sb-242084 and Disease-Models--Animal

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

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

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

Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT(2C)R activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT(2C)R agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT(2C)R antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT(2C)R protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT(2C)R can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT(2C)R may represent a new avenue for the treatment of opioid addiction.

Topics: Aminopyridines; Analgesics, Opioid; Animals; Benzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Indoles; Locomotion; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Reaction Time; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Substance Withdrawal Syndrome; Time Factors

Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine.. Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis.. Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus.. Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Topics: Aminopyridines; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Anxiety; Benzodiazepines; Buspirone; Clozapine; Conditioning, Classical; Dibenzocycloheptenes; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Fear; Heterocyclic Compounds, 4 or More Rings; Hippocampus; Indoles; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Stress, Psychological

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

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

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

Stressors that are controllable not only protect an individual from the acute consequences of the stressor, but also the consequences of stressors that occur later. This phenomenon, termed "behavioral immunization", is studied in the rat by first administering tailshocks each of which can be terminated (escapable tailshock) by an instrumental wheel-turn response prior to exposure to a second stressor. Previous research has shown that exposure to escapable tailshock blocks the neurochemical and behavioral consequences of later inescapable tailshock or social defeat stress. Here we explored the generality of behavioral immunization by examining the impact of prior escapable tailshock on the behavioral consequences of cold swim stress. Exposure to a 5min cold-water (19°C) swim caused an anxiety-like reduction in social interaction that was dependent upon 5-HT2C receptor activation. Rats with prior exposure to escapable tailshock did not develop the swim-induced anxiety. Plasticity in the medial prefrontal cortex, a hypothetical neural mechanism underlying behavioral immunization, is discussed.

Topics: Aminopyridines; Animals; Anxiety; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Escape Reaction; Exploratory Behavior; Immobility Response, Tonic; Indoles; Male; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Stress, Physiological; Stress, Psychological; Swimming; Time Factors

Dopamine and serotonin (5-HT) in the nucleus accumbens (ACC) and ventral tegmental area of the mesoaccumbens reward pathways have been implicated in the mechanisms underlying development of alcohol dependence. We used a C57BL/6J mouse model with increased voluntary alcohol-drinking behavior by exposing the mice to alcohol vapor for 20 consecutive days. In the alcohol-exposed mice, the expression of 5-HT(2C) receptor mRNA increased in the ACC, caudate nucleus and putamen, dorsal raphe nucleus (DRN), hippocampus and lateral hypothalamus, while the protein level of 5-HT(2C) receptor significantly increased in the ACC. The expression of 5-HT(7) receptor mRNA increased in the ACC and DRN. Contents of 5-HT decreased in the ACC shell (ACC(S) ) and DRN of the alcohol-exposed mice. The basal extracellular releases of dopamine (DA) and 5-HT in the ACC(S) increased more in the alcohol-exposed mice than in alcohol-naïve mice. The magnitude of the alcohol-induced ACC(S) DA and 5-HT release in the alcohol-exposed mice was increased compared with the control mice. Intraperitoneal (i.p.) administration or local injection into ACC(S) of the 5-HT(2C) receptor antagonist, SB-242084, suppressed voluntary alcohol-drinking behavior in the alcohol-exposed mice. But the i.p. administration of the 5-HT(7) receptor antagonist, SB-258719, did not have significant effects on alcohol-drinking behavior in the alcohol-exposed mice. The effects of the 5-HT(2C) receptor antagonist were not observed in the air-exposed control mice. These results suggest that adaptations of the 5-HT system, especially the upregulation of 5-HT(2C) receptors in the ACC(S) , are involved in the development of enhanced voluntary alcohol-drinking behavior.

Topics: Alcohol Drinking; Aminopyridines; Analysis of Variance; Animals; Biogenic Monoamines; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Disease Models, Animal; Ethanol; Gene Expression Regulation; Indoles; Male; Mice; Mice, Inbred C57BL; Microdialysis; Microinjections; Nucleus Accumbens; Piperidines; Raphe Nuclei; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine; RNA, Messenger; Serotonin Agents; Sulfonamides

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

Exposure to uncontrollable stressors often increases anxiety-like behavior in both humans and rodents. In rat, this effect depends on stress-induced activity within the dorsal raphe nucleus (DRN). However, the role of serotonin in DRN projection regions is largely unknown. The goals of this study were to 1) assess the effect of uncontrollable stress on extracellular serotonin in the basolateral amygdala during the anxiety test, 2) determine whether DRN activity during a poststress anxiety test is involved in anxiety-like behavior, and 3) determine the role of the serotonin 2C receptor (5-HT(2C)) in uncontrollable stress-induced anxiety.. Rats were exposed to tail shocks that were either controllable or uncontrollable. On the following day, anxiety-like behavior was assessed in a Juvenile Social Exploration (JSE) test. Basolateral amygdala (BLA) extracellular serotonin concentrations were assessed during JSE by in vivo microdialysis 24 hours after uncontrollable stress, controllable stress, or no stress. In separate experiments, drugs were administered before the JSE test to inhibit the DRN or to block 5-HT(2C) receptors.. Exposure to uncontrollable shock reduced later social exploration. Prior uncontrollable stress potentiated serotonin efflux in the BLA during social exploration, but controllable stress did not. Intra-DRN 8-OH-DPAT and systemic and intra-BLA 5-HT(2C) receptor antagonist SB 242,084 prevented the expression of potentiated anxiety in uncontrollably stressed rats. Intra-BLA injection of the 5-HT(2C) agonist CP 809,101 mimicked the effect of stress.. These results suggest that the anxiety-like behavior observed after uncontrollable stress is mediated by exaggerated 5-HT acting at BLA 5-HT(2C) receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Amygdala; Analysis of Variance; Animals; Animals, Newborn; Anxiety; Disease Models, Animal; Electroshock; Indoles; Microdialysis; Rats; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Social Behavior; Stress Disorders, Traumatic

Serotonin 2C receptor (5-HT(2C)R) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT(2C)R agonist MK212 (0, 10, 30, 100 ng/side/0.2 microl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions before tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions before tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 microl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT(2C)R antagonist SB242084 (200 ng/side/0.2 microl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT(2C)Rs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.

Topics: Aminopyridines; Animals; Cocaine-Related Disorders; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Extinction, Psychological; Indoles; Male; Prefrontal Cortex; Pyrazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Self Administration; Serotonin Antagonists; Serotonin Receptor Agonists

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

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.

Topics: Action Potentials; Aminopyridines; Animals; Citalopram; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electromyography; Epilepsy, Absence; Fluoxetine; Indoles; Injections, Intraperitoneal; Injections, Intraventricular; Male; Piperazines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists

m-Chlorophenylpiperazine (mCPP) induces panic in humans and dose dependently increases unconditioned escape behaviour in a novel pre-clinical model of extreme anxiety in rats, the unstable elevated exposed plus maze (UEEPM). Numerous studies indicate that the anxiogenic effects of mCPP may be mediated by its action at the 5-HT2C receptor. This study aimed to examine the involvement of the 5-HT2C receptor in the unconditioned fear responses observed in the UEEPM (after an acute dose of mCPP) by pre-treatment with the selective 5-HT2C receptor antagonist SB-242084.. Male Hooded Lister rats received a single dose of SB-242084 (0.1-1.0 mg/kg IP) or vehicle 40 min pre-test followed by a single dose of mCPP (1.0 mg/kg IP) or saline 30 min before being exposed to the UEEPM for a period of 5 min. Subjects' behaviour was analysed to determine the effects of SB-242084 on mCPP-induced increases in escape behaviour.. mCPP alone increased animals' propensity to escape from the UEEPM despite producing marked decreases in locomotor/exploratory behaviour. SB-242084 dose dependently inhibited the increases in escape and hypolocomotor effects induced by mCPP.. These results suggest that the escape-related behaviours exhibited by animals in the UEEPM are mediated, at least in part, by activation of the 5-HT2C receptor subtype.

Topics: Aminopyridines; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Escape Reaction; Exploratory Behavior; Fear; Indoles; Male; Maze Learning; Motor Activity; Piperazines; Random Allocation; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors