Head Twitches In Mice Research Articles

An Assessment of Antidepressant Activity of Etlingera elatior Alone and in Combination with Fluoxetine

Aim: Present study deals to access the antidepressant activity of Etlingera elatior leaves extract in rodent. Background: Etlingera elatior is a species of herbaceous perennial plant in the family Zingiberaceae; native to Indonesia, Thailand, Malaysia and New Guinea. Depression is one of the most common mental disorders affecting humans, pathological basis of which is not fully understood. The current antidepressant drugs have several adverse effects including their effects on cognition. Therefore, natural product are being evaluated for their antidepressant activities. Objective: In this study, Etlingera elatior leaf extracts are being evaluated for antidepressant activity in rodent models. A wide range of synthetic medicines that can be used to treat depression which may exerts various side effects such as dry mouth, gastrointestinal problems, nausea, respiratory problems, cardiac arrhythmias, drowsiness, anxiety etc. Hence, it becomes essential to discover new anti-depressant drug with more potency, efficacy and safety profile than those of marketed synthetic drugs. Methods: Using the forced swimming test, the tail suspension test, mouse 5-HTP-induced head twitches and estimation of brain lipid peroxidation modelsthe antidepressant efficacy of Etlingera elatior ethanolic extract was examined. Imipramine was used as reference standards. result: According to our study, Etlingera elatior significantly (p0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Results: According to our study, Etlingera elatior significantly (p 0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Conclusion: Based on the results obtained we can conclude that Etlingera elatior leaves extract possess significant antidepressant activity. The antidepressant effectiveness of Etlingera elatior leaves extract can be confirmed in the future by adding more models, and attempts can also be made to isolate and characterise the phytoconstituents responsible for the pharmacological action.

Investigation of the Structure-Activity Relationships of Psilocybin Analogues.

The 5-HT2A receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and other serotonergic hallucinogens (psychedelic drugs). Although a large amount of experimental work has been conducted to characterize the pharmacology of psilocybin and its dephosphorylated metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine), there has been little systematic investigation of the structure-activity relationships (SAR) of 4-substituted tryptamine derivatives. In addition, structural analogs of psilocybin containing a 4-acetoxy group, such as 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), have appeared as new designer drugs, but almost nothing is known about their pharmacological effects. To address the gap of information, studies were conducted with 17 tryptamines containing a variety of symmetrical and asymmetrical N,N-dialkyl substituents and either a 4-hydroxy or 4-acetoxy group. Calcium mobilization assays were conducted to assess functional activity at human and mouse 5-HT2 subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT2A activation in vivo. All of the compounds acted as full or partial agonists at 5-HT2 subtypes, displaying similar potencies at 5-HT2A and 5-HT2B receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT2C receptors and higher 5-HT2B receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT2A potency of 4-hydroxy-N,N-dialkyltryptamines by about 10- to 20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.

Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT7/2 inhibitors leading to the identification of a clinical candidate

We report here the synthesis and characterization of a dual 5-HT7 / 5-HT2 receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A receptor ligand having a pKi = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT2A and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo model for central 5-HT7 activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED50 = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1 h).

Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of d-lysergic acid diethylamide (LSD)

The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD.This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Serotonergic-like profile of 4-propyl-2H-benzo[h]-chromen-2-one (FCS-304) in mice and rats

ANTECEDENTES: 4-propil-2H-benzo [h] -cromen-2-ona (FCS-304) es una cumarina semisintética con actividad inhibidora de MAO-A y resultados positivos en natación forzada y prueba de suspensión de cola en ratones, pero hasta ahora, no se ha estudiado en otros modelos de antidepresivos de detección en ratones y ratas.OBJETIVOS: El objetivo de este trabajo fue evaluar el efecto similar a la serotonina de FCS-304 en la prueba de 5-hidroxitriptófano (5-HTP) en ratones, en la prueba de desesperación del comportamiento en ratas y en la prueba de reserpina en ratas.MÉTODOS: Se evaluó la potenciación de 5-HTP (100 mg / kg, ip), sacudidas de cabeza inducidas en ratones, previamente tratados con FCS-304 (50-75-150 mg / Kg, po). La prueba de desesperación del comportamiento se realizó en ratas tratadas con FCS-304, registrando el tiempo de inmovilidad alcanzado por los animales sometidos a natación forzada. Se examinó el antagonismo de la ptosis inducida por reserpina en ratas, evaluando el nivel de cierre palpebral. La imipramina (30 mg / kg, po) y el vehículo (aceite de canola) sirvieron como controles positivos y negativos, respectivamente.RESULTADOS: FCS-304 potenció significativamente las contracciones en la cabeza inducidas por 5-HTP en ratones, de una manera dependiente de la dosis. En ratas, FCS-304 redujo significativamente el tiempo de inmovilidad en la prueba de desesperación conductual y antagonizó la ptosis inducida por reserpina.CONCLUSIÓN: Estos resultados agregan apoyo para proponer que el FCS-304 podría provocar efectos antidepresivos relacionados con la actividad inhibidora de MAO-A.

Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds. In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens. Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes. ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7nmol/kg) was slightly less potent than ECPLA. These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.

Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022.

Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.

Tolerance to Hallucinogen-Induced Head Twitches in Mice

Tolerance to Hallucinogen-Induced Head Twitches in Mice

Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.

RationaleSchizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed.ObjectivesAs a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007.ResultsITI-007 is a potent 5-HT2A receptor ligand (K i = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (K i = 32 nM) and the serotonin transporter (SERT) (K i = 62 nM) but negligible binding to receptors (e.g., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT2A antagonist, blocking (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50) = 0.09 mg/kg, per oral (p.o.), and has dual properties at D2 receptors, acting as a postsynaptic D2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neurotransmission. Further, in microdialysis studies, this compound significantly and preferentially enhances mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by increasing phosphorylation of GluN2B-type N-methyl-d-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3β (GSK-3β) in mesolimbic/mesocortical dopamine systems.ConclusionThe combination of in vitro and in vivo activities of this compound support its development for the treatment of schizophrenia and other psychiatric and neurologic disorders.

The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies.

RationaleDiverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia.ObjectivesTo begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated.ResultsThe effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release.ConclusionsThe actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-014-3657-4) contains supplementary material, which is available to authorized users.

Comparison of sentenced inmates’ drug use patterns before and during incarceration

Comparison of sentenced inmates’ drug use patterns before and during incarceration

Xiaochaihutang prevents depressive-like behaviour in rodents by enhancing the serotonergic system

Xiaochaihutang (XCHT) has been used in China for thousands of years to treat 'Shaoyang syndrome', which involves depressive-like symptoms. However, no studies were conducted to demonstrate its antidepressant effect and mechanism. This study was designed to confirm the antidepressant effect of XCHT and explore its mechanism using the pharmacological methods. Ultra-HPLC and mass spectrometry was used to identify the chemical constituents of XCHT. Forced swimming test (FST) and tail suspension test (TST) were used to determine the antidepressant-like activity of XCHT in mice and rats. The possible mechanism of XCHT was elucidated by the reserpine-induced hypothermia and 5-hydroxytryptophan (5-HTP)-induced head-twitch in mice. The levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in prefrontal cortex and hippocampus tissue of both mice and rats. Moreover, the extracellular 5-HT in rat hippocampus was assessed by using microdialysis coupled to HPLC with electrochemical detection. Forty-four components were detected in XCHT. XCHT significantly reduced immobility time in the TST and the FST, antagonized reserpine-induced depressive-like behaviours, increased 5-HTP-induced head-twitches, elevated 5-HT and 5-HIAA levels, and increased 5-HT turnover at doses that did not affect general activity. These data demonstrate that XCHT has therapeutic effects in animal models of depression by enhancing the serotoninergic system in the prefrontal cortex and hippocampus.

NEW 7-(2-(BENZOL[d]THIAZOL-2-YLAMINO)ETHOXY)-4-METHYL-2HCHROMEN-2-0NE DERIVATIES WITH ATYPICAL ANTIPSYCHOTIC ACTIVITY

A new series of 7-(2-(benzo[d]thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2-one derivatives(4a4k) was synthesized and evaluated for their D2 and 51HT2 antagonistic activity as a measure of atypical antipsychotic properly. Compounds 7-(2-(benzo[d]thiazo/-2-ylamino)ethoxy)-4-methyl-2H-chromen-2- one derivatives (4a-4k) was synthesized by refluxing 2-amino benzothiazoles substituted derivatives (3a3k) and 7-(2-Chloroethoxy)-4-melhyl-2H-chromen-2-one (2) in dry pyridine. The synthesized compounds were characterized with the help of spectral and analytical data. Most of these compounds showed dopamine D2 receptor antagonistic activity from moderate to high potency along with serotonin 5-HT2 receptor blockage activity: a property that has been suggested to be necessary for the atypical nature of antipsychotic agents. The D2 and 5-HT2 receptor blockage activity was evaluated by inhibition of apomorphine-induced climbing behavior and 5HTP induced head twitches in mice respectively.

The antipsychotic-like effects of the mGlu group III orthosteric agonist, LSP1-2111, involves 5-HT1A signalling

RationaleSeveral studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia.ObjectivesHere, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations.ResultsLSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used.ConclusionsAltogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent.

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl]phenyl}thiazoles as atypical antipsychotic agents

A series of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were designed, synthesized, and characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The D2 and 5-HT2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized final compounds (10a–g; 11a–g; 12a–g) were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 12d, 11f, and 10a were found to be the most active compounds with 5-HT2A/D2 ratio of 1.23077, 1.14286, and 1.12857, respectively, while the standard drug risperidone exhibited 5-HT2A/D2 ratio of 1.0989. Among the twenty one new chemical entities, three compounds (12d, 11f, and 10a) were found to exhibit better atypical antipsychotic activity as they were found to have higher Meltzer index than the standard drug risperidone.

Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia

RationaleSeveral studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity.ObjectivesHere, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects.ResultsLSP1-2111 (1, 2, and 5 mg kg−1) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg-1, i.p.). In contrast, AMN082 (3 and 6 mg kg−1) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates.ConclusionsAltogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.

Gastroprotective and antidepressant effects of a new zinc(II)–curcumin complex in rodent models of gastric ulcer and depression induced by stresses

Curcumin, a yellow pigment found in the rhizome of Curcuma loga, has been used to treat a variety of digestive and neuropsychiatric disorders since ancient times in China. Curcumin can chelate various metal ions to form metallocomplexes of curcumin which show greater effects than curcumin alone. This study investigated the antiulcerogenic and antidepressant effects of a Zn(II)–curcumin complex on cold-restraint stress (CRS)-induced gastric ulcers in rats, and on the forced swimming test (FST), tail suspension test (TST) and 5-hydroxy-l-tryptophan (5-HTP)-induced head twitch test in mice. CRS disrupted the rat mucosal barrier and induced gastric ulcers by decreasing the activities of the antioxidant enzymes, and increasing H+–K+–ATPase activity and malondialdehyde (MDA) level. Pretreatment with Zn(II)–curcumin (12, 24, and 48mg/kg) dose-dependently reversed these trends, reduced gastric lesions and H+–K+–ATPase activity, and increased antioxidant activities compared with control groups. Zn(II)–curcumin significantly increased HSP70 mRNA, and attenuated increased iNOS mRNA in the mucosa. Zn(II)–curcumin (17, 34, and 68mg/kg) also significantly decreased immobility time in the FST and TST, and enhanced 5-HTP-induced head twitches in mice. These results demonstrate that the Zn(II)–curcumin complex showed significant gastroprotective and antidepressant effects compared with curcumin alone via a synergistic effect between curcumin and zinc.

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 2-{4-[4-(2,5-disubstituted thiazol-4-yl)phenylethyl]piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles as atypical antipsychotic agents

A series of 2-{4-[4-(2,5-disubstituted thiazolyl)phenylethyl] piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized either by microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The D2 and 5-HT2A affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. The D2 antagonism studies were performed using climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 10f is the most active among the synthesized compounds with 5-HT2A/D2 ratio of 1.1286 although the standard drug risperidone exhibited 5-HT2A/D2 ratio of 1.0989.

A novel 5-HT 2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT 2A) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [α] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT 2A receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25–4 mg/kg) pretreatment reduced the quipazine-induced head twitches in mice and produced antidepressant-like effects in mouse forced swim and tail suspension tests. BIP-1 reversed the depressogenic-like effects of meta-chlorophenyl piperazine and augmented the antidepressant-like effects of amitryptiline and harmane. Chronic (14 days) treatment with BIP-1 (1 and 2 mg/kg) or amitriptyline (10 mg/kg) alleviated the behavioural anomalies of olfactory bulbectomised rats in modified open field exploration, social interaction, hyperemotionality and sucrose preference paradigms. When BIP-1 treatment was combined with amitryptyline, a short duration regimen (7 days) was sufficient to reverse the bulbectomy induced anomalies. This investigation revealed that 5-HT 2A receptor antagonism is the principal mechanism behind the antidepressant-like effects of BIP-1. Finally, we propound the combination of 5-HT 2A receptor antagonists and tricyclic antidepressants as a likely strategy to achieve an early-onset of antidepressant action.

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D2 antagonism studies were performed using the climbing mouse assay model and 5-HT2A antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.