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1.
Bioorg Med Chem Lett ; 96: 129497, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37806499

RESUMO

In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT6 receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure-activity relationship (SAR) of these compounds. Our main objective is to improve their activity and selectivity against off-target receptors. Overall, our findings contribute to the advancement of novel compounds targeting the 5-HT6 receptor. Compound 29 exhibits significant promise in terms of pharmacological, physicochemical, and ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Consequently, it merits thorough exploration as a potential drug candidate due to its favorable activity profile and successful outcomes in a range of in vivo experiments.


Assuntos
Piridinas , Antagonistas da Serotonina , Piridinas/química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
2.
Molecules ; 28(3)2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36770761

RESUMO

Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand-receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT6 receptor and D3 receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT6R affinity and more potent 5-HT6R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT6R/D3R antagonist; nevertheless, the proposed modifications did not improve the activity at D3R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT6R binding site; however, they are unfavorable for such interactions at D3R.


Assuntos
Quinolinas , Serotonina , Relação Estrutura-Atividade , Ligantes , Aminas , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Quinolinas/química , Receptores de Dopamina D3
3.
Appl Microbiol Biotechnol ; 106(22): 7671-7681, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36322250

RESUMO

Amplicon-based next-generation sequencing (NGS) of the 16S ribosomal RNA (16S) regions is a culture-free method used to identify and analyze Procaryota occurring within a given sample. The prokaryotic 16S rRNA gene contains conserved regions and nine variable regions (V1-V9) frequently used for phylogenetic classification of genus or species in diverse microbial populations. This work compares the accuracy and efficacy of two platforms, iSeq and MiSeq from Illumina, used in sequencing 16S rRNA. The most important similarities and differences of 16S microbiome sequencing in 20 fecal rat samples were described. Genetic libraries were prepared according to 16S Metagenomic Sequencing Library Preparation (Illumina) for the V3 and V4 regions of the 16S. The species richness obtained using iSeq technology was lower compared to MiSeq. At the second taxonomy level (L2), the abundance of taxa was comparable for both platforms. At the L7, the taxa abundance was significantly different, and the number of taxa was higher for the MiSeq. The alpha diversity was lower for iSeq than for MiSeq, starting from the order to the species level. The beta diversity estimation revealed statistically significant differences in microbiota diversity starting from the class level to the species level in samples sequenced on two investigated platforms. This work disclosed that the iSeq platform could be used to evaluate the bacterial profile of the samples to characterize the overall profile. The MiSeq System seems to be better for a detailed analysis of the differences in the microbiota composition. KEY POINTS: • iSeq platform allows to shorten the sequencing time three times compared to the MiSeq. • iSeq can only be used for an initial and quick microbiome assessment. • MiSeq is better for a detailed analysis of the differences in the microbiota composition.


Assuntos
Microbiota , Ratos , Animais , RNA Ribossômico 16S/genética , Filogenia , DNA Bacteriano/genética , Microbiota/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos
4.
Int J Mol Sci ; 22(21)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34768975

RESUMO

Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only "gluing" neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD.


Assuntos
Astrócitos/patologia , Astrócitos/fisiologia , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Animais , Transtorno do Espectro Autista/psicologia , Comportamento Animal , Sinalização do Cálcio , Forma Celular , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Microglia/patologia , Microglia/fisiologia , Modelos Neurológicos , Oligodendroglia/patologia , Oligodendroglia/fisiologia , Fatores Sexuais , Habilidades Sociais
5.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467149

RESUMO

Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced 'drug-seeking' behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2'-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the 'affective' aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.


Assuntos
Benzazepinas/uso terapêutico , Hipocampo/efeitos dos fármacos , Nicotina/efeitos adversos , Agonistas do Receptor de Serotonina/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Proteína Duplacortina , Comportamento de Procura de Droga , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Locomoção , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia
6.
Behav Pharmacol ; 27(4): 331-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26580130

RESUMO

Inhibitors of phosphodiesterase 10A (PDE10A) represent a novel class of potential antipsychotic compounds. These principles increase the level of cAMP and cGMP in the medium spiny neurons of the striatum and resemble the neurochemical consequences of dopamine D2 receptor inhibition and dopamine D1 receptor stimulation. Cognitive dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. In the present study, we investigated the involvement of D1 receptors in the procognitive action of the PDE10A inhibitor using the attentional set-shifting task in rats. The performance of the rats in the extradimensional shift stage of the attentional set-shifting task was taken as an index of cognitive flexibility. We first assessed the effects of the D1 agonist in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. We then investigated the procognitive effects of the PDE10A inhibitor, MP-10, in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. The dopamine D1 receptor antagonist SCH-23390 produced cognitive impairment at the dose of 0.0125 mg/kg, but not at 0.0063 mg/kg. The D1 receptor agonist, SKF-81,297, produced a procognitive effect that was abolished by 0.0063 mg/kg of SCH-23390. The compound MP-10 produced a procognitive effect at the dose of 0.3 mg/kg, but not at 0.1 mg/kg. Rat pretreatment with 0.0063 mg/kg of SCH-23390 did not block the procognitive effect of 0.3 mg/kg of MP-10. The present study demonstrates that the blockade of dopamine D1 receptors is unlikely to affect the procognitive effects of PDE10A inhibition.


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores de Dopamina D1/metabolismo , Animais , Atenção , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Inibidores de Fosfodiesterase/administração & dosagem , Pirazóis/administração & dosagem , Quinolinas/administração & dosagem , Ratos , Ratos Sprague-Dawley
7.
Behav Pharmacol ; 26(8 Spec No): 766-75, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25769091

RESUMO

Social withdrawal, one of the core negative symptoms of schizophrenia, can be modelled in the social interaction (SI) test in rats using N-methyl-D-aspartate receptor glutamate receptor antagonists. We have recently shown that amisulpride, an antipsychotic with a high affinity for serotonin 5-HT7 receptors, reversed ketamine-induced SI deficits in rats. The aim of the present study was to further elucidate the potential involvement of 5-HT7 receptors in the prosocial action of amisulpride. Acute administration of amisulpride (3 mg/kg) and SB-269970 (1 mg/kg), a 5-HT7 receptor antagonist, reversed ketamine-induced social withdrawal, whereas sulpiride (20 or 30 mg/kg) and haloperidol (0.2 mg/kg) were ineffective. The 5-HT7 receptor agonist AS19 (10 mg/kg) abolished the prosocial efficacy of amisulpride (3 mg/kg). The coadministration of an inactive dose of SB-269970 (0.2 mg/kg) showed the prosocial effects of inactive doses of amisulpride (1 mg/kg) and sulpiride (20 mg/kg). The anxiolytic chlordiazepoxide (2.5 mg/kg) and the antidepressant fluoxetine (2.5 mg/kg) were ineffective in reversing ketamine-induced SI deficits. The present study suggests that the antagonism of 5-HT7 receptors may contribute towards the mechanisms underlying the prosocial action of amisulpride. These results may have therapeutic implications for the treatment of negative symptoms in schizophrenia and other disorders characterized by social withdrawal.


Assuntos
Comportamento Animal/efeitos dos fármacos , Ketamina/farmacologia , Receptores de Serotonina/metabolismo , Transtornos do Comportamento Social/metabolismo , Sulpirida/análogos & derivados , Amissulprida , Animais , Antipsicóticos/farmacologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Masculino , Fenóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Antagonistas da Serotonina/farmacologia , Transtornos do Comportamento Social/induzido quimicamente , Transtornos do Comportamento Social/tratamento farmacológico , Sulfonamidas/farmacologia , Sulpirida/farmacologia
8.
Rev Neurosci ; 25(3): 367-82, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24501158

RESUMO

In addition to positive and negative symptoms, cognitive deficits are increasingly being recognized as a core feature of schizophrenia. Neurocognitive impairments are strongly associated with functional outcomes; thus, the treatment of cognitive impairments is of central importance. A large body of evidence suggests that the serotonin 6 (5-HT6) receptors may be potential targets for cognitive improvement. Clinical and preclinical studies have supported the notion that using 5-HT6 receptor antagonists is a promising component in the treatment of cognitive dysfunctions associated with aging and Alzheimer's disease. However, less is known about the efficacy of this strategy in the treatment of schizophrenia-like cognitive disturbances. The purpose of this review is to summarize existing data on the effects of 5-HT6 receptor antagonists in animal experiments, utilizing tasks that assess cognitive domains that are relevant to the cognitive deficits characterizing schizophrenia. This review focuses primarily on animal models of schizophrenia that are based on the blockade of N-methyl-d-aspartate receptors; however, when relevant, data obtained in other models are also discussed. The putative procognitive actions of 5-HT6 agonists are also reviewed. Finally, the mechanisms that are putatively responsible for the procognitive effects of 5-HT6 receptor ligands are briefly discussed.


Assuntos
Ligantes , Receptores de Serotonina/metabolismo , Esquizofrenia/complicações , Antagonistas da Serotonina/uso terapêutico , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Humanos
9.
Eur Neuropsychopharmacol ; 78: 30-42, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37866191

RESUMO

Social and cognitive dysfunctions are the most persistent symptoms of schizophrenia. Since oxytocin (OXT) is known to play a role in social functions and modulates cognitive processes, we investigated the effects of a novel, nonpeptide, selective OXT receptor agonist, LIT-001, in a neurodevelopmental model of schizophrenia. Administration of methylazoxymethanol acetate (MAM; 22 mg/kg) on the 17th day of rat pregnancy is known to cause developmental disturbances of the brain, which lead to schizophrenia-like symptomatology in the offspring. Here, we examined the effects of acutely administered LIT-001 (1, 3, and 10 mg/kg) in MAM-exposed males and females on social behaviour, communication and cognition. We report that MAM-treated adult male and female rats displayed reduced social behaviour, ultrasonic communication and novel object recognition test performance. LIT-001 partially reversed these deficits, increasing the total social interaction time and the number of 'positive', highly-modulated 50 kHz ultrasonic calls in male rats. The compound ameliorated MAM-induced deficits in object discrimination in both sexes. Present results confirm the pro-social activity of LIT-001 and demonstrate its pro-cognitive effects following acute administration.


Assuntos
Pirazóis , Pirrolidinas , Esquizofrenia , Gravidez , Ratos , Feminino , Masculino , Animais , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Ocitocina/farmacologia , Receptores de Ocitocina , Cognição , Acetato de Metilazoximetanol/toxicidade , Modelos Animais de Doenças
10.
Sci Rep ; 13(1): 1918, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36732579

RESUMO

A wide body of evidence suggests a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD). Since social and communicative deficits are included in the first diagnostic criterion of ASD, we aimed to characterize socio-communicative behaviors in the MIA model based on prenatal exposure to poly(I:C). Our previous studies demonstrated impaired socio-communicative functioning in poly(I:C)-exposed adolescent rats. Therefore, the current study sought to clarify whether these changes would persist beyond adolescence. For this purpose, we analyzed behavior during the social interaction test and recorded ultrasonic vocalizations (USVs) accompanying interactions between adult poly(I:C) rats. The results demonstrated that the altered pattern of social behavior in poly(I:C) males was accompanied by the changes in acoustic parameters of emitted USVs. Poly(I:C) males also demonstrated an impaired olfactory preference for social stimuli. While poly(I:C) females did not differ from controls in socio-positive behaviors, they displayed aggression during the social encounter and were more reactive to somatosensory stimulation. Furthermore, the locomotor pattern of poly(I:C) animals were characterized by repetitive behaviors. Finally, poly(I:C) reduced parvalbumin and GAD67 expression in the cerebellum. The results showed that prenatal poly(I:C) exposure altered the pattern of socio-communicative behaviors of adult rats in a sex-specific manner.


Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Masculino , Humanos , Feminino , Ratos , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Comportamento Social , Poli I-C/farmacologia
11.
Eur Neuropsychopharmacol ; 67: 37-52, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36476352

RESUMO

(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mg/kg) that resemble fluoxetine's (2.5-10 mg/kg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Weber's fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mg/kg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers' actions, but unexpectedly, increased fluoxetine' performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies.


Assuntos
Transtorno Depressivo , Ketamina , Ratos , Masculino , Animais , Fluoxetina/farmacologia , Ketamina/farmacologia , Reforço Psicológico , Antidepressivos/farmacologia , Esquema de Reforço
12.
Front Pharmacol ; 14: 1329424, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38269275

RESUMO

Traditional methods of rat social behavior assessment are extremely time-consuming and susceptible to the subjective biases. In contrast, novel digital techniques allow for rapid and objective measurements. This study sought to assess the feasibility of implementing a digital workflow to compare the effects of (R,S)-ketamine and a veterinary ketamine preparation Vetoquinol (both at 20 mg/kg) on the social behaviors of rat pairs. Historical and novel videos were used to train the DeepLabCut neural network. The numerical data generated by DeepLabCut from 14 video samples, representing various body parts in time and space were subjected to the Simple Behavioral Analysis (SimBA) toolkit, to build classifiers for 12 distinct social and non-social behaviors. To validate the workflow, previously annotated by the trained observer historical videos were analyzed with SimBA classifiers, and regression analysis of the total time of social interactions yielded R 2 = 0.75, slope 1.04; p < 0.001 (N = 101). Remarkable similarities between human and computer annotations allowed for using the digital workflow to analyze 24 novel videos of rats treated with vehicle and ketamine preparations. Digital workflow revealed similarities in the reduction of social behavior by both compounds, and no substantial differences between them. However, the digital workflow also demonstrated ketamine-induced increases in self-grooming, increased transitions from social contacts to self-grooming, and no effects on adjacent lying time. This study confirms and extends the utility of deep learning in analyzing rat social behavior and highlights its efficiency and objectivity. It provides a faster and objective alternative to human workflow.

13.
Behav Pharmacol ; 23(4): 434-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22743605

RESUMO

Chronic stress exerts detrimental effects on higher order executive functions that are governed by the prefrontal cortex. Experimental data suggest that dopamine D1 receptor-mediated hypodopaminergic dysfunction may underlie stress-induced cognitive deficits. However, although the involvement of D1 receptors in working memory is well established, less is known about their role in the modulation of set-shifting ability. Therefore, the aim of the present study was to examine the impact of the selective D1 receptor agonist, SKF 81297, on the attentional set-shifting task performance of rats subjected to repeated restraint stress and of unrestrained controls. The acute administration of SKF 81297 to control rats facilitated extradimensional set-shifting. However, only intermediate doses (0.1 and 0.3 mg/kg) were effective, whereas no effect was observed after the administration of either lower (0.01 mg/kg) or higher (1 mg/kg) doses. This dose-response curve was shifted to the left in stressed animals as the effectiveness of SKF 81297 (as compared with either vehicle-treated controls or stressed animals) was found only after the administration of lower drug doses (0.01 and 0.1 mg/kg). The beneficial effects of SKF 81297 on the attentional set-shifting task performance of stressed rats may have therapeutic implications for the treatment of frontal-like disturbances, particularly cognitive inflexibility, in stress-related psychiatric disorders.


Assuntos
Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , Enquadramento Psicológico , Animais , Atenção/efeitos dos fármacos , Benzazepinas/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia
14.
Pharmaceuticals (Basel) ; 15(11)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36422547

RESUMO

There is still no effective treatment that addresses the core symptoms of autism spectrum disorders (ASD), including social and communication deficits. A comprehensive body of evidence points to the cholinergic system, including alpha7-nicotinic acetylcholine receptors (α7-nAChRs), as a potential target of pharmacotherapy. A promising approach is based on positive allosteric modulators (PAMs) of these receptors due to their advantages over direct agonists. Nevertheless, α7 n-AChR ligands have not been widely studied in the context of autism. Therefore, using one of the most widely used rodent models of ASD, that is, prenatal exposure to valproic acid (VPA), we examined the impact of α7-nAChR PAMs (PNU-120596 and CCMI) on socio-communicative behavior during social play in adolescent male and female rats. The current study demonstrated that PAM treatment affected certain aspects of socio-communicative behavior in adolescent rats. Accordingly, PNU-120596 ameliorated deficient play abilities in VPA-exposed males, as revealed by increased play time during a social encounter. In addition, this compound enhanced the emission of ultrasonic vocalizations that accompanied playful interactions. Moreover, we observed the overall effect of PNU-120596 on non-playful forms of social behavior (i.e., social exploration) and acoustic parameters (i.e., the duration) of emitted calls. The present results suggest the ability of α7-nAChR PAMs to facilitate socio-communicative behavior in adolescent rats.

15.
Psychopharmacology (Berl) ; 239(6): 1689-1703, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35234983

RESUMO

RATIONALE: Ketamine and psilocybin belong to the rapid-acting antidepressants but they also produce psychotomimetic effects including timing distortion. It is currently debatable whether these are essential for their therapeutic actions. As depressed patients report that the "time is dragging," we hypothesized that ketamine and psilocybin-like compounds may produce an opposite effect, i.e., time underestimation, purportedly contributing to their therapeutic properties. OBJECTIVES: Timing was tested following administration of (R)- and (S)-ketamine, and psilocybin, psilocin, and norpsilocin in the discrete-trial temporal discrimination task (TDT) in male rats. Timing related to premature responses, and cognitive and unspecific effects of compounds were tested in the 5-choice serial reaction time task (5-CSRTT) in the standard 1-s, and "easier" 2-s stimulus duration conditions, as well as in the vITI variant promoting impulsive responses. RESULTS: (S)-ketamine (15 but not 3.75 or 7.5 mg/kg) shifted psychometric curve to the right in TDT and reduced premature responses in 5-CSRTT, suggesting expected time underestimation, but it also decreased the accuracy of temporal discrimination and increased response and reward latencies, decreased correct responses, and increased incorrect responses. While (R)-ketamine did not affect timing and produced no unspecific actions, it reduced incorrect responses in TDT and increased accuracy in 5-CSRTT, suggesting pro-cognitive effects. Psilocin and psilocybin produced mainly unspecific effects in both tasks, while norpsilocin showed no effects. CONCLUSIONS: Time underestimation produced by (S)-ketamine could be associated with its antidepressant effects; however, it was accompanied with severe behavioral disruption. We also hypothesize that behavioral disruption produced by psychedelics objectively reflects their psychotomimetic-like actions.


Assuntos
Ketamina , Psilocibina , Animais , Antidepressivos/farmacologia , Cognição , Humanos , Ketamina/farmacologia , Masculino , Psilocibina/análogos & derivados , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Ratos , Serotonina/análogos & derivados
16.
Behav Brain Res ; 409: 113338, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-33940049

RESUMO

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the treatment of cognitive decline in patients with schizophrenia, Alzheimer's disease, and attention-deficit/hyperactivity disorder. Here we examined the promnesic activity of the α7 nAChR agonist (A582941), the type I (CCMI), and the type II (PNU120596) positive allosteric modulators (PAMs) in rats following single and repeated (once daily for seven days) treatment. To determine the neuronal mechanisms underlying the procognitive activity of the tested compounds, levels of the extracellular signal-regulated kinases (Erk1/2) and the activity-regulated cytoskeleton-associated protein (Arc) mRNAs were assessed in the frontal cortical and hippocampal brain regions. Using the novel object recognition test, we demonstrate that the lower doses of A582941 (0.1 mg/kg), CCMI (1 mg/kg), and PNU120596 (0.3 mg/kg) improved recognition memory after repeated but not single administration, suggesting a cumulative effect of repeated dosing. In contrast, the higher doses of A582941 (0.3 mg/kg), CCMI (3 mg/kg) and PNU120596 (1 mg/kg) demonstrated promnesic efficacy following both single and repeated administration. Subsequent in situ hybridization revealed that repeated treatment with A582941 and CCMI, but not PNU120596 enhanced mRNA expression of the Erk1/2 and Arc in the frontal cortex and hippocampus. Present data suggest that both the α7 nAChR agonist and PAMs exhibit procognitive effects after single and repeated administration. The increased level of the Erk1/2 and Arc genes is likely to be at least partially involved in this effect.


Assuntos
Comportamento Animal/efeitos dos fármacos , Proteínas do Citoesqueleto/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Nootrópicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Animais , Masculino , Agonistas Nicotínicos/administração & dosagem , Nootrópicos/administração & dosagem , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Brain Sci ; 11(3)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803154

RESUMO

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

18.
J Med Chem ; 64(18): 13279-13298, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34467765

RESUMO

In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.


Assuntos
Antipsicóticos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Nootrópicos/uso terapêutico , Receptores 5-HT3 de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Animais , Antipsicóticos/síntese química , Antipsicóticos/metabolismo , Antipsicóticos/farmacocinética , Combinação de Medicamentos , Cobaias , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Nootrópicos/síntese química , Nootrópicos/metabolismo , Nootrópicos/farmacocinética , Ondansetron/uso terapêutico , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT3 de Serotonina/síntese química , Antagonistas do Receptor 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/uso terapêutico
19.
ACS Chem Neurosci ; 12(7): 1228-1240, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33705101

RESUMO

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.


Assuntos
Pirróis , Receptores de Serotonina , Animais , Cognição , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade
20.
J Pharmacol Exp Ther ; 335(3): 665-73, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20739457

RESUMO

Orthosteric group II metabotropic glutamate receptor (mGluR) agonists are regarded as novel, effective medications for all major symptom domains of schizophrenia, including cognitive disturbances. mGluR2s also can be affected in a more subtle way by positive allosteric modulators (PAMs) characterized by a unique degree of subtype selectivity and neuronal frequency-dependent activity. Because currently available treatments for schizophrenia do not improve cognitive dysfunction, the main aim of the present study was to examine the effects of a mGluR2 PAM, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine (LY487379), on rat cognitive flexibility and impulsive-like responding, assessed in an attentional set-shifting task (ASST) and a differential reinforcement of low-rate 72 s (DRL72) schedule of food reinforcement. In addition, in vivo microdialysis was used to assess the drug's impact on cortical levels of dopamine, norepinephrine, serotonin, and glutamate. Rats treated with LY487379 (30 mg/kg) required significantly fewer trials to criteria during the extradimensional shift phase of the ASST. Under a DRL72 schedule, LY487379 (30 mg/kg) decreased the response rate and increased the number of reinforcers obtained. These effects were accompanied by the shift of the frequency distribution of responses toward longer inter-response time durations. LY487379 significantly enhanced extracellular norepinephrine and serotonin levels in the medial prefrontal cortex. In summary, the present study demonstrates that a mGluR2 PAM, LY487379, promotes cognitive flexibility and facilitates behavioral inhibition. These procognitive effects may contribute to the therapeutic efficacy of agents stimulating mGluR2 in schizophrenia.


Assuntos
Cognição/efeitos dos fármacos , Comportamento Impulsivo/tratamento farmacológico , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Microdiálise , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Norepinefrina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reforço Psicológico , Serotonina/metabolismo , Sulfonamidas/uso terapêutico
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