2A receptors after surgery compared with vehicle treatment.. A selective 5-HT2A receptor antagonist attenuated pain-related behavior and suppressed 5-HT2A receptor expression in the DRG, but did not affect peripheral 5-HT production. Selective 5-HT2A receptor antagonists may attenuate sciatica by blocking and downregulating 5-HT2A receptors in DRGs in lumbar disc herniation.. NA.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Female; Ganglia, Spinal; Intervertebral Disc Displacement; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Antagonists

Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats.

Topics: Animals; Antipsychotic Agents; Cells, Cultured; Cricetinae; Cricetulus; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Hyperkinesis; Male; Piperazines; Piperidines; Protein Binding; Rats, Sprague-Dawley; Receptors, Dopamine D3; Serotonin 5-HT2 Receptor Antagonists

Melatonin is an endogenous synchronizer of biological rhythms and a modulator of physiological functions and behaviors of all mammals. Reduced levels of melatonin and a delay of its nocturnal peak concentration have been found in alcohol-dependent patients and rats. Here we investigated whether the melatonergic system is a novel target to treat alcohol addiction. Male Wistar rats were subjected to long-term voluntary alcohol consumption with repeated abstinence phases. Circadian drinking rhythmicity and patterns were registered with high temporal resolution by a drinkometer system and analyzed by Fourier analysis. We examined potential antirelapse effect of the novel antidepressant drug agomelatine. Given that agomelatine is a potent MT1 and MT2 receptor agonist and a 5-HT2C antagonist we also tested the effects of melatonin itself and the 5-HT2C antagonist SB242084. All drugs reduced relapse-like drinking. Agomelatine and melatonin administered at the end of the light phase led to very similar changes on all measures of the post-abstinence drinking behavior, suggesting that effects of agomelatine on relapse-like behavior are mostly driven by its melatonergic activity. Both drugs caused a clear phase advance in the diurnal drinking pattern when compared with the control vehicle-treated group and a reduced frequency of approaches to alcohol bottles. Melatonin given at the onset of the light phase had no effect on the circadian phase and very small effects on alcohol consumption. We conclude that targeting the melatonergic system in alcohol-dependent individuals can induce a circadian phase advance, which may restore normal sleep architecture and reduce relapse behavior.

Topics: Acetamides; Alcohol Deterrents; Alcohol Drinking; Alcohol-Related Disorders; Aminopyridines; Animals; Choice Behavior; Circadian Rhythm; Disease Models, Animal; Indoles; Male; Melatonin; Motor Activity; Rats, Wistar; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists

To determine if sarpogrelate, a selective 5-HT2A receptor antagonist, is protective against light-induced retinopathy in BALB/c mice.. BALB/c mice were dosed intraperitoneally with 5, 15, 30, 40, or 50 mg/kg sarpogrelate 48, 24, and 0 hours prior to bright light exposure (10,000 lux) as well as 24 and 48 hours after exposure. Additionally, a single injection regimen was evaluated by injecting mice with 50 mg/kg sarpogrelate once immediately prior to light exposure. To investigate the potential for additive effects of serotonin receptor agents, a combination therapy consisting of sarpogrelate (15 mg/kg) and 8-OH-DPAT (1 mg/kg) was evaluated with the 5-day treatment regimen. Neuroprotection was characterized by the preservation of retinal thickness and function, measured by spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG), respectively.. Mice that were light damaged and injected with saline had significantly reduced outer retinal thickness, total retinal thickness, and ERG amplitudes compared with naïve mice. A 5-day administration of 15, 30, or 40 mg/kg of sarpogrelate was able to partially protect retinal morphology and full protection of retinal morphology was achieved with a 50 mg/kg dose. Both 15 and 30 mg/kg doses of sarpogrelate partially preserved retinal function measured by ERG, whereas 40 and 50 mg/kg doses fully preserved retinal function. Additionally, a single administration of 50 mg/kg sarpogrelate was able to fully preserve both retinal morphology and function. Administration of 15 mg/kg of sarpogrelate and 1 mg/kg of 8-OH-DPAT together demonstrated an additive effect and fully preserved retinal morphology.. A 5- or 1-day treatment with 50 mg/kg sarpogrelate can completely protect the retina of BALB/c mice from light-induced retinopathy. Partial protection can be achieved with lower doses starting at 15 mg/kg and protection increases in a dose-dependent manner. Treatment with low doses of sarpogrelate and 8-OH-DPAT elicits an additive effect that results in full protection of retinal morphology.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Disease Models, Animal; Electroretinography; Injections, Intraperitoneal; Light; Mice; Mice, Inbred BALB C; Radiation Injuries, Experimental; Radiation-Protective Agents; Retina; Retinal Degeneration; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Succinates; Tomography, Optical Coherence

The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Female; Glutamic Acid; Mice; Mice, Inbred BALB C; Mice, Transgenic; Nerve Net; Serotonin 5-HT2 Receptor Antagonists; Somatosensory Cortex; Thalamic Nuclei; Tics; Tourette Syndrome

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Chronic Disease; Citalopram; Cyclic AMP Response Element-Binding Protein; Depressive Disorder; Disease Models, Animal; Elongation Factor 2 Kinase; Female; Mice, Inbred BALB C; Olfactory Bulb; Prefrontal Cortex; Pyramidal Cells; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine D1; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological; Time Factors; TOR Serine-Threonine Kinases

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating "higher order" RRBs, for example cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach, as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present study investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved probabilistic reversal learning performance in the BTBR T + tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects.

Topics: Animals; Antipsychotic Agents; Autistic Disorder; Disease Models, Animal; Fluorobenzenes; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Piperidines; Probability Learning; Receptor, Serotonin, 5-HT2A; Reversal Learning; Risperidone; Serotonin 5-HT2 Receptor Antagonists

Stress-induced alterations in neuronal plasticity and in hippocampal functions have been suggested to be involved in the development of mood disorders. In this context, we investigated in the hippocampus the activation of intracellular signaling cascades, the expression of epigenetic markers and plasticity-related genes in a mouse model of stress-induced hyperactivity and of mixed affective disorders. We also determined whether the antidepressant drug agomelatine, a MT1/MT2 melatonergic receptor agonist/5-HT2C receptor antagonist, could prevent some neurobiological and behavioral alterations produced by stress. C57BL/6J mice, exposed for 3 weeks to daily unpredictable socio-environmental stressors of mild intensity, were treated during the whole procedure with agomelatine (50 mg kg(-1) per day, intraperitoneal). Stressed mice displayed robust increases in emotional arousal, vigilance and motor activity, together with a reward deficit and a reduction in anxiety-like behavior. Neurobiological investigations showed an increased phosphorylation of intracellular signaling proteins, including Atf1, Creb and p38, in the hippocampus of stressed mice. Decreased hippocampal level of the repressive epigenetic marks HDAC2 and H3K9me2, as well as increased level of the permissive mark H3K9/14ac suggested that chronic mild stress was associated with increased gene transcription, and clear-cut evidence was further indicated by changes in neuroplasticity-related genes, including Arc, Bcl2, Bdnf, Gdnf, Igf1 and Neurod1. Together with other findings, the present data suggest that chronic ultra-mild stress can model the hyperactivity or psychomotor agitation, as well as the mixed affective behaviors often observed during the manic state of bipolar disorder patients. Interestingly, agomelatine could normalize both the behavioral and the molecular alterations induced by stress, providing further insights into the mechanism of action of this new generation antidepressant drug.

Topics: Acetamides; Affective Symptoms; Animals; Antidepressive Agents; Behavior, Animal; Depression; Disease Models, Animal; Epigenesis, Genetic; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Psychomotor Agitation; Receptors, Melatonin; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Stress, Psychological

Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Down Syndrome; Gene Expression; Mice; Nesting Behavior; Phenotype; Receptor, Serotonin, 5-HT2A; Risperidone; Serotonin 5-HT2 Receptor Antagonists

Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Topics: Age Factors; Analysis of Variance; Animals; Aorta; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Echocardiography; Fluorobenzenes; Gene Expression Regulation; Hemodynamics; Histone Deacetylases; Male; Mice; Mice, Inbred C57BL; Myocardium; Piperidines; Receptor, Serotonin, 5-HT2A; RNA, Messenger; Serotonin Antagonists

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment (P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment (P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment (P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model.

Topics: Adult; Animals; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Familial Primary Pulmonary Hypertension; Fetus; Gene Expression; Humans; Hypertension, Pulmonary; Infant, Newborn; Ketanserin; Lung; Pulmonary Artery; Receptor, Serotonin, 5-HT2A; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Sertraline; Sheep, Domestic; Tryptophan Hydroxylase; Vascular Resistance

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control.

Topics: Aminopyridines; Animals; Atomoxetine Hydrochloride; Disease Models, Animal; Impulsive Behavior; Indoles; Inhibition, Psychological; Male; Methylphenidate; Mice; Prefrontal Cortex; Propylamines; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists

Desvenlafaxine succinate (DVS) is a novel serotonin and norepinephrine reuptake inhibitor. The aim of this study was to investigate the effects of DVS on visceral hypersensitivity and solid gastric emptying in a rodent model of gastric hyperalgesia. Twenty-eight gastric hyperalgesia rats and 20 control rats were used. Visceral sensitivity during gastric distention (GD) was assessed by recording of electromyogram (EMG) at pressures of 20, 40, 60, and 80 mmHg. DVS with doses of 1, 10, and 30 mg/kg were administrated by gavage, 5-HT1A antagonist (WAY-100635, 0.3 mg/kg) was given subcutaneously, and 5-HT2A antagonist (ketanserin, 1 mg/kg) was given intraperitoneally. The level of norepinephrine in plasma was measured by enzyme-linked immunosorbent assay. We found that 1) visceral hypersensitivity induced by acetic acid was validated. 2) DVS dose-dependently reduced visceral hypersensitivity in the gastric hypersensitivity rats. The EMG (% of baseline value without GD) during GD at 60 and 80 mmHg with DVS at a dose of 30 mg/kg were 119.4 ± 2.3% (vs. saline 150.9 ± 2.7%, P < 0.001) and 128.2 ± 3.2% (vs. saline 171.1 ± 2.4%, P < 0.001). Similar findings were observed at a dose of 10 mg/kg. DVS at a dose of 1 mg/kg reduced visceral hypersensitivity only during GD at 60 mmHg. 3) Neither WAY-100635 nor ketanserin blocked the effect of DVS on visceral sensitivity. 4) DVS at 30 mg/kg significantly increased plasma NE level (P = 0.012 vs. saline). 5) DVS at 30 mg/kg significantly delayed solid gastric emptying (P < 0.05 vs. saline). We conclude that DVS reduces visceral sensitivity in a rodent model of visceral hypersensitivity and delays solid gastric emptying. Caution should be made when DVS is used for treating patients.

Topics: Acetic Acid; Administration, Oral; Adrenergic Uptake Inhibitors; Animals; Cyclohexanols; Desvenlafaxine Succinate; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Gastric Emptying; Gastroparesis; Hyperalgesia; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mechanotransduction, Cellular; Norepinephrine; Pain Measurement; Pain Threshold; Pressure; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Stomach; Stomach Ulcer

The anticompulsive potential of agomelatine, a potent MT1/2 receptor agonist, and its combined effect with m-chlorophenylpiperazine hydrochloride (mCPP), bicuculline, and diazepam, were investigated in male C57BLJ/6 mice using marble-burying behavior (MBB) test. Acute administration of agomelatine (30-40 mg/kg, intraperitoneal (i.p.)) significantly inhibited the MBB in mice without influencing their locomotor activity. Further, chronic (28 days) administration of lower doses of agomelatine (10 and 20 mg/kg, i.p.) dose-dependently reduced the MBB without influencing their locomotor activity. Interaction studies revealed that pretreatment with mCPP (0.5 mg/kg, i.p.), a serotonin 5HT2C agonist, partially attenuated the anticompulsive effect of agomelatine (30 mg/kg). Further, a GABAA receptor agonist (diazepam, 1.25 mg/kg, i.p.) and antagonist (bicuculline, 1 mg/kg, i.p.) had no influence on the effects of agomelatine on MBB and locomotor activity. The doses of modulators were selected on the basis of dose-response studies. The results indicate that agomelatine has a potent anticompulsive effect that can be attributed to 5HT2C antagonism and MT1/2 agonism, and is certainly not mediated via its effects on the GABAergic system. Thus, the study adds to the growing literature on the psychopharmacological effects of agomelatine, and warrants further exploration in multiple paradigms.

Topics: Acetamides; Animals; Antidepressive Agents; Behavior, Animal; Bicuculline; Diazepam; Disease Models, Animal; Drug Interactions; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obsessive-Compulsive Disorder; Piperazines; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Disrupting the interaction between the PDZ protein PSD-95 and the C-terminal domain of the 5-HT2A serotonin receptor has been shown to reduce hyperalgesia in a rodent model of neuropathic pain. Here, we designed and synthesized PDZ ligands capable of binding to the first PDZ domain (PDZ1) of the PSD-95 protein and evaluated their biological activity in vitro and in vivo. A series of substituted indoles was identified by docking simulations, and six novel analogues were synthesized. Three analogues displayed strong interactions with the first PDZ domain (PDZ1) of PDZ-95 in (1)H-(15)N heteronuclear single-quantum coherence (HSQC) experiments and two of them were able to inhibit the interaction between PSD-95 and the 5-HT2A receptor in vitro. We identified compound 8b as the analogue able to significantly suppress mechanical hyperalgesia in an experimental model of traumatic neuropathic pain in the rat. This effect was suppressed by the coadministration of the 5-HT2A receptor antagonist M100907, consistent with an inhibitory effect upon 5-HT2A receptor/PSD-95 interaction. Finally, we determined an NMR-restraint driven model structure for the PSD95 PDZ1/8b complex, which confirms that indole 8b binds to the putative PDZ-ligand binding site.

Topics: Amino Acid Sequence; Analgesics; Animals; Computer Simulation; Disease Models, Animal; Hyperalgesia; Ligands; Magnetic Resonance Spectroscopy; Molecular Structure; PDZ Domains; Rats; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Structure-Activity Relationship

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α(1), α(2c), 5-HT(2A) 5-HT₇, moderate affinity for adrenergic α(2a) and D₂ receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT₇ receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antipsychotic Agents; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Investigational; Male; Memory, Short-Term; Mice; Mice, Inbred Strains; Nootropic Agents; Piperidines; Pyridazines; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Olfactory bulbectomy (OBX) in rodents represents a valuable experimental model of depression. This study was designed to shed further light on the impact of putative serotonergic neuronal degeneration in OBX mice and to assess the effect of a widely used antidepressant on serotonergic related behavioral changes induced by OBX.. Adult male ddY mice were subject to bilateral OBX or sham surgery. The serotonin (5-HT)(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) enhanced a head-twitch response (HTR) in OBX mice. Effects of 5-HT(2A), 5-HT(2C) antagonists and fluvoxamine were observed in OBX mice following DOI administration.. The HTR elicited by the administration of DOI (0.5 mg/kg and 1 mg/kg, i.p.) was increased about twofold in OBX mice when compared with controls on the 14th day after the surgery. The injection of ketanserin (0.025 mg/kg, i.p.), a 5-HT(2A) receptor antagonist, inhibited the enhancement of the DOI-induced HTR after OBX. Likewise, the administration of SB 242084 (1 mg/kg, s.c.), a 5-HT(2C) receptor antagonist, also inhibited the DOI-induced HTR in OBX mice. Chronic but not acute treatment with the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), suppressed the enhancement of DOI-induced HTR after OBX.. These findings indicate that OBX, and the subsequent degeneration of neurons projecting from the olfactory bulb, caused a supersensitivity of 5-HT(2A/2C) receptors which may be involved in symptoms of depression.

Topics: Amphetamines; Animals; Behavior, Animal; Depressive Disorder; Disease Models, Animal; Fluvoxamine; Head Movements; Male; Mice; Olfactory Bulb; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists

In rats, quinpirole, a dopaminergic D2/D3 receptor agonist, elicits both hyperdipsia and water "contrafreeloading" (CFL), a putative model of compulsivity. The role of D3 receptors in this effect remains unclear. Clomipramine (CIM) was found to contrast both hyperdipsia and CFL, but the role of serotonin in this effect requires further investigation.. We studied the effects of the preferential D3 agonist pramipexole (PPX) in both models. Furthermore, we tested the sensitivity of PPX-induced CFL to CIM and to the 5HT2c antagonist SB242084.. In experiment 1, drinking was measured at 2 and 5 h after eight daily injections of PPX (0 to 1.0 mg/kg intraperitoneally). In the CFL study, every other third lever press, the rat was reinforced by the delivery of water. On days 1-6, water was only available upon lever pressing. On days 7-15, choice between response-contingent and free access was provided. PPX doses as in the experiment 1 were given. In two further experiments, PPX (0.5 mg/kg) was administered alone or in combination with CIM (5 or 10 mg/kg) or SB242084 (0.3 or 1.0 mg/kg).. PPX did not produce hyperdipsia but enhanced spontaneous CFL. SB242084 attenuated PPX-induced CFL more effectively than CIM, restoring the preference for free access to water.. CFL, but not polydipsia, was induced by preferential D3 activation, an effect prevented by 5HT2c receptor blockade. Since PPX interferes with decision making and 5HT2c receptor supersensitivity is involved in the expression of compulsive behaviors, this study supports the compulsive nature of dopaminergic-induced CFL.

Topics: Aminopyridines; Animals; Benzothiazoles; Compulsive Behavior; Disease Models, Animal; Dopamine Agonists; Drinking; Indoles; Male; Pramipexole; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; Reinforcement Schedule; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Decreased pulmonary artery smooth muscle cell (PASMC) apoptosis play a key role in pulmonary artery remodeling during pulmonary artery hypertension (PAH), but the mechanisms involved are unclear. Serotonin (5-HT) inhibits apoptosis in many pathologic processes by activating the 5-HT2A receptor. Therefore, we hypothesized that 5-HT may be the promoter of decreased apoptosis in PAH through the 5-HT2A receptor. We found that inhibition of the 5-HT2A receptor prevented the increase in pulmonary artery pressure and pulmonary artery remodeling in rats stimulated by monocrotaline. This effect was accompanied by increased apoptosis in the pulmonary artery. Cultured PASMCs stimulated with 5-HT showed a decrease in apoptosis with increased phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), pyruvate dehydrogenase kinase (PDK), and mitochondrial transmembrane potential. These effects were markedly prevented by a 5-HT2A receptor inhibitor, an ERK1/2 activation inhibitor peptide I, or a PDK inhibitor. In conclusion, 5-HT inhibited PASMC apoptosis by activating the 5-HT2A receptor through the pERK1/2 and PDK pathways.5-HT decreasing apoptosis through 5-HT2A receptor is involved, at least in part, in pulmonary artery remolding.

Topics: Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Ketanserin; Male; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Muscle, Smooth, Vascular; Protein Serine-Threonine Kinases; Pulmonary Artery; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Antagonists

The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD.. Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence.. Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence.. These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Male; Obsessive-Compulsive Disorder; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists

Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse behavioural deficits related to depression/anxiety compared to the classical selective serotonin reuptake inhibitor, fluoxetine. Adult mice were treated for 8 wk with either vehicle or corticosterone (35 μg/ml.d) via drinking water. During the final 4 wk, animals were treated with vehicle, agomelatine (10 or 40 mg/kg i.p.) or fluoxetine (18 mg/kg i.p.) and tested in several behavioural paradigms and also evaluated for home-cage activity. Our results showed that the depressive/anxiety-like phenotype induced by corticosterone treatment is reversed by either chronic agomelatine or fluoxetine treatment. Moreover, agomelatine increased the dark/light ratio of home-cage activity in vehicle-treated mice and reversed the alterations in this ratio induced by chronic corticosterone, suggesting a normalization of disturbed circadian rhythms. Finally, we investigated the effects of this new antidepressant on neurogenesis. Agomelatine reversed the decreased cell proliferation in the whole hippocampus in corticosterone-treated mice and increased maturation of newborn neurons in both vehicle- and corticosterone-treated mice. Overall, the present study suggests that agomelatine, with its distinct mechanism of action based on the synergy between the melatonergic agonist and 5-HT2C antagonist properties, provides a distinct antidepressant/anxiolytic spectrum including circadian rhythm normalization.

Topics: Acetamides; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Cell Proliferation; Circadian Rhythm; Corticosterone; Dendrites; Depressive Disorder; Disease Models, Animal; Fluoxetine; Hippocampus; Male; Mice, Inbred C57BL; Motor Activity; Neurogenesis; Neurons; Serotonin 5-HT2 Receptor Antagonists

The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.

Topics: Amphetamine; Animals; Animals, Outbred Strains; Cognition; Disease Models, Animal; Fluorobenzenes; Locomotion; Male; Phencyclidine; Phenols; Piperidines; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Recognition, Psychology; Serotonin Antagonists; Sulfonamides

To determine the effect of non-selective 5-HT2C antagonist mesulergine and 5-HT2C agonist mCPP (metachlorophenylpiperazine) on learning acquisition (LA), short-term memory (STM) and long-term memory (LTM).. Experimental study.. Department of Biochemistry, University of Karachi, from December 2009 to June 2010.. Twenty-four male albino Wistar rats were used in this study. The agonist and antagonist (mCPP and mesulergine) were injected intraperitoneally at a dose 3.0 mg/kg in volumes of 1 ml/kg. Control animals were injected with saline (1 ml/kg). Animals were randomly divided into four groups (n=6). 1st being control group, 2nd being mCPP injected group, 3rd being mesulergine injected group and 4th group being injected with both mesulergine and mCPP. Behavioural activities of rats were monitored after 30 minutes of injection. For assessment of memory functions, water maze apparatus was used.. Administration of mCPP impaired STM, LTM and LA of rats. Mesulergine injected rats exhibited no alteration in memory functions. However, when it was injected with mCPP then there were no memory deficits induced by mCPP.. Ability of 5-HT2C receptor antagonist mesulergine to block the memory impairment effect of mCPP indicated an important regulatory role of 5-HT2C receptors in cognitive processes.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Ergolines; Male; Maze Learning; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Piperazines; Random Allocation; Rats; Rats, Wistar; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Our previous study has demonstrated that topical and systemic administration of the 5-HT(2A) receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3 mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT(2A) receptors in neuropathic pain and (3) the blockade of 5-HT(2A) receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain.

Topics: Animals; Calcitonin Gene-Related Peptide; Denervation; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Immunohistochemistry; Ketanserin; Male; Neuralgia; Neuronal Plasticity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Spinal Cord; Spinal Nerves; Up-Regulation

Acute intermittent hypoxia [AIH; 3, 5-min episodes; 35-45 mmHg arterial PO(2) (Pa(O(2)))] elicits serotonin-dependent phrenic long-term facilitation (pLTF), a form of phrenic motor facilitation (pMF) initiated by G(q) protein-coupled metabotropic 5-HT(2) receptors. An alternate pathway to pMF is induced by G(s) protein-coupled metabotropic receptors, including adenosine A(2A) receptors. AIH-induced pLTF is dominated by the serotonin-dependent pathway and is actually restrained via inhibition from the adenosine-dependent pathway. Here, we hypothesized that severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent form of pMF. pLTF induced by severe (25-30 mmHg Pa(O(2))) and moderate (45-55 mmHg Pa(O(2))) AIH were compared in anesthetized rats, with and without intrathecal (C4) spinal A(2A) (MSX-3, 130 ng/kg, 12 μl) or 5-HT receptor antagonist (methysergide, 300 μg/kg, 15 μl) injections. During severe, but not moderate AIH, progressive augmentation of the phrenic response during hypoxic episodes was observed. Severe AIH (78% ± 8% 90 min post-AIH, n = 6) elicited greater pLTF vs. moderate AIH (41% ± 12%, n = 8; P < 0.05). MSX-3 (28% ± 6%; n = 6; P < 0.05) attenuated pLTF following severe AIH, but enhanced pLTF following moderate AIH (86% ± 26%; n = 8; P < 0.05). Methysergide abolished pLTF after moderate AIH (12% ± 5%; n = 6; P = 0.035), but had no effect after severe AIH (66 ± 13%; n = 5; P > 0.05). Thus severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent mechanism; the adenosinergic pathway inhibits the serotonergic pathway following moderate AIH. Here we demonstrate a novel adenosine-dependent pathway to pLTF following severe AIH. Shifts in the mechanisms of respiratory plasticity provide the ventilatory control system greater flexibility as challenges that differ in severity are confronted.

Topics: Acute Disease; Adenosine; Adenosine A2 Receptor Antagonists; Animals; Blood Pressure; Carbon Dioxide; Disease Models, Animal; Hypoxia; Injections, Spinal; Lung; Male; Neuronal Plasticity; Oxygen; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptors, Serotonin, 5-HT2; Respiration; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Time Factors

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT(2A) serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid β(25-35) peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT(2A) receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid β might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT(2A) inverse agonist. This in turn suggests that 5-HT(2A) inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients.

Topics: Alzheimer Disease; Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Drug Inverse Agonism; Male; Mice; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP) because of Fmr1 gene silencing. Serotonin (5-HT) is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR) is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5-HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca(2+) concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation.

Topics: Animals; Blotting, Western; Cells, Cultured; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gyrus Cinguli; Humans; Ketanserin; Long-Term Potentiation; Male; Mice; Mice, 129 Strain; Mice, Knockout; Patch-Clamp Techniques; Pyrrolidines; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Serotonin 5-HT2 Receptor Antagonists; Synaptic Potentials

Although 5HT(2A) receptors mediate contractions of normal arteries to serotonin (5HT), in some cardiovascular diseases, other receptor subtypes contribute to the marked increase in serotonin contractions. We hypothesized that enhanced contractions of arteries from diabetics to 5HT are mediated by an increased contribution from multiple 5HT receptor subtypes. We compared responses to selective 5HT receptor agonists and expression of 5HT receptor isoforms (5HT(1B), 5HT(2A), and 5HT(2B)) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7(m)+/+Lepr(db)/J). 5HT, 5HT(2A) (TCB2 and BRL54443), and 5HT(2B) (norfenfluramine and BW723C86) receptor agonists produced concentration-dependent contractions of ND arteries that were markedly increased in DB arteries. Neither ND nor DB arteries contracted to a 5HT(1B) receptor agonist. MDL11939, a 5HT(2A) receptor antagonist, and LY272015, a 5HT(2B) receptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of 5HT(1B), 5HT(2A), and 5HT(2B) receptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and 5HT(2A) and 5HT(2B) receptor agonists in ND and DB. We conclude that in contrast to other cardiovascular diseases, enhanced contraction of arteries from diabetics to 5HT is not due to a change in expression of multiple 5HT receptor subtypes.

Topics: Animals; Aorta; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Kinase Inhibitors; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; rho-Associated Kinases; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Vasoconstriction; Vasoconstrictor Agents

Activation of central 5-HT(2A) receptor signaling and its subsequent alterations have been implicated in the pathophysiological response to stress and the pathogenesis of stress-associated psychiatric disorders. To further examine the association between alterations in central 5-HT(2A) receptor signaling and the occurrence of stress-induced psychiatric symptoms, the present study, utilizing a learned helplessness stress model in rats, determined whether 5-HT(2A) receptor signaling blockade during stress could prevent the occurrence of stress-induced physical and behavioral abnormalities. Rats subjected to restraint/tail shock for three days developed long-lasting elevated acoustic startle response (ASR) and reduced body weight, compared to non-stressed control animals. However, administration of the selective 5-HT(2A) receptor antagonist, MDL 11,939 (α-phenyl-1-(2-phenylethyl)-4-piperidinemethanol), 30 min prior to exposure of the animals to the stress protocol prevented the subsequent occurrence of elevated ASR and reduced body weight in a dose-dependent manner in stressed subjects. Administration of MDL 11,939 to the animals immediately after exposure to the stress protocol also prevented the occurrence of exaggerated ASR, but was not able to normalize body weight. These findings suggest a critical role of the central 5-HT(2A) receptor activation in developing the pathophysiology associated with elevated ASR and reduced body weight during stress. The differential effects of MDL 11,939 on startle response and body weight and its potential clinical significance are discussed.

Topics: Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Helplessness, Learned; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Reflex, Startle; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological

Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits.. Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry.. The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice.. We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness.

Topics: Affective Symptoms; Aminopyridines; Analysis of Variance; Animals; Conditioning, Operant; Corpus Striatum; Disease Models, Animal; Gene Expression; Indoles; Mice; Mice, Transgenic; Motivation; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine D2; Reward; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Up-Regulation

The use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") as a recreational drug has spread worldwide. Fatal hyperthermia is a likely side effect of using MDMA in combination with monoamine oxidase inhibitors. However, most antidepressants do not pose a high risk of developing hyperthermia when used in conjunction with MDMA. Mirtazapine is a novel antidepressant and a potent 5-HT(2A) receptor antagonist. It remains to be elucidated whether mirtazapine is unlikely to have life-threatening implications in combination with MDMA. In the present study, we evaluated whether mirtazapine and fluoxetine influence MDMA-induced hyperthermia in rats. The rectal temperature of the rats increased to above 41°C following an injection of MDMA (10mg/kg). Pre- and post-treatment administration of mirtazapine (5mg/kg) significantly attenuated MDMA-induced hyperthermia. Administration of WAY100635 (1mg/kg), a 5-HT(1A) receptor antagonist, did not influence the ability of mirtazapine to decrease hyperthermia induced by MDMA. Although pretreatment administration of fluoxetine (10mg/kg) significantly attenuated MDMA-induced hyperthermia, post-treatment administration of the same drug had no effect. The differences in body temperature between the groups post-treated mirtazapine and the groups post-treated fluoxetine may be due to differing mechanisms of action of the two antidepressants. The present study indicates that mirtazapine is unlikely to induce fatal hyperthermia when used with MDMA, and it may be rather effective against MDMA-induced hyperthermia. Considering our previous study demonstrating that potent 5-HT(2A) antagonists completely inhibit MDMA-induced hyperthermia, the findings of the present study suggest that mirtazapine inhibits MDMA-induced hyperthermia mainly by blocking the activation of 5-HT(2A) receptors.

Topics: Animals; Antidepressive Agents, Tricyclic; Disease Models, Animal; Fever; Fluoxetine; Male; Mianserin; Mirtazapine; N-Methyl-3,4-methylenedioxyamphetamine; Rats; Rats, Wistar; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents

The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the α(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects.

Topics: Adrenergic alpha-2 Receptor Antagonists; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phenols; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Serotonin 5-HT2 Receptor Antagonists; Tapentadol

Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dyskinesias; Fenfluramine; Fluorobenzenes; Hyperkinesis; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Psychotic Disorders; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Sensory Gating; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Serotonin Receptor Agonists; Substantia Nigra; Tyrosine 3-Monooxygenase; Urea

This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats.. In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457.. The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism.. The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

Topics: Animals; Antipsychotic Agents; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorobenzenes; Imidazoles; Indoles; Memory Disorders; Phencyclidine; Piperidines; Quinolines; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reversal Learning; Schizophrenia; Sulfones

Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype.. To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina.. In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury+stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin.. APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P<0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation.. 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.

Topics: Animals; Benzamides; Blood Platelets; Coronary Circulation; Coronary Thrombosis; Disease Models, Animal; Dogs; Drug Inverse Agonism; Fibrinolytic Agents; Hemodynamics; Hemorrhage; Morpholines; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazoles; Receptor, Serotonin, 5-HT2A; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Time Factors; Vascular Patency

The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5-5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na(+) K(+) ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT(2A/2C) and 5-HT(3) receptors).

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Analysis of Variance; Animals; Antidepressive Agents; Depression; Disease Models, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Exploratory Behavior; Hindlimb Suspension; Immobility Response, Tonic; Male; Mice; Monoamine Oxidase; Organoselenium Compounds; Propranolol; Receptors, Serotonin, 5-HT2; Receptors, Serotonin, 5-HT3; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Agents; Sodium-Potassium-Chloride Symporters; Swimming; Time Factors; Yohimbine

A possible role of 5-hydroxytryptamine (5-HT) in the origin of antigen-induced airway hyperresponsiveness (AI-AHR) has been scarcely investigated.. To explore the participation of different 5-HT receptors in the development of AI-AHR in guinea-pigs.. Lung resistance was measured in anaesthetized guinea-pigs sensitized to ovalbumin (OVA). Dose-response curves to intravenous (i.v.) acetylcholine (ACh) were performed before and 1 h after antigenic challenge and expressed as the 200% provocative dose (PD(200)). Organ bath experiments, confocal microscopy and RT-PCR were additionally used. The 5-HT content in lung homogenates was measured by HPLC.. Antigenic challenge significantly decreased PD(200), indicating the development of AI-AHR. This hyperresponsiveness was abolished by a combination of methiothepin (5-HT(1)/5-HT(2)/5-HT(5)/5-HT(6)/5-HT(7) receptors antagonist) and tropisetron (5-HT(3)/5-HT(4) antagonist). Other 5-HT receptor antagonists showed three different patterns of response. Firstly, WAY100135 (5-HT(1A) antagonist) and ondansetron (5-HT(3) antagonist) did not modify the AI-AHR. Secondly, SB269970 (5-HT(7) antagonist), GR113808 (5-HT(4) antagonist), tropisetron or methiothepin abolished the AI-AHR. Thirdly, ketanserin (5-HT(2A) antagonist) produced airway hyporresponsiveness. Animals with bilateral vagotomy did not develop AI-AHR. Experiments in tracheal rings showed that pre-incubation with LP44 or cisapride (agonists of 5-HT(7) and 5-HT(4) receptors, respectively) induced a significant increase of the cholinergic contractile response to the electrical field stimulation. In sensitized lung parenchyma strips, ketanserin diminished the contractile responses to ACh. Sensitization was associated with a ninefold increase in the 5-HT content of lung homogenates. Confocal microscopy showed that sensitization enhanced the immunolabelling and co-localization of nicotinic receptor and 5-HT in airway epithelium, probably located in pulmonary neuroendocrine cells (PNECs). RT-PCR demonstrated that neither sensitization nor antigen challenge modified the 5-HT(2A) receptor mRNA levels.. Our results suggested that 5-HT was involved in the development of AI-AHR to ACh in guinea-pigs. Specifically, 5-HT(2A), 5-HT(4) and 5-HT(7) receptors seem to be particularly involved in this phenomenon. Participation of 5-HT might probably be favoured by the enhancement of the PNECs 5-HT content observed after sensitization.

Topics: Animals; Bronchial Hyperreactivity; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Male; Ovalbumin; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensitivity and Specificity; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists

Irritable bowel syndrome (IBS) is associated with an enhanced perception to visceral stimuli and exaggerated stress response. The serotonergic neurotransmitter system has been strongly implicated as a key player in the manifestation of IBS symptomatology including visceral hypersensitivity. However the role of 5-HT(2B) receptors in visceral pain, although speculated, is currently unclear. Thus we assessed the impact of a selective 5-HT(2B) receptor antagonist, RS-127445, on visceral hypersensitivity in a model of brain gut axis dysfunction the Wistar Kyoto (WKY) rat.. Colorectal distension (CRD) was used to assess the visceral sensitivity of the WKY rat compared to normosensitive Sprague Dawley (SD) rats. Once we verified the visceral sensitivity of the WKY rat we assessed the efficacy of RS-127445 in pain signalling from the colorectum. We administered the compound peripherally (i.p.) and centrally (i.c.v.) in order to ascertain the site of action of RS 127445. Behavioural responses to colorectal distention were then monitored.. The WKY rats were more viscerally hypersensitive than the SD as previously shown. RS-127445 (5 mg kg(-1), i.p.) significantly reversed visceral hypersensitivity in WKY animals. Moreover, when administered intracerebroventricularly RS-127445 (100 nM) also decreased the number of pain behaviours during noxious CRD in the WKY animals.. Taken together, blockade of 5-HT(2B) receptors offers an exciting novel therapeutic target for pain relief in stress-related gastrointestinal disorders such as IBS.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Hyperalgesia; Intestine, Large; Irritable Bowel Syndrome; Pain; Pain Measurement; Pain Threshold; Pyrimidines; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

To determine the involvement of 5-HT(2A) (5-HT(2A)) receptor in the process of trigeminal plasticity induced by chronic analgesic exposure and in the process of inflammatory-induced thermal hyperalgesia.. Derangement in 5-HT(2A) serotonin receptor has been reported to implicate in pathogenesis of medication-overuse headache. No clear explanation concerning the precise roles of these receptors in the process.. Wistar rats were daily administered with paracetamol (200 mg/kg) for 30 days. On the next day, ketanserin, a 5-HT(2A) antagonist, or saline was given prior to cortical spreading depression (CSD) induction. Electrocorticogram, cortical blood flow, Fos and 5-HT(2A)-immunoreactivity in cortex and trigeminal pathway were studied. In the other experiment, complete Freund's adjuvant was injected into the rat hind paw to induce tissue inflammation. Three days later, ketanserin was given and noxious heat was applied to both inflamed and noninflamed paws. The response between 2 sides was compared by measuring paw withdrawal latency.. Chronic paracetamol exposure led to an increase in CSD frequency and CSD-evoked Fos expression in cerebral cortex indicating the increase in neuronal excitability. Prolonged medication exposure also facilitated trigeminal nociception as evident by an increase in CSD-evoked Fos expression in trigeminal nucleus caudalis. The expression of 5-HT(2A) receptor in cerebral cortex and trigeminal ganglia was enhanced by chronic paracetamol administration. Pretreatment with ketanserin significantly attenuated these effects. The second experiment showed that ketanserin was able to lengthen the paw withdrawal latency in the inflamed side but did not alter nociceptive response in the noninflamed side.. These findings suggest that up-regulation of pro-nociceptive 5-HT(2A) receptor is an important step in the process of cortical hyper-excitation and nociceptive facilitation induced by chronic analgesic exposure.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Headache Disorders, Secondary; Hyperalgesia; Inflammation; Inflammation Mediators; Ketanserin; Male; Neuronal Plasticity; Nociceptors; Pain Measurement; Pain Threshold; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Reaction Time; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Trigeminal Nerve

Stress and anxiety disorders are risk factors for depression and these behaviors are modulated by corticotrophin-releasing factor receptor 1 (CRFR1) and serotonin receptor (5-HT(2)R). However, the potential behavioral and cellular interaction between these two receptors is unclear. We found that pre-administration of corticotrophin-releasing factor (CRF) into the prefrontal cortex of mice enhanced 5-HT(2)R-mediated anxiety behaviors in response to 2,5-dimethoxy-4-iodoamphetamine. In both heterologous cell cultures and mouse cortical neurons, activation of CRFR1 also enhanced 5-HT(2) receptor-mediated inositol phosphate formation. CRFR1-mediated increases in 5-HT(2)R signaling were dependent on receptor internalization and receptor recycling via rapid recycling endosomes, resulting in increased expression of 5-HT(2)R on the cell surface. Sensitization of 5-HT(2)R signaling by CRFR1 required intact PDZ domain-binding motifs at the end of the C-terminal tails of both receptor types. These data suggest a mechanism by which CRF, a peptide known to be released by stress, enhances anxiety-related behavior via sensitization of 5-HT(2)R signaling.

Topics: Amphetamines; Animals; Anxiety; Behavior, Animal; Biotinylation; Cells, Cultured; Corticotropin-Releasing Hormone; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Fluorobenzenes; Hormones; Humans; Inositol Phosphates; Ionophores; Male; Maze Learning; Mice; Monensin; Mutation; Neurons; Piperidines; Prefrontal Cortex; Rats; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Signal Transduction; Transfection

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro.. Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β(1)- or WNT3a-induced collagen production.. The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

Topics: Animals; Bleomycin; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Lisuride; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins

Temperature dysfunction, clinically described as hot flashes/flushes and night sweats, commonly occur in women transitioning through menopause. Research in this field has yet to fully elucidate the biological underpinnings explaining this dysfunction. The need to develop animal models that can be used to study hormone-dependent temperature regulation is essential to advancing this scientific area. Development of telemetric transmitters for monitoring tail-skin (TST) and core body (CBT) temperatures for animal research has increased the accuracy of data by reducing extraneous factors associated with previous methods. However, until recently, TST and CBT could not be simultaneously measured telemetrically within the same animal. In this report, new dual temperature monitoring transmitters were validated by simultaneously evaluating them with the single measurement transmitters using the ovariectomized (OVX) rat thermoregulatory dysfunction model. A major advantage of measuring TST and CBT in the same animal is the ability to relate temporal changes on these two temperature parameters. Comparative experimentation was performed by single administration of clonidine (alpha(2) adrenergic agonist), MDL-100907 (5-HT(2a) antagonist), or a 7-day treatment of 17alpha-ethinyl estradiol (EE). Clonidine caused decreases in TST and CBT, MDL-100907 caused increases in TST while decreasing CBT, and EE caused decreases in TST with minor CBT decreases only at the higher dose. Data from either probe type showed similar results on temperature parameters regardless of transmitter used. These findings support the use of the new dual temperature transmitters and should enhance the quality and interpretation of data being generated in thermoregulation studies.

Topics: Adrenergic alpha-Agonists; Animals; Body Temperature; Body Temperature Regulation; Clonidine; Disease Models, Animal; Estradiol; Estrogens; Female; Fluorobenzenes; Monitoring, Physiologic; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Skin Temperature; Tail; Telemetry; Time Factors

Neural adaptations in the medial prefrontal cortex (mPFC) are thought to be crucial in the development and maintenance of addictive behaviors. The mPFC receives a dense serotonergic (5-hydroxytryptamine, 5-HT) innervation from raphe nuclei and 5-HT exerts complex actions on mPFC pyramidal neurons. The present study, using a rat model of behavioral sensitization to cocaine, was designed to determine whether repeated cocaine exposure in vivo is capable of altering 5-HT-induced regulation of glutamatergic transmission in the mPFC. In layer V pyramidal neurons of the mPFC, application of 5-HT, through activation of 5-HT(2A) receptors, induced a massive enhancement of spontaneous excitatory postsynaptic currents (sEPSCs). Repeated cocaine administration for 5 days resulted in an attenuation in the ability of 5-HT to enhance sEPSCs. This effect was prevented when cocaine was co-administered with the selective 5-HT(2A) receptor antagonist ketanserin and was mimicked by repeated 5-HT(2A) receptor agonist (-)4-iodo-2,5-dimethoxyphenylisopropylamine administration. Repeated cocaine administration is not associated with any changes in the levels of 5-HT(2A) receptors or regulator of GTP-binding protein signaling 4. These results suggest that cocaine-induced inhibition of 5-HT(2A) receptor-mediated enhancement of glutamatergic transmission in the mPFC may be caused, at least in part, by the impairment of coupling of 5-HT(2A) receptors with GTP-binding proteins during cocaine withdrawal. These alterations in 5-HT(2A) receptor responsiveness in the mPFC may be relevant to the development of behavioral sensitization and withdrawal effects following repeated cocaine administration.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug Administration Schedule; Drug Interactions; Excitatory Postsynaptic Potentials; Glutamic Acid; GTP-Binding Proteins; Male; Organ Culture Techniques; Patch-Clamp Techniques; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Substance Withdrawal Syndrome; Synaptic Transmission

Serotonin (5-HT)(2A) receptors are involved in cytokine production in infection or sepsis. Therefore, 5-HT(2A) receptor antagonist might be useful to treat sepsis. The present study investigates the effects of a 5-HT(2A) receptor antagonist, sarpogrelate on endotoxin shock. Catheters were inserted into the femoral artery and vein of Sprague-Dawley rats. First, sarpogrelate 0 (control), 3, or 10 mg/kg dissolved in 0.5 ml of distilled water has been given, followed by endotoxin 10 mg/kg in saline 0.5 ml 5 min later. Blood pressure, pulse rate and survival rate were monitored in 20 rats per dose. Blood gas and plasma cytokine concentrations were measured in 8 rats per dose. In four rats each of sarpogrelate 0, 3, or 10 mg/kg, and sham operation, the lung histology was examined. Zero, 15, and 12 rats survived for 8 h in the control, 3 mg/kg, and 10 mg/kg groups, respectively. The control group had the lowest blood pressure, pulse rate, pH and arterial oxygen tension, and the highest arterial carbon dioxide tension and plasma IL-1beta concentration. The increase of TNF-alpha was significantly lower in 3 mg/kg group than in the control group. Pathological changes of the lung were inhibited in 3 and 10 mg/kg groups. In conclusion, sarpogrelate might be effective to decrease production of pro-inflammatory cytokines, to keep hemodynamics, to inhibit lung damage, and to decrease mortality in endotoxin shock.

Topics: Animals; Cytokines; Disease Models, Animal; Hemodynamics; Lung; Male; Rats; Rats, Sprague-Dawley; Respiration; Serotonin 5-HT2 Receptor Antagonists; Shock, Septic; Succinates; Survival Rate

The serotonin 5-HT2A receptor (5-HT-sub(2A)R) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT-sub(2A)R antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in naïve, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT-sub(2A)R antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001-0.8 mg/kg ip) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (high extinction responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT-sub(2A)R attenuates the incentive-motivational effects of cocaine-paired cues, particularly in high extinction responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse.

Topics: Analysis of Variance; Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Disease Models, Animal; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Extinction, Psychological; Fluorobenzenes; Food Deprivation; Male; Piperidines; Rats; Rats, Sprague-Dawley; Self Administration; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

The dorsomedial medulla oblongata (DMM) includes the solitary tract nucleus and the hypoglossal nucleus, to which 5-HT neurons project. Effects of 5-HT in the DMM on ventilatory augmentation and airway dilation are mediated via 5-HT2 receptors, which interact with the CO(2) drive. The interaction may elicit cycles between hyperventilation with airway dilation and hypoventilation with airway narrowing. In the present study, effects of 5-HT2 receptors in the DMM on hypoxic ventilatory and airway responses were investigated, while 5-HT release in the DMM was monitored. Adult male mice were anesthetized, and then a microdialysis probe was inserted into the DMM. The mice were placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to hypoxic gas (7% O(2) in N(2)) for 5 min with or without a 5-HT2 receptor antagonist (LY-53857) perfused in the DMM. 5-HT release in the DMM was increased by hypoxia regardless of the presence of LY-53857. Immediate onset and the peak of initial hypoxic hyperventilatory responses were delayed. Subsequent ventilatory decline and airway dilation during initial hypoxic hyperventilation were suppressed with LY-53857. These results suggest that 5-HT release increased by hypoxia acts on 5-HT2 receptors in the DMM, which contributes to the immediate onset of initial hypoxic hyperventilation, airway dilation, and subsequent ventilatory decline. Hypoxic ventilatory and airway responses mediated via 5-HT2 receptors in the DMM may play roles in immediate rescue and defensive adaptation for hypoxia and may be included in periodic breathing and the pathogenesis of obstructive sleep apnea.

Topics: Airway Resistance; Animals; Body Weight; Disease Models, Animal; Ergolines; Hyperventilation; Hypoxia; Lung; Male; Medulla Oblongata; Mice; Mice, Inbred C57BL; Microdialysis; Plethysmography; Pulmonary Ventilation; Receptors, Serotonin, 5-HT2; Respiratory Mechanics; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep Apnea, Obstructive; Time Factors

Serotonin (5-hydroxytryptamine; 5-HT)-toxicity syndrome, an iatrogenic brain disorder induced by excessive efflux of 5-HT, has received much attention because of increasing incidents of serotonergic antidepressants. However, the neural mechanism by which extracellular 5-HT is elevated to a toxic level for the syndrome remains to be determined. The goal of the present study was to test the hypothesis that extracellular 5-HT is composed of two component effluxes responsible for distinct aspects of the syndrome. The first set of experiments was to characterize the syndrome by measuring changes in neuromuscular signs, body-core temperature and mortality rate. Our results indicate that the syndrome severity can be categorized into mild, moderate and severe levels. The second set of experiments was to determine a threshold of extracellular 5-HT for induction of each level of the syndrome. Our results demonstrate that there were an 11-fold increase in the mild syndrome and an over 55-fold increase in the severe syndrome. In the last series of experiments, the excessive increases in 5-HT were pharmacologically separated into primary and secondary component effluxes with the 5-HT2A receptor antagonists cyproheptadine and ketanserin and NMDA receptor antagonist (+)-MK-801. Our results suggest that the primary component efflux was caused by direct drug effects on 5-HT biosynthetic and metabolic pathways and secondary efflux ascribed to indirect drug effect on a positive-feedback circuit involving 5-HT2A and NMDA receptors. In summary, the primary efflux could be an initial cause for the induction of the syndrome while the secondary efflux might involve deterioration of the syndrome.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Body Temperature; Clorgyline; Cyproheptadine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ketanserin; Male; Microdialysis; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Syndrome

The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.

Topics: Animals; Antidepressive Agents, Second-Generation; Autoradiography; Brain; Citalopram; Depression; Disease Models, Animal; Fenclonine; Fenfluramine; Fluorobenzenes; Freezing Reaction, Cataleptic; Male; Paroxetine; Piperidines; Protein Binding; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Swimming; Time Factors; Tritium

Feeding behavior control and dietetics with consequent weight reduction can be the most efficacious and fundamental methods to normalize fasting blood glucose. However, pioglitazone treatment has been found to incrementally increase body weight. In this study, we investigated whether the combined application of a 5-HT(2A) receptor antagonist, sarpogrelate, with pioglitazone can provide a clinical benefit.. Diabetic male KK-A(y) mice were randomly assigned to four groups: those receiving 10 mg/kg/day pioglitazone treatment for 30 days (pioglitazone group, n = 7), those receiving 30 mg/kg/day sarpogrelate treatment for 30 days (sarpogrelate group, n = 7), those receiving both agents for 30 days (pioglitazone + sarpogrelate group, n = 7) and those receiving no treatment (control group, n = 7).. Feed intake was lower in the pioglitazone + sarpogrelate group than in the pioglitazone group. Water intake was also significantly lower in the pioglitazone, sarpogrelate and pioglitazone + sarpogrelate groups than in the control group. Combined application (pioglitazone + sarpogrelate) resulted in a 176% increase in leptin concentration compared with vehicle control. Body weight was significantly higher in the pioglitazone group, and there was a trend toward a smaller increment in body weight in the pioglitazone + sarpogrelate group. Mean values, calculated by multiplying insulin concentration and nonfasting glucose concentration, were significantly lower in the pioglitazone + sarpogrelate group than in the control group.. These results suggest that the combined application of sarpogrelate with pioglitazone provides therapeutic benefits not only in preventing adverse effects but also in the treatment of diabetes.

Topics: Abdominal Fat; Adipocytes; Animals; Blood Glucose; Cell Count; Diabetes Mellitus, Type 2; Disease Models, Animal; Drinking; Drug Therapy, Combination; Eating; Hypoglycemic Agents; Insulin; Leptin; Lipids; Male; Mice; Pioglitazone; Serotonin 5-HT2 Receptor Antagonists; Succinates; Thiazolidinediones

The role of fibroblast growth factor receptors (FGFR) in normal brain development has been well-documented in transgenic and knock-out mouse models. Changes in FGF and its receptors have also been observed in schizophrenia and related developmental disorders. The current study examines a transgenic th(tk-)/th(tk-) mouse model with FGF receptor signaling disruption targeted to dopamine (DA) neurons, resulting in neurodevelopmental, anatomical, and biochemical alterations similar to those observed in human schizophrenia. We show in th(tk-)/th(tk-) mice that hypoplastic development of DA systems induces serotonergic hyperinnervation of midbrain DA nuclei, demonstrating the co-developmental relationship between DA and 5-HT systems. Behaviorally, th(tk-)/th(tk-) mice displayed impaired sensory gaiting and reduced social interactions correctable by atypical antipsychotics (AAPD) and a specific 5-HT2A antagonist, M100907. The adult onset of neurochemical and behavioral deficits was consistent with the postpubertal time course of psychotic symptoms in schizophrenia and related disorders. The spectrum of abnormalities observed in th(tk-)/th(tk-) mice and the ability of AAPD to correct the behavioral deficits consistent with human psychosis suggests that midbrain 5-HT2A-controlling systems are important loci of therapeutic action. These results may provide further insight into the complex multi-neurotransmitter etiology of neurodevelopmental diseases such autism, bipolar disorder, Asperger's Syndrome and schizophrenia.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Exploratory Behavior; Female; Fluorobenzenes; Gait Disorders, Neurologic; Grooming; Hydroxyindoleacetic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Inhibition; Piperidines; Protein-Tyrosine Kinases; Psychotic Disorders; Rats; Receptors, Fibroblast Growth Factor; Reflex, Startle; Serotonin; Serotonin Antagonists; Social Behavior

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy. AG 3 was found to be the most active compound.

Topics: Acetamides; Animals; Antipsychotic Agents; Combinatorial Chemistry Techniques; Disease Models, Animal; Head Movements; Mice; Molecular Structure; Motor Activity; Piperazines; Quipazine; Serotonin 5-HT2 Receptor Antagonists

Blood vessel clots are found around the nerve root in patients with lumbar disc herniation. Thrombosis formation in the experimental application of nucleus pulposus to the nerve root has been shown in histological studies. In addition, reduction of blood flow and nerve conduction velocity are induced by the application of nucleus pulposus, which mimics lumbar disc herniation. In patients with lumbar disc herniation, nerve root block, which is thought to increase nerve blood flow, improves radiculopathy. 5-HT(2A) receptor antagonists are used in chronic arterial occlusive diseases to improve blood flow and have been reported to work as well as nonsteroidal anti-inflammatory drugs in improving radiculopathy due to lumbar disc herniation in clinical studies. This study investigated the effects of a 5-HT(2A) receptor antagonist on blood vessel diameter and blood flow in a canine experimental model of lumbar disc herniation. A total of 13 dogs were used. The animals were divided into three experimental groups and surgery was performed 1 week before measurements. In the nucleus pulposus group (NP; n = 5), the nucleus pulposus was applied to the nerve roots from the ventral side. In the sham group (n = 5), nucleus pulposus was not applied. In the naive group (n = 3), the animals did not undergo surgery. Measurements of vessel diameter and blood flow were done before and after administration of saline and drugs. The diameters and blood flow volume of the observed blood vessels were measured on video-recordings every 10 min for 65 min. In all groups, vessel diameter and blood flow did not change before or after administration of saline. In the NP and sham groups, vessel diameter and blood flow increased significantly after administration of 5-HTRA compared with the naive group. 5-HTRA improved blood vessel diameter and blood flow in the nerve roots inflamed by the application of nucleus pulposus but not in the intact nerve roots. 5-HTRA might be a potential agent to improve blood flow in the nerve roots of patients with lumbar disc herniation.

Topics: Animals; Blood Vessels; Disease Models, Animal; Dogs; Female; Intervertebral Disc; Intervertebral Disc Displacement; Lumbar Vertebrae; Radiculopathy; Regional Blood Flow; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Spinal Nerve Roots; Succinates

In severe hypoxia or ischemia, normal eupneic breathing fails and is replaced by gasping. Gasping serves as part of a process of autoresuscitation by which eupnea is reestablished. Medullary neurons, having a burster, pacemaker discharge, underlie gasping. Conductance through persistent sodium channels is essential for the burster discharge. This conductance is modulated by norepinephrine, acting on alpha 1-adrenergic receptors, and serotonin, acting on 5-HT2 receptors. We hypothesized that blockers of 5-HT2 receptors and alpha 1-adrenergic receptors would alter autoresuscitation. The in situ perfused preparation of the juvenile rat was used. Integrated phrenic discharge was switched from an incrementing pattern, akin to eupnea, to the decrementing pattern comparable to gasping in hypoxic hypercapnia. With a restoration of hyperoxic normocapnia, rhythmic, incrementing phrenic discharge returned within 10 s in most preparations. Following addition of blockers of alpha 1-adrenergic receptors (WB-4101, 0.0625-0.500 microM) and/or blockers of 5-HT2 (ketanserin, 1.25-10 microM) or multiple 5-HT receptors (methysergide, 3.0-10 microM) to the perfusate, incrementing phrenic discharge continued. Fictive gasping was still induced, although it ceased after significantly fewer decrementing bursts than in preparations than received no blockers. Moreover, the time for recovery of rhythmic activity was significantly prolonged. This prolongation was in excess of 100 s in all preparations that received both WB-4101 (above 0.125 microM) and methysergide (above 2.5 microM). We conclude that activation of adrenergic and 5-HT2 receptors is important to sustain gasping and to restore rhythmic respiratory activity after hypoxia-induced depression.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Amphetamines; Animals; Decerebrate State; Diaphragm; Dioxanes; Disease Models, Animal; Dose-Response Relationship, Drug; Hypoxia; Ketanserin; Methoxamine; Methysergide; Periodicity; Phrenic Nerve; Rats; Receptors, Adrenergic, alpha-1; Receptors, Serotonin, 5-HT2; Respiratory Mechanics; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists

Serotonin 5-HT2A and 5-HT2C receptors have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and in the mechanism mediating the anti-compulsive effects of serotonin reuptake inhibitors. Yet it is currently unclear whether activation or blockade of these receptors would have an anti-compulsive effect. The present study tested the effects of 5-HT2A and 5-HT2C activation and blockade in the signal attenuation rat model of OCD. In this model, 'compulsive' behaviour is induced by attenuating a signal indicating that a lever-press response was effective in producing food. Experiments1-4 revealed that systemic administration of the 5-HT2C antagonist RS 102221 (2 mg/kg) selectively decreases compulsive lever-pressing, whereas systemic administration of the 5-HT2A antagonist MDL11,939(0.2-5 mg/kg) or of the 5-HT2A/2C agonist DOI (0.05-5 mg/kg) did not have a selective effect on this behaviour. Experiments 5 and 6 found that systemic co-administration of DOI (0.5 mg/kg) withMDL11,939 (1 mg/kg) or with RS 102221 (2 mg/kg) had a non-selective effect on lever-press responding,with the former manipulation increasing and the latter manipulation decreasing lever-pressing. Finally,experiment 7 demonstrated that administration of RS 102221 directly into the orbitofrontal cortex also exerts an anti-compulsive effect. The results of these experiments suggest that blockade of 5-HT2Creceptors may have an anti-compulsive effect in OCD patients, and that this effect may be mediated by5-HT2C receptors within the orbitofrontal cortex.

Topics: Amphetamines; Analysis of Variance; Animals; Behavior, Animal; Compulsive Behavior; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Extinction, Psychological; Male; Obsessive-Compulsive Disorder; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Spiro Compounds; Sulfonamides

Chemotherapy with an anticancer agent generally causes gastrointestinal tract disorders such as vomiting and anorexia, but the mechanism remains unclear. Rikkunshito, a kampo preparation, is known to alleviate such adverse reactions. In this study, we attempted to clarify the mechanism.. We investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists, and vagotomy as well as the decrease-suppressing effects of rikkunshito and 5-HT antagonists. In addition, binding affinities of rikkunshito components were determined in receptor-binding assays using 5-HT2B and 5-HT2C receptors.. Cisplatin, 5-HT, BW723C86 (5-HT2B-receptor agonist), and m-chlorophenylpiperazine HCl (5-HT2C agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT3 and 5-HT4 agonists had no effect. In contrast, 5-HT2B and 5-HT2C antagonists suppressed the cisplatin-induced decrease of plasma acylated-ghrelin level and food intake. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylated-ghrelin level, which was decreased further by cisplatin. Rikkunshito suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of rikkunshito was blocked by a ghrelin antagonist. Components of rikkunshito, 3,3',4',5,6,7,8-heptamethoxyflavone, hesperidin, and iso-liquiritigenin showed a 5-HT2B-antagonistic effect in vitro, and oral administration of rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level.. The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.

Topics: Acylation; Aminopyridines; Animals; Anorexia; Antineoplastic Agents; Body Weight; Chalcones; Cisplatin; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Eating; Flavones; Gastric Mucosa; Gastrointestinal Agents; Ghrelin; Hesperidin; Indoles; Male; Oligopeptides; Piperazines; Protein Binding; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Stomach; Thiophenes; Vagotomy

In severe hypoxia or ischemia, normal eupneic breathing is replaced by gasping, which can serve as a powerful mechanism for "autoresuscitation." We have proposed that gasping is generated by medullary neurons having intrinsic pacemaker bursting properties dependent on a persistent sodium current. A number of neuromodulators, including serotonin, influence persistent sodium currents. Thus we hypothesized that endogenous serotonin is essential for gasping to be generated. To assess such a critical role for serotonin, a preparation of the perfused, juvenile in situ rat was used. Activities of the phrenic, hypoglossal, and vagal nerves were recorded. We added blockers of type 1 and/or type 2 classes of serotonergic receptors to the perfusate delivered to the preparation. Eupnea continued following additions of any of the blockers. Changes were limited to an increase in the frequency of phrenic bursts and a decline in peak heights of all neural activities. In ischemia, gasping was induced following any of the blockers. Few statistically significant changes in parameters of gasping were found. We thus did not find a differential suppression of gasping, compared with eupnea, following blockers of serotonin receptors. Such a differential suppression had been proposed based on findings using an in vitro preparation. We hypothesize that multiple neurotransmitters/neuromodulators influence medullary mechanisms underlying the neurogenesis of gasping. In greatly reduced in vitro preparations, the importance of any individual neuromodulator, such as serotonin, may be exaggerated compared with its role in more intact preparations.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Decerebrate State; Disease Models, Animal; Dose-Response Relationship, Drug; Hypoglossal Nerve; Ischemia; Ketanserin; Lung; Methysergide; Peripheral Nerves; Phrenic Nerve; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin, 5-HT1; Respiratory Mechanics; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors; Vagus Nerve

The protective effect of 5-HT(2) receptor blockade with ketanserin or ritanserin against cadmium liver injury was investigated. Male Wistar rats were injected intraperitoneally with a sublethal dose of cadmium (3.5 mg/kg body weight). Rats were treated with normal saline (group I), ketanserin (3 mg/kg body weight; group II), or ritanserin (3 mg/kg body weight; group III) 2 hr prior and 4 hr after cadmium administration and killed at different time points. Hematoxylin/eosin-stained liver sections were assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay. Nonparenchymal liver cells and activated Kupffer cells were identified histochemically. Necrosis, hepatocyte apoptosis, nonparenchymal cell apoptosis, and macroscopic and microscopic peliosis were markedly reduced or minimized in ketanserin- or ritanserin-treated rats. The observed protective effect was almost identical for both ketanserin and ritanserin administration. 5-HT(2) receptor blockade exerts a protective effect against acute cadmium-induced hepatotoxicity.

Topics: Animals; Apoptosis; Cadmium; Disease Models, Animal; In Situ Nick-End Labeling; Ketanserin; Liver Failure, Acute; Male; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT2; Ritanserin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Treatment Outcome

1. Ketanserin may influence baroreflex function by blocking 5-HT(2A) receptors and/or alpha(1)-adrenoceptors through central and/or peripheral mechanisms. 2. In the present study, we tested the hypothesis that the baroreflex sensitivity (BRS)-enhancing effects of ketanserin are mediated by central 5-HT(2A) receptors in spontaneously hypertensive rats (SHR). 3. Using a conjugate of a monoclonal antibody to the serotonin reuptake transporter (SERT) and the toxin saporin (anti-SERT-SAP), which specifically eliminates the neurons that express SERT, the effects of ketanserin (0.3 and 3.0 mg/kg, i.g.) on BRS, blood pressure (BP), heart period (HP) and blood pressure variability (BPV) were compared between conscious intact SHR and SHR pretreated with anti-SERT-SAP. 4. Immunochemistry showed that, 2 weeks after intracerebroventricular injection of the toxin, 5-HT expression was strikingly attenuated in the brain, whereas values of BRS, BPV and BP were similar to those in the sham group. In intact SHR, 0.3 mg/kg ketanserin significantly improved BRS (191% control) and reduced BPV without affecting BP; at 3.0 mg/kg, ketanserin significantly increased BRS (197% control) and decreased BPV and BP. In toxin-pretreated SHR, only the high dose of ketanserin improved BRS (132% control), neither of the ketanserin doses reduced BPV, but both significantly decreased BP. 5. We conclude that the BRS-enhancing effects of ketanserin are mediated largely by central 5-HT(2A) receptors, whereas the antihypertensive effect of ketanserin persists even after destruction of serotonergic neurons in the central nervous system.

Topics: Animals; Antibodies, Monoclonal; Antihypertensive Agents; Baroreflex; Blood Pressure; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Immunotoxins; Ketanserin; N-Glycosyl Hydrolases; Neurons; Plant Proteins; Rats; Rats, Inbred SHR; Receptor, Serotonin, 5-HT2A; Ribosome Inactivating Proteins, Type 1; Saporins; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins

Pregnant women with preeclampsia have increased serotonin levels, suggesting a possible role of this amine in abnormal pregnancy. With the hypothesis that an increase in serotonin would reduce volume expansion and cause fetal growth restriction, we evaluated the maternal and fetal effects of the administration of the serotonin precursor 5-hidroxytryptophan (5-HTP) to Sprague-Dawley rats. At pregnancy day 13 (n=19) or in random cycle nonpregnant rats (n=10), animals were assigned to a single injection of 5-HTP (100 mg/kg IP) or to a control group. Animals were studied at day 21, after overnight urinary collection. Additional pregnant rats received ketanserin (1 mg/kg), a 5-HT(2) receptor antagonist, 1 hour before 5-HTP injection. In pregnant rats, 5-HTP lowered plasma volume (control: 22+/-1.1; 5-HTP: 17+/-0.7 mL; P<0.001) and creatinine clearance, whereas serum creatinine and urinary protein excretion were increased; no changes were observed in nonpregnant rats. Systolic blood pressure did not change significantly. Urinary kallikrein activity and plasma aldosterone levels decreased only in pregnant animals. Fetal (control: 5.5+/-0.1; 5-HTP: 4.2+/-0.2 g; P<0.001) and placental weights were reduced. In nonpregnant and pregnant animals, 5-HTP caused profound renal morphological alterations and decreased kallikrein immunostaining. Preadministration of ketanserin abolished all of the changes associated with the use of 5-HTP. These data indicate that the administration of a serotonin precursor to pregnant rats limits plasma volume expansion and fetal growth via 5-HT(2) receptors, suggesting a possible role for serotonin in abnormal pregnancy. We postulate that an increased vascular resistance, both at the placental and renal levels, mediates these effects.

Topics: 5-Hydroxytryptophan; Aldosterone; Animals; Blood Pressure; Creatinine; Disease Models, Animal; Female; Fetal Weight; Kallikreins; Ketanserin; Plasma Volume; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Random Allocation; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists

Rats with congestive heart failure (CHF) develop ventricular inotropic responsiveness to serotonin (5-HT), mediated through 5-HT(2A) and 5-HT(4) receptors. Human ventricle is similarly responsive to 5-HT through 5-HT(4) receptors. We studied isolated ventricular cardiomyocytes to clarify the effects of 5-HT on intracellular Ca(2+) handling. Left-ventricular cardiomyocytes were isolated from male Wistar rats 6 wk after induction of postinfarction CHF. Contractile function and Ca(2+) transients were measured in field-stimulated cardiomyocytes, and L-type Ca(2+) current (I(Ca,L)) and sarcoplasmic reticulum (SR) Ca(2+) content were measured in voltage-clamped cells. Protein phosphorylation was measured by Western blotting or phosphoprotein gel staining. 5-HT(4)- and 5-HT(2A)-receptor stimulation induced a positive inotropic response of 33 and 18% (both P < 0.05) and also increased the Ca(2+) transient (44 and 6%, respectively; both P < 0.05). I(Ca,L) and SR Ca(2+) content increased only after 5-HT(4)-receptor stimulation (57 and 65%; both P < 0.05). Phospholamban serine(16) (PLB-Ser(16)) and troponin I phosphorylation increased by 26 and 13% after 5-HT(4)-receptor stimulation (P < 0.05). 5-HT(2A)-receptor stimulation increased the action potential duration and did not significantly change the phosphorylation of PLB-Ser(16) or troponin I, but it increased myosin light chain 2 (MLC2) phosphorylation. In conclusion, the positive inotropic response to 5-HT(4) stimulation results from increased I(Ca,L) and increased phosphorylation of PLB-Ser(16), which increases the SR Ca(2+) content. 5-HT(4) stimulation is thus, like beta-adrenoceptor stimulation, possibly energetically unfavorable in CHF. 5-HT(2A)-receptor stimulation, previously studied in acute CHF, induces a positive inotropic response also in chronic CHF, probably mediated by MLC2 phosphorylation.

Topics: Action Potentials; Adrenergic beta-Agonists; Animals; Calcium Channels, L-Type; Calcium Signaling; Calcium-Binding Proteins; Cardiac Myosins; Cardiotonic Agents; Coronary Vessels; Disease Models, Animal; Heart Failure; Indoles; Isoproterenol; Ketanserin; Ligation; Male; Myocardial Contraction; Myocardial Infarction; Myocytes, Cardiac; Myosin Light Chains; Phosphorylation; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin, 5-HT4; Sarcoplasmic Reticulum; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Sulfonamides; Time Factors; Troponin I; Ventricular Function

Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Antipsychotic Agents; Brain; Disease Models, Animal; Dopamine; Dopamine D2 Receptor Antagonists; Humans; Nerve Net; Norepinephrine; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, beta-1; Receptors, Dopamine D2; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Antagonists

Enteric nematode infection induces a smooth muscle hypercontractility that depends on interleukin (IL)-4 and IL-13 activation of the signal transducer and activator of transcription (STAT) 6. Serotonin (5-HT) is involved in the physiologic regulation of gut function. The present study investigated the contribution of 5-HT and its receptors in nematode-induced intestinal smooth muscle hypercontractility.. Mice were infected with Nippostrongylus brasiliensis (N brasiliensis) or Heligmosomoides polygyrus (H polygyrus) or injected intravenously with IL-13. Segments of jejunum were suspended in organ baths, and smooth muscle responses to 5-HT were determined in the presence or absence of specific 5-HT antagonists. IL-4, IL-13, and 5-HT receptor messenger RNA expressions were determined by real-time quantitative polymerase chain reaction.. 5-HT evoked a modest contraction of smooth muscle in wild-type (WT) mice that was unaltered by the 5-HT2A antagonist ketanserin. N brasiliensis infection induced a smooth muscle hypercontractility to 5-HT that was abolished by 5-HT(2A) antagonists but not by other 5-HT antagonists. Infection-induced up-regulation of 5-HT2A expression was correlated with the smooth muscle hypercontractility to 5-HT. The infection-induced up-regulation of 5-HT2A in WT mice was observed also in IL-4(-/-) mice but was not seen in IL-13(-/-) or STAT6(-/-) mice. In addition, smooth muscle responses to 5-HT and 5-HT2A expression in WT mice were also enhanced by IL-13 or H polygyrus infection.. These data show that 5-HT2A is one of the molecules downstream from STAT6 activation that mediates changes in smooth muscle function. 5-HT2A represents a novel therapeutic target for modulating immune-mediated effects on intestinal motility.

Topics: Animals; Disease Models, Animal; Female; Gene Expression; Ketanserin; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle Hypertonia; Muscle, Smooth; Nematode Infections; Nippostrongylus; Polymerase Chain Reaction; Receptor, Serotonin, 5-HT2A; RNA, Messenger; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

Dopamine release in the nucleus accumbens mediates motivation and reward, making it a likely candidate to be involved in anhedonia, one of the major symptoms of depression. In the current study, alterations in basal extracellular dopamine levels and 5HT2C receptor-mediated inhibition of accumbal dopamine release in Flinders Sensitive Line (FSL) rats, an animal model of depression, were investigated. We found that FSL rats have decreased extracellular dopamine levels in the nucleus accumbens and an increased inhibitory-like effect of 5HT2C receptors on accumbal dopamine release. However, neither basal 5HT levels nor the accumbal 5HT response to the local 5HT2C receptor antagonist (RS 102221) differed between Sprague-Dawley and FSL rats. Seven-day treatment with the nefazodone (a serotonin/noradrenaline reuptake inhibitor and 5HT2C antagonist) as well as 7-day and 14-day treatments with a tricyclic antidepressant desipramine increased extracellular dopamine levels in the nucleus accumbens of FSL rats. However, only 14-day treatment with desipramine or 7-day treatment with nefazodone, but not 7-day treatment with desipramine, decreased 5HT2C receptor-mediated inhibition of accumbal dopamine release. Based on a possible correlation between the onset of 5HT2C receptor-mediated inhibition and the behavioral effects of desipramine and nefazodone treatment that was described in our previous studies, we suggest that 5HT2C receptor activation may be important for the onset of the behavioral effects of antidepressant treatment.

Topics: Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Depression; Desipramine; Disease Models, Animal; Dopamine; Extracellular Space; Male; Microdialysis; Models, Animal; Nucleus Accumbens; Piperazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Spiro Compounds; Staining and Labeling; Sulfonamides; Time Factors; Triazoles

Modification of spinal serotonergic receptors caudal to spinal injury occurs in rats that received spinal cord transections as neonates. Evaluation of the serotonin syndrome, a group of motor stereotypies elicited by serotonergic (5-HT) agents in 5-HT-depleted animals, and open field locomotor behavior were used to assess behavioral consequences of injury and treatment. We extend these findings to show that a partial 5-HT(1A) agonist activity is revealed by the 5-HT(2C) receptor antagonist (SB 206,553) in this animal model, as measured by evaluation of serotonin syndrome behavior. Treadmill stimulation enhances this motor response, caudal to the injury, in the hindlimbs and tail. These results imply a broader modification of serotonergic receptors than previously thought and suggest a potential strategy by which serotonergic agents may enhance functional recovery following neonatal injury.

Topics: Animals; Animals, Newborn; Behavior, Animal; Disease Models, Animal; Female; Indoles; Male; Motor Activity; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Serotonin Syndrome; Spinal Cord Injuries

We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT 1A receptor antagonist, (-)-pindolol, a 5-HT 1A/1B receptor antagonist, and tropisetron, a 5-HT(3/4) receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT 2A receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In spite of its high affinity for the 5-HT 2A receptor, methysergide only slightly elevated the pain threshold in the hyperalgesic hind limb. Pre-treatment with methysergide significantly antagonized the inhibitory effect of sarpogrelate on hyperalgesia. Furthermore, the 5-HT 2A receptor specific binding activity of 3H-ketanserin determined for the hyperalgesic hind limb did not differ from that of the normal hind limb. From these results, we propose that the 5-HT 2A receptor in the hyperalgesic hind paw function as an agonist-independent active receptor following constriction of the sciatic nerve, and that sarpogrelate and ketanserin act as inverse agonists of this receptor and suppress its activation. Methysergide may act as a neutral antagonist that blocks the effect of inverse agonists on the 5-HT 2A receptor.

Topics: Animals; Binding Sites; Binding, Competitive; Denervation; Disease Models, Animal; Drug Interactions; Hyperalgesia; Ketanserin; Ligation; Male; Neuralgia; Pain Threshold; Peripheral Nerves; Peripheral Nervous System Diseases; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Sciatic Neuropathy; Sensory Receptor Cells; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Succinates

Early microvascular constriction following atherosclerotic plaque rupture may be mediated via serotonin and/or endothelin-1. Atherosclerotic lesions in the rabbit hindlimb underwent plaque rupture, resulting in a rapid reduction of distal flow (7.1+/-0.7 ml/min pre-rupture versus 3.6+/-0.6 ml/min post-rupture, P<0.001) and a rise in distal microvascular resistance (10.5+/-0.9 mm Hg min/ml pre-rupture versus 23.5+/-3.5 mm Hg min/ml post-rupture, P=0.01). Distal microvascular resistance remained elevated following endothelin-1 receptor antagonism and control vehicle, but normalised after serotonin receptor antagonism with ritanserin (10.5+/-0.9 mm Hg min/ml pre-rupture versus 22.2+/-6.0 mm Hg min/ml post-endothelin-1 receptor antagonism [P<0.05] versus 21.6+/-6.2 mm Hg min/ml post-control vehicle [P<0.05] versus 11.6+/-2.0 mm Hg min/ml post-ritanserin [P=NS]). Early antagonism of serotonin receptors protects against distal microvascular constriction following atherosclerotic plaque rupture.

Topics: Animals; Arteriosclerosis; Blood Flow Velocity; Disease Models, Animal; Iliac Artery; Indans; Microcirculation; Rabbits; Receptors, Serotonin, 5-HT2; Ritanserin; Rupture; Serotonin 5-HT2 Receptor Antagonists; Vasoconstriction

R-102444 is a prodrug that is metabolized into R-96544, a potent and selective 5-hydroxytryptamine2A (5-HT2A) receptor antagonist. The effects of R-102444 on peripheral vascular disease were examined using two different rat models: one induced by lauric acid and the other by ergotamine plus epinephrine. R-96544 (0.3-30 nM) relaxed the 5-HT (3 microM)-precontracted rat caudal artery in a concentration-dependent manner. The intravenous administration of R-96544 (0.3-3 microg/kg) to anesthetized rats inhibited the pressor response to 5-HT (50 microg/kg i.v.) dose dependently. The oral administration of R-102444 (1 mg/kg) to rats resulted in a marked inhibition of platelet aggregation induced by 5-HT plus ADP, and statistically significant inhibition was still evident 8 h after the dosing. In contrast, sarpogrelate, at a dose of 100 mg/kg p.o., produced only a moderate antiplatelet effect. Oral administration of R-102444 (1 mg/kg/day, o.d.) significantly prevented the progression of peripheral vascular lesion induced by the injection of lauric acid into a rat femoral artery, whereas sarpogrelate (100 mg/kg/day) showed only a minimal effect. Both 5-day treatments with R-102444 (1-30 mg/kg/day p.o., o.d.), one commenced 1 h before the injection of epinephrine plus ergotamine and one just after injection, resulted in the prevention of rat tail gangrene in a dose-dependent manner, whereas sarpogrelate (100 mg/kg) produced a minimal protection in this model. Based on these results, we conclude that 5-HT2A receptor activation is involved in peripheral vascular disease in the rat and that R-102444 is a useful oral agent for the investigation of diseases involving 5-HT2A receptor activation.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Peripheral Vascular Diseases; Pyrrolidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Vasodilation

Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.

Topics: Amidines; Amphetamines; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endocrine System Diseases; Estradiol; Estrogens; Female; Fluorobenzenes; Naloxone; Ovariectomy; Piperidines; Rats; Reaction Time; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Serotonin Receptor Agonists; Skin Temperature; Substance Withdrawal Syndrome; Telemetry; Time Factors

An atypical antipsychotic drug risperidone reduced ethanol drinking of ethanol-preferring Alko, Alcohol (AA) rats in a limited access paradigm. Its effect was transient at a dose known to preferentially antagonize the 5-HT(2) receptors (0.1 mg/kg, s.c.), but long-lasting when the dose was increased to 1.0 mg/kg that also blocks dopamine D(2) receptors. Risperidone also reduced dose-dependently locomotor activity and limited access saccharin intake of the AA rats, indicating that its effect on ethanol drinking was not selective. Risperidone at 0.1 mg/kg given before four successive daily ethanol-drinking sessions significantly reduced the ethanol intake. These data from an animal model of high ethanol intake suggest that risperidone should be tested in various populations of alcoholics for reducing ethanol consumption.

Topics: Alcohol Drinking; Alcoholism; Animals; Antipsychotic Agents; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Motor Activity; Rats; Risperidone; Saccharin; Self Administration; Serotonin 5-HT2 Receptor Antagonists

Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential preexposure. Amphetamine-induced disruption of LI and its potentiation by antipsychotic drugs (APDs) in the adult rat are well-established models of schizophrenia and antipsychotic drug action, respectively. It is not clear whether LI can be similarly modulated at prepubertal age.. In view of the notion that schizophrenia is a neurodevelopmental disorder whose overt expression depends on postpubertal brain maturational processes, we investigated whether several manipulations known to modulate LI in adult rats, including systemic administration of amphetamine and the atypical APD clozapine, are capable of producing the same effects in prepubertal (35-day-old) rats.. LI was measured in a thirst motivated conditioned emotional response (CER) procedure in which rats received 10 or 40 tone preexposures followed by 2 or 5 tone-footshock pairings.. Like in adults, LI was present with 40 preexposures and 2 conditioning trials. In contrast to findings in adults, LI was resistant to disruption by amphetamine at a dose (1 mg/kg) that significantly increased locomotor activity, as well as by reducing the number of preexposures to ten, increasing the number of conditioning trials to five, or changing the context between preexposure and conditioning. Clozapine (5 mg/kg) and the selective 5HT2A antagonist M100907 (0.3 mg/kg) administered in conditioning were without an effect on "persistent" LI with extended conditioning, but were capable of disrupting LI when administered in the preexposure stage, as found in adults.. The results point to functionality within brain systems regulating LI acquisition but not those regulating LI expression in periadolescent rats, further suggesting that postpubertal maturation of the latter systems may underlie schizophrenia-mimicking LI disruption reported in adult rats following perinatal manipulations and possibly disrupted LI observed in schizophrenia.

Topics: Aging; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Clozapine; Conditioning, Classical; Disease Models, Animal; Drinking Behavior; Fluorobenzenes; Male; Models, Neurological; Movement; Neural Inhibition; Piperidines; Rats; Rats, Wistar; Schizophrenia; Time Factors

The present study has shown that a subthreshold dose of the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801, combined with a subthreshold dose of LSD, produces marked locomotor stimulation in monoamine-depleted mice. Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the alpha-adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT2 receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT2A receptor antagonist MDL 100,907. On the other hand, MDL 100,907 did not antagonize the hyperactivity response produced by clonidine given in combination with MK-801 or atropine in monoamine-depleted mice, nor the response produced by the mixed DA receptor agonist apomorphine, underlining the selectivity in the antagonistic action of MDL 100,907. Furthermore, MDL 100,907 attenuated the hyperactivity produced in intact mice by such disparate agents as MK-801, atropine or the DA uptake inhibitor GBR 12,909. A putative "permissive" role of the 5-HT2 receptor in the context of psychomotor activation is discussed, as well as its possible importance as target for antipsychotic therapy.

Topics: Animals; Biogenic Monoamines; Disease Models, Animal; Dizocilpine Maleate; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Fluorobenzenes; Glutamic Acid; Hallucinogens; Lysergic Acid Diethylamide; Male; Mice; Mice, Inbred Strains; Neurotransmitter Agents; Piperazines; Piperidines; Psychomotor Performance; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Muscarinic; Receptors, Serotonin; Serotonin; Serotonin Antagonists