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1.
Horm Behav ; 144: 105218, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35785712

RESUMO

Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Histonas , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Anticoncepcionais/metabolismo , Anticoncepcionais/farmacologia , Feminino , Hipocampo , Histonas/metabolismo , Humanos , Plasticidade Neuronal , Processamento de Proteína Pós-Traducional , Ratos
2.
Biomolecules ; 14(2)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38397408

RESUMO

Previous work from our laboratory demonstrated that parental stress, induced by social isolation starting at puberty, leads to behavioral, endocrine, and biochemical changes in the male, but not female, offspring (ISO-O) of Sprague-Dawley rats. Here, we report alterations in the gut microbiota composition of ISO-O vs. grouped-housed offspring (GH-O), although all animals received the same diet and were housed in the same conditions. Analysis of bacterial communities by next-generation sequencing (NGS) of 16S rRNA gene revealed alterations at family and order levels within the main phyla of Bacteroides, Proteobacteria, and Firmicutes, including an almost total deficit in Limosilactobacillus reuteri (formerly Lactobacillus reuteri) and a significant increase in Ligilactobacillus murinus (formerly Lactobacillus murinus). In addition, we found an increase in the relative abundance of Rhodospirillales and Clostridiales in the families of Lachnospiraceae and Ruminococcaceae, and Bacteroidales in the family of Prevotellaceae. Furthermore, we examined plasma levels of the proinflammatory cytokines interleukin-1-beta and tumor necrosis factor-alpha, which did not differ between the two groups, while corticosterone concentrations were significantly increased in ISO-O rats. Our findings suggest that adverse environmental conditions experienced by parents may have an impact on the likelihood of disease development in the subsequent generations.


Assuntos
Microbioma Gastrointestinal , Lactobacillus , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Isolamento Social
3.
Front Behav Neurosci ; 16: 893835, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35755407

RESUMO

Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABABR using the 2-bottle choice paradigm. We found that GABAB(1), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB(1) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABABR and δ-containing GABAA receptor (δ-GABA A R), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABAAR δ subunit in the hippocampus of the GABAB(1) KO alcohol-naïve mice that was associated with increased É£2 subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABAAR responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABAAR occurring in the GABAB(1) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABAB(1) KO and WT mice because of previous involvement of GABABR in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABAB(1) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABAB(1) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABAAR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABAB(1) KO mice. In addition, we documented that GABAB(1) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.

4.
J Neurosci ; 29(6): 1755-65, 2009 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-19211882

RESUMO

Pregnancy is associated with changes in mood and anxiety level as well as with marked hormonal fluctuations. Increases in the brain concentrations of neuroactive steroids during pregnancy in rats are accompanied by changes in expression of subunits of the GABA type A receptor (GABA(A)-R) in the brain. Granule cells of the dentate gyrus (DGGCs) exhibit two components of inhibitory GABAergic transmission: a phasic component mediated by synaptic GABA(A)-Rs, and a tonic component mediated by extrasynaptic GABA(A)-Rs. Recordings of GABAergic currents were obtained from hippocampal slices prepared from rats in estrus, at pregnancy day 15 (P15) or P19, or at 2 d after delivery. Exogenous GABA or 3alpha,5alpha-THP induced an increase in tonic current in DGGCs that was significantly greater at P19 than in estrus. Neither tonic nor phasic currents were affected by pregnancy in CA1 pyramidal cells. Immunohistochemical analysis revealed a marked increase in the abundance of the delta subunit of the GABA(A)-R and a concomitant decrease in that of the gamma(2) subunit in the hippocampus at P19. Expression of the alpha(4) subunit did not change during pregnancy but was increased 2 d after delivery. Treatment of rats from P12 to P18 with the 5alpha-reductase inhibitor finasteride prevented the changes in tonic current and in delta and gamma(2) subunit expression normally apparent at P19. These data suggest that the number of extrasynaptic GABA(A)-Rs is increased in DGGCs during late pregnancy as a consequence of the associated marked fluctuations in the brain levels of neuroactive steroids.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/fisiologia , Período Pós-Parto/fisiologia , Prenhez/fisiologia , Receptores de GABA-A/fisiologia , Sinapses/fisiologia , Animais , Feminino , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Gravidez , Subunidades Proteicas/biossíntese , Subunidades Proteicas/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/biossíntese
5.
Neuropharmacology ; 157: 107686, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31247268

RESUMO

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by changes in social interactions, impaired language and communication, fear responses and presence of repetitive behaviours. Although the genetic bases of ASD are well documented, the recent increase in clinical cases of idiopathic ASD indicates that several environmental risk factors could play a role in ASD aetiology. Among these, maternal exposure to psychosocial stressors during pregnancy has been hypothesized to affect the risk for ASD in offspring. Here, we tested the hypothesis that preconceptional stressful experiences might also represent crucial elements in the aetiology of ASD. We previously showed that social isolation stress during adolescence results in a marked decrease in the brain and plasma concentrations of progesterone and in the quality of maternal care that these female rats later provide to their young. Here we report that male offspring of socially isolated parents showed decreased agonistic behaviour and social transmission of flavour preference, impairment in reversal learning, increased seizure susceptibility, reduced plasma oxytocin levels, and increased plasma and brain levels of BDNF, all features resembling an ASD-like phenotype. These alterations came with no change in spatial learning, aggression, anxiety and testosterone plasma levels, and were sex-dependent. Altogether, the results suggest that preconceptional stressful experiences should be considered as crucial elements for the aetiology of ASD, and indicate that male offspring of socially isolated parents may be a useful animal model to further study the neurobiological bases of ASD, avoiding the adaptations that may occur in other genetic or pharmacologic experimental models of these disorders.


Assuntos
Transtorno do Espectro Autista/etiologia , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Isolamento Social/psicologia , Estresse Psicológico/psicologia , Animais , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Isoniazida/efeitos adversos , Masculino , Ocitocina/sangue , Fenótipo , Córtex Pré-Frontal/metabolismo , Gravidez , Ratos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Comportamento Social , Testosterona/sangue
6.
J Neurochem ; 106(6): 2502-14, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18624910

RESUMO

The role of neuroactive steroids and GABA(A) receptors in the generation of spontaneous spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The plasma, cerebrocortical, and thalamic concentrations of the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) were increased in the WAG/Rij rat at 2 months of age compared with those in control (Wistar) rats. In contrast, the brain and peripheral levels of 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) did not differ between the two rat strains at this age. At 6 months of age, when absence epilepsy worsens in WAG/Rij rats, the plasma concentration of 3alpha,5alpha-TH PROG remained high whereas that of 3alpha,5alpha-TH DOC had increased, the cerebrocortical levels of both 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC had increased, and the thalamic concentrations of these metabolites had decreased. At 6 months of age the expression of the alpha(4) and delta subunits of the GABA(A) receptor in relay nuclei was increased. Finally, chronic stress induced by social isolation elicited a reduction in the amount of 3alpha,5alpha-TH PROG in the thalamus of 2-month-old WAG/Rij rats that was associated with a reduction in the number and overall duration of SWDs at 6 months of age. Absence epilepsy in the WAG/Rij rat is thus associated with changes in the abundance of neuroactive steroids and in the expression of specific GABA(A) receptor subunits in the thalamus, a brain area key to the pathophysiology of this condition.


Assuntos
Encéfalo/metabolismo , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/metabolismo , Plasticidade Neuronal/genética , Receptores de GABA-A/metabolismo , Esteroides/metabolismo , Envelhecimento/metabolismo , Animais , Animais Geneticamente Modificados , Encéfalo/fisiopatologia , Química Encefálica/genética , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Epilepsia Tipo Ausência/fisiopatologia , Masculino , Pregnanolona/análogos & derivados , Pregnanolona/metabolismo , Subunidades Proteicas/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Tálamo/metabolismo , Tálamo/fisiopatologia , Regulação para Cima/fisiologia , Ácido gama-Aminobutírico/metabolismo
7.
Bioorg Med Chem ; 16(6): 3428-37, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18294852

RESUMO

The exploration of the structure-affinity relationships concerning a new class of peripheral benzodiazepine receptor (PBR) ligands related to alpidem has been pursued in order to evaluate the consistency of the structure-affinity relationships among different classes (and subclasses) of PBR ligands. The target amide derivatives were prepared following a previously published procedure based on the condensation of pyrrolo[3,4-b]quinoline derivatives 11a,b with glyoxylic acid mono-hydrate and the subsequent amidation of the acids obtained via mixed anhydride. On the other hand, the preparation of compound 9g lacking the pharmacophoric (delta1) carbonyl group involved: (a) the double sequential attack of the dimethylmethyleneammonium salt obtained from bis(dimethylamino)methane and acetyl chloride to pyrrolo[3,4-b]quinoline derivative 11b, (b) the quaternization of the obtained allylamine derivative 13 with methyl iodide, and (c) the palladium-catalyzed allylation of N-methyl-p-anisidine by quaternary allylammonium cation 14. The structure-affinity relationship trends observed in this subclass of tricyclic alpidem-related PBR ligands find correlations in other classes (or subclasses) of PBR ligands. This result supports the initial pharmacophoric hypothesis and suggests a common mode of interaction at the PBR binding site.


Assuntos
Proteínas de Transporte/metabolismo , Imidazóis/farmacologia , Piridinas/farmacologia , Receptores de GABA-A/metabolismo , Receptores de GABA/metabolismo , Amidas/química , Animais , Imidazóis/síntese química , Imidazóis/química , Ligantes , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/química , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
Eur J Pharmacol ; 558(1-3): 37-42, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17234181

RESUMO

Thiocolchicoside is a myorelaxant drug with anti-inflammatory and analgesic properties as well as pronounced convulsant activity. To characterize the mechanisms of action of this drug at the molecular level, we examined its effects on the function of various recombinant neurotransmitter receptors expressed in Xenopus oocytes. Electrophysiological recordings from recombinant human gamma-aminobutyric acid type A (GABA(A)) receptors consisting of alpha1beta1gamma2L, alpha1beta2gamma2L, or alpha2beta2gamma2L subunit combinations revealed that thiocolchicoside inhibited GABA-evoked Cl(-) currents with similar potencies (median inhibitory concentrations of 0.13 to 0.2 microM) and in a competitive manner. Consistent with previous observations, thiocolchicoside also inhibited the binding of GABA to rat cerebral cortical membranes. Thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. It also inhibited the function of human nicotinic acetylcholine receptors composed of the alpha4 and beta2 subunits, but this effect was only partial and apparent at high concentrations. In contrast, thiocolchicoside had no effect on the function of 5-HT(3A) serotonin receptors. Our results thus provide molecular evidence that the epileptogenic activity of thiocolchicoside might be due to inhibition of the function of inhibitory receptors in the central nervous system, especially that of GABA(A) receptors.


Assuntos
Colchicina/análogos & derivados , Antagonistas de Receptores de GABA-A , Animais , Colchicina/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/classificação , Receptores de Glicina/antagonistas & inibidores , Receptores Nicotínicos/fisiologia , Receptores 5-HT3 de Serotonina/fisiologia , Proteínas Recombinantes/antagonistas & inibidores , Xenopus laevis
9.
Pharmacol Biochem Behav ; 85(1): 76-81, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16938341

RESUMO

Stressful stimuli and anxiogenic drugs increase the plasma and brain concentrations of neuroactive steroids. Moreover, in rats trained to consume their daily meal during a fixed period, the anticipation of food is associated with changes in the function of various neurotransmitter systems. We have now evaluated the effects of anticipation and consumption of food in such trained rats on the plasma and brain concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH DOC), two potent endogenous positive modulators of type A receptors for gamma-aminobutyric acid (GABA). The abundance of these neuroactive steroids was increased in both the cerebral cortex and plasma of the rats during both food anticipation and consumption. In contrast, the concentration of their precursor, progesterone, was increased in the brain only during food consumption, whereas it was increased in plasma only during food anticipation. Intraperitoneal administration of the selective agonist abecarnil (0.1 mg/kg) 40 min before food presentation prevented the increase in the brain levels of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC during food anticipation but not that associated with consumption. The change in emotional state associated with food anticipation may thus result in an increase in the plasma and brain levels of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC in a manner sensitive to the activation of GABA(A) receptor-mediated neurotransmission. A different mechanism, insensitive to activation of such transmission, may underlie the changes in the concentrations of these neuroactive steroids during food consumption.


Assuntos
Encéfalo/metabolismo , Comportamento Alimentar , Esteroides/metabolismo , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Esteroides/sangue
10.
Eur J Pharmacol ; 516(3): 204-11, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15967425

RESUMO

Ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate (TG41) enhanced the binding both of gamma-aminobutyric acid (GABA) and of flunitrazepam to rat cerebral cortical membranes. Electrophysiological recordings from Xenopus oocytes expressing various recombinant GABA(A) receptor subtypes revealed that TG41 enhanced the function of all receptor subunit combinations tested. The potency of TG41 at receptors containing alpha1, beta2, and gamma2L subunits was greater than that of alphaxalone, etomidate, propofol, or pentobarbital. The potency of TG41 was also greater at receptors containing alpha1 or alpha2 subunits than at those containing alpha4 and it was markedly higher at receptors containing beta2 or beta3 subunits than at those containing beta1. This drug induced a reversible loss of the righting reflex in Xenopus tadpoles and it elicited hypnosis (5 mg/kg) after intravenous administration in rats. These results indicate that the pharmacological profile of TG41 is similar to that of general anesthetics which potentiate the activity of GABA(A) receptors containing the beta2 or beta3 subunit.


Assuntos
Moduladores GABAérgicos/farmacologia , Hidrocarbonetos Halogenados/farmacologia , Imidazóis/farmacologia , Receptores de GABA-A/fisiologia , Animais , Ligação Competitiva/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Etomidato/farmacologia , Feminino , Flunitrazepam/metabolismo , Glicina/farmacologia , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Oócitos/fisiologia , Pentobarbital/farmacologia , Pregnanodionas/farmacologia , Propofol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/genética , Receptores de Glicina/genética , Receptores de Glicina/fisiologia , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/fisiologia , Serotonina/farmacologia , Trítio , Xenopus laevis , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
11.
Eur J Pharmacol ; 519(1-2): 31-42, 2005 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-16107249

RESUMO

The effects of prolonged exposure to and subsequent withdrawal of the thienotriazolobenzodiazepine etizolam on gamma-aminobutyric acid (GABA) type A receptor gene expression and function were compared with those of the benzodiazepine lorazepam. Exposure of rat hippocampal neurons in culture to 10 microM etizolam for 5 days reduced the amounts of alpha5 and gamma2S receptor subunit mRNAs, whereas etizolam withdrawal was associated with a persistent reduction in gamma2S mRNA and an increase in alpha2 and alpha3 mRNAs. Neither chronic exposure to nor withdrawal of etizolam affected the acute modulatory effects of etizolam or lorazepam on GABA-evoked Cl- current. Treatment with 10 microM lorazepam for 5 days reduced the amounts of alpha1 and gamma2S subunit mRNAs and increased that of alpha3 mRNA, whereas lorazepam withdrawal was associated with persistence of the changes in alpha3 and gamma2S mRNAs and an increase in alpha2 and alpha4 mRNAs. Parallel changes in the abundance of alpha1 and alpha4 subunit proteins induced by chronic exposure to and withdrawal of lorazepam, but not etizolam, were detected by immunocytofluorescence analysis. Chronic lorazepam treatment resulted in a reversible reduction in the modulatory efficacy of this drug and conferred on flumazenil the ability to potentiate GABA-evoked Cl- current. The anticonvulsant action of etizolam was not altered in mice chronically treated with this drug, whereas lorazepam-treated animals became tolerant to the acute anticonvulsant effect of this benzodiazepine. These data suggest that etizolam is endowed with a reduced liability to induce tolerance and dependence compared with classical benzodiazepines.


Assuntos
Diazepam/análogos & derivados , Receptores de GABA-A/genética , Animais , Animais Recém-Nascidos , Ligação Competitiva/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Diazepam/farmacologia , Imunofluorescência , Moduladores GABAérgicos/farmacologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Isoniazida/toxicidade , Lorazepam/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/fisiologia , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Radioisótopos de Enxofre , Tranquilizantes/farmacologia
12.
J Med Chem ; 45(21): 4655-68, 2002 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-12361392

RESUMO

A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a-r) were designed and synthesized as possible ligands with mixed dopamine (DA) D(2)/serotonin 5-HT(1A) affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D(2) like, 5-HT(1A), and 5-HT(2A) receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D(2) like, serotonin 5-HT(1A), and 5-HT(2A) receptors, with IC(50) values ranging from 25 to >10,000 nM. As for the modification of the piperazine N(4)-phenyl ring, the affinities for both D(2) like and 5-HT(1A) receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D(2) like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT(1A) receptors. A quantitative structure-affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D(2) like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a-r to 5-HT(1A) receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT(2A) receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D(2)/5-HT(1A) IC(50) ratio of approximately 1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl(-) currents at recombinant GABA(A) receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.


Assuntos
Clozapina/farmacologia , Imidazóis/síntese química , Piperazinas/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Animais , Córtex Cerebral/metabolismo , Canais de Cloreto/antagonistas & inibidores , Dopamina/metabolismo , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Desenho de Fármacos , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Piperazinas/química , Piperazinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Ratos , Receptor 5-HT2A de Serotonina , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Xenopus laevis
13.
J Med Chem ; 46(17): 3568-71, 2003 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-12904061

RESUMO

The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands have been refined with the aim of using these ligands as carriers of radionuclides and boron atoms. Some new ligands show enhanced affinity and steroidogenic activity with respect to reference compound 1 and are interesting candidates for radiolabeling and PET studies. Moreover, carborane derivative 3q, representing the first example of PBR ligand bearing a carborane cage, can be useful to explore an alternative mechanism in BNCT.


Assuntos
Amidas/síntese química , Boranos/síntese química , Quinolinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Receptores de GABA-A/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Animais , Boranos/química , Boranos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas In Vitro , Ligantes , Pregnanolona/biossíntese , Pregnenolona/biossíntese , Progesterona/biossíntese , Quinolinas/química , Quinolinas/farmacologia , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Ratos , Relação Estrutura-Atividade
14.
Eur J Pharmacol ; 451(2): 103-10, 2002 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-12231378

RESUMO

The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition site of GABA(A) receptors. Zaleplon, like the hypnotic agent zolpidem but unlike classical benzodiazepines, exhibits preferential affinity for type I benzodiazepine (BZ(1)/omega(1)) receptors in binding assays. The modulatory action of zaleplon at GABA(A) receptors has now been compared with those of zolpidem and the triazolobenzodiazepine triazolam. Zaleplon potentiated GABA-evoked Cl(-) currents in Xenopus oocytes expressing human GABA(A) receptor subunits with a potency that was higher at alpha1beta2gamma2 receptors than at alpha2- or alpha3-containing receptors. Zolpidem, but not triazolam, also exhibited selectivity for alpha1-containing receptors. However, the potency of zaleplon at these various receptors was one-third to one-half that of zolpidem. Zaleplon and zolpidem also differed in their actions at receptors containing the alpha5 or gamma3 subunit. Zaleplon, zolpidem, and triazolam exhibited similar patterns of efficacy among the different receptor subtypes. The affinities of zaleplon for [(3)H]flunitrazepam or t-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding sites in rat brain membranes were lower than those of zolpidem or triazolam. Furthermore, zaleplon, unlike zolpidem, exhibited virtually no affinity for the peripheral type of benzodiazepine receptor.


Assuntos
Acetamidas/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Receptores de GABA-A/metabolismo , Triazolam/metabolismo , Animais , Córtex Cerebral/metabolismo , Feminino , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Xenopus laevis , Zolpidem
15.
Farmaco ; 59(11): 849-56, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15544788

RESUMO

A series of new pyrazole-condensed 6,5,5 tricyclic compounds were synthesized and tested to evaluate their binding affinities at both central (CBR) and peripheral (PBR) benzodiazepine receptors. Some 1-aryl-5-phenylpyrazole derivatives were also prepared and tested for comparison with their corresponding rigid tricyclic analogs. Among the newly synthesized 1-aryl-1,4-dihydro-indeno[1,2-c]pyrazoles bearing both an ethoxycarbonyl group at position 3 and a carbonyl function at the position 4, compound 4b emerged as a new potent (IC(50) = 26.4 nM) and selective CBR ligand. The 4-oxo-1-aryl-1,4-dihydro-indeno[1,2-c]pyrazole diethylamide derivative 14a was instead identified as a relatively potent (IC(50) = 124 nM) but highly selective PBR ligand.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos/síntese química , Pirazóis/síntese química , Pirazóis/metabolismo , Receptores de GABA-A/metabolismo , Animais , Concentração Inibidora 50 , Ligantes , Masculino , Ratos , Ratos Sprague-Dawley
16.
Farmaco ; 58(2): 129-40, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12581779

RESUMO

A large number of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines were synthesised and tested to evaluate their binding affinities at both central (CBR) and peripheral (PBR) benzodiazepine receptors. Relatively good PBR binding affinities were found for ligands belonging to the 3-arylmethyloxy-pyridazinoindole series, whereas only 2-aryl-indenopyridazines 7a, 8a and 10a display a weak binding affinity for CBR. To find out the main structural determinants affecting PBR affinity, a molecular modelling study based on the comparative analysis of the three-dimensional properties of four properly selected derivatives 24a, 3b, 18a and 10d, with those of highly active and selective PBR ligands, taken as reference, was performed.


Assuntos
Piridazinas/síntese química , Piridazinas/metabolismo , Receptores de GABA-A/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Ratos , Ratos Sprague-Dawley
17.
Eur J Pharmacol ; 733: 1-6, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24704372

RESUMO

Several aryl pyrazoles characterized by a different molecular structure (flexible vs constrained), but chemically related to rimonabant and AM251, were tested for their ability to modulate the function of recombinant α1ß2γ2L GABAA receptors expressed in Xenopus laevis oocytes. The effects of 6Bio-R, 14Bio-R, NESS 0327, GP1a and GP2a (0.3-30 µM) were evaluated using a two-electrode voltage-clamp technique. 6Bio-R and 14Bio-R potentiated GABA-evoked Cl(-) currents. NESS 0327, GP1a and GP2a did not affect the GABAA receptor function, but they acted as antagonists of 6Bio-R. Moreover, NESS 0327 inhibited the potentiation of the GABAA receptor function induced by rimonabant. The benzodiazepine site seems to participate in the action of these compounds. In fact, flumazenil antagonized the potentiation of the GABAA receptor induced by 6Bio-R, and NESS 0327 reduced the action of lorazepam and zolpidem. On the contrary, NESS 0327 did not antagonize the action of "classic" GABAergic modulators (propanol, anesthetics, barbiturates or steroids). In α1ß2 receptors 6Bio-R potentiated the GABAergic function, but flumazenil was still able to antagonize the potentiation induced by 6Bio-R. Aryl pyrazole derivatives activity at the GABAA receptor depends on their molecular structure. These compounds bind to both an αßγ binding site, and to an α/ß site which do not require the γ subunit and that may provide structural leads for drugs with potential anticonvulsant effects.


Assuntos
Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores de GABA-A/metabolismo , Animais , Potenciais Evocados/efeitos dos fármacos , Feminino , Humanos , Ligantes , Estrutura Molecular , Oócitos/metabolismo , Técnicas de Patch-Clamp , Subunidades Proteicas , Receptores de GABA-A/genética , Proteínas Recombinantes , Relação Estrutura-Atividade , Transfecção , Xenopus laevis
18.
Eur Neuropsychopharmacol ; 21(5): 414-25, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21067904

RESUMO

Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. This mildly stressful condition reduces the cerebrocortical and plasma concentrations of 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) as well as increases the sensitivity of rats to the effects of acute ethanol administration on the concentrations of this neuroactive steroid. We further investigated the effects of voluntary consumption of ethanol at concentrations increasing from 2.5 to 10% over 4 weeks of isolation. Isolated rats showed a reduced ethanol preference compared with group-housed animals. Ethanol consumption did not affect the isolation-induced down-regulation of BDNF or Arc, but it attenuated the increase in the cerebrocortical concentration of 3α,5α-TH PROG induced by foot-shock stress in both isolated and group-housed animals as well as increased the percentage of number of entries made by socially isolated rats into the open arms in the elevated plus-maze test. Ethanol consumption did not affect expression of the α4 subunit of the GABA(A) receptor in the hippocampus of group-housed or isolated rats, whereas it up-regulated the δ subunit throughout the hippocampus under both conditions. The results suggest that low consumption of ethanol may ameliorate some negative effects of social isolation on stress sensitivity and behavior.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Emoções/efeitos dos fármacos , Etanol/farmacologia , Isolamento Social/psicologia , Análise de Variância , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Eletrochoque/efeitos adversos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pregnanolona/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/fisiopatologia
19.
J Neurochem ; 99(1): 321-32, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16879715

RESUMO

Type A receptors for GABA (GABA(A) receptors) that contain the delta subunit are located predominantly at extrasynaptic sites and are implicated in modulation of neuronal excitability through tonic inhibition. We have examined the effects of chronic exposure to and subsequent withdrawal of progesterone or the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THPROG) on expression of the delta subunit of GABA(A) receptors and on receptor function in cultured rat hippocampal neurons. Progesterone treatment for 1 day increased the amounts of both delta subunit mRNA and protein, whereas such treatment for 6 days induced marked decreases in the abundance of both the mRNA and protein. Subsequent progesterone withdrawal up-regulated expression of the delta subunit, which was significantly increased at 9-12 h after withdrawal. These effects of progesterone were mimicked by 3alpha,5alpha-THPROG and blocked by the 5alpha-reductase inhibitor finasteride. They were also accompanied by parallel changes in the function of GABA(A) receptors in hippocampal neurons. These results show that chronic exposure to and withdrawal of progesterone induce differential effects on both expression of the delta subunit of GABA(A) receptors and receptor function that are mediated by 3alpha,5alpha-THPROG. They are consistent with the notion that this progesterone metabolite plays a key physiological role in modulation of GABAergic synapses.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Progesterona/farmacologia , Células Piramidais/fisiologia , Receptores de GABA-A/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Hipocampo/fisiologia , Células Piramidais/efeitos dos fármacos , Sondas RNA , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
J Neurochem ; 98(1): 122-33, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16805802

RESUMO

Previously we have demonstrated that social isolation of rats reduces both the cerebrocortical and plasma concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG), and potentiates the positive effects of acute ethanol administration on the concentrations of this neurosteroid. We now show that the ethanol-induced increase in 3alpha,5alpha-TH PROG is more pronounced in the brain than in the plasma of isolated rats. The ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect is prevented by treatment with finasteride. Social isolation modified the effects of ethanol on the amounts of steroidogenic regulatory protein mRNA and protein in the brain. Moreover, ethanol increased the amplitude of GABA(A) receptor-mediated miniature inhibitory postsynaptic currents recorded from CA1 pyramidal neurones with greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed rats, an effect inhibited by finasteride. The amounts of the alpha(4) and delta subunits of the GABA(A) receptor in the hippocampus were increased in isolated rats as were GABA(A) receptor-mediated tonic inhibitory currents in granule cells of the dentate gyrus. These results suggest that social isolation results in changes in GABA(A) receptor expression in the brain, and in an enhancement of the stimulatory effect of ethanol on brain steroidogenesis, GABA(A) receptor function and associated behaviour.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de GABA/fisiologia , Isolamento Social , Análise de Variância , Animais , Bicuculina/farmacologia , Western Blotting , Inibidores Enzimáticos/farmacologia , Finasterida/farmacologia , Antagonistas GABAérgicos/farmacologia , Regulação da Expressão Gênica/fisiologia , Hipocampo/citologia , Imuno-Histoquímica/métodos , Técnicas In Vitro , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp/métodos , Pregnanolona/sangue , Pregnanolona/líquido cefalorraquidiano , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
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