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1.
Biol Aujourdhui ; 213(3-4): 121-129, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829932

RESUMO

Psychedelic drugs, often referred to as hallucinogens, are quite distinct from other classes of psychotropic drugs. Although the subjective and behavioral effects they induce are quite dramatic, they possess little addictive potential when compared to nicotine, alcohol or opiates. Since the discovery of ketamine antidepressant effects, there has been growing interest for these molecules. Serotonergic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) are gaining attention as potential treatments for depression and addiction, similarly to 3,4-methylenedioxymethamphetamine (MDMA) for post-traumatic stress disorder (PTSD), and ibogaine for addiction. Although they possess distinct pharmacological profiles, their kinetics of action are quite similar: the therapeutic effects are felt within the hours following administration, and last well beyond drug elimination by the organism. This strongly suggests the induction of neurogenic and plastic mechanisms, including the involvement of trophic factors. This review will explore the literature dealing with the effects of psychedelics on neurotrophins, as well as the plastic adaptations that they induce, in an attempt to understand their surprising therapeutic potential. We will show that although ketamine and serotonergic psychedelics have affinity for very different receptors (NMDA, 5-HT2A), they ultimately initiate similar plastic adaptations in the prefrontal cortex through the involvement of the brain-derived neurotrophic factor (BDNF). We will see that although MDMA uses the same receptors as serotonergic psychedelics to alleviate PTSD symptoms, its effect on BDNF levels seem paradoxical and quite different. Finally, we show how ibogaine could exert its anti-addictive properties through a completely different neurotrophic factor than other psychedelic drugs, the glial cell line-derived neurotrophic factor (GDNF). While the current literature concerning the psychiatric applications of psychedelic therapy is encouraging, it remains to be determined whether their benefits could be obtained without their psychotomimetic effects, or concerns over potential toxicity.


Assuntos
Alucinógenos/uso terapêutico , Fatores de Crescimento Neural/fisiologia , Psiquiatria/métodos , Animais , Humanos , Ibogaína/farmacologia , Ibogaína/uso terapêutico , Ketamina/farmacologia , Transtornos Mentais/etiologia , Transtornos Mentais/terapia , Fatores de Crescimento Neural/farmacologia , Psiquiatria/tendências , Serotonina/farmacologia , Serotoninérgicos/farmacologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
2.
ACS Chem Neurosci ; 10(11): 4476-4491, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31618004

RESUMO

G-protein-coupled receptors (GPCRs), also known as 7-transmembrane receptors, are the single largest class of drug targets. Consequently, a large amount of preclinical assays having GPCRs as molecular targets has been released to public sources like the Chemical European Molecular Biology Laboratory (ChEMBL) database. These data are also very complex covering changes in drug chemical structure and assay conditions like c0 = activity parameter (Ki, IC50, etc.), c1 = target protein, c2 = cell line, c3 = assay organism, etc., making difficult the analysis of these databases that are placed in the borders of a Big Data challenge. One of the aims of this work is to develop a computational model able to predict new GPCRs targeting drugs taking into consideration multiple conditions of assay. Another objective is to perform new predictive and experimental studies of selective 5-HTA2 receptor agonist, antagonist, or inverse agonist in human comparing the results with those from the literature. In this work, we combined Perturbation Theory (PT) and Machine Learning (ML) to seek a general PTML model for this data set. We analyzed 343 738 unique compounds with 812 072 end points (assay outcomes), with 185 different experimental parameters, 592 protein targets, 51 cell lines, and/or 55 organisms (species). The best PTML linear model found has three input variables only and predicted 56 202/58 653 positive outcomes (sensitivity = 95.8%) and 470 230/550 401 control cases (specificity = 85.4%) in training series. The model also predicted correctly 18 732/19 549 (95.8%) of positive outcomes and 156 739/183 469 (85.4%) of cases in external validation series. To illustrate its practical use, we used the model to predict the outcomes of six different 5-HT2A receptor drugs, namely, TCB-2, DOI, DOB, altanserin, pimavanserin, and nelotanserin, in a very large number of different pharmacological assays. 5-HT2A receptors are altered in schizophrenia and represent drug target for antipsychotic therapeutic activity. The model correctly predicted 93.83% (76 of 86) experimental results for these compounds reported in ChEMBL. Moreover, [35S]GTPγS binding assays were performed experimentally with the same six drugs with the aim of determining their potency and efficacy in the modulation of G-proteins in human brain tissue. The antagonist ketanserin was included as inactive drug with demonstrated affinity for 5-HT2A/C receptors. Our results demonstrate that some of these drugs, previously described as serotonin 5-HT2A receptor agonists, antagonists, or inverse agonists, are not so specific and show different intrinsic activity to that previously reported. Overall, this work opens a new gate for the prediction of GPCRs targeting compounds.


Assuntos
Big Data , Bases de Dados de Compostos Químicos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Aprendizado de Máquina , Receptores Acoplados a Proteínas-G/metabolismo , Radioisótopos de Enxofre/metabolismo , Adulto , Idoso , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Serotoninérgicos/metabolismo , Serotoninérgicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
3.
PLoS Negl Trop Dis ; 13(8): e0007573, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31408466

RESUMO

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct.


Assuntos
Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Clonorchis sinensis/efeitos dos fármacos , Clonorchis sinensis/fisiologia , Fasciola hepatica/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Ácido Cólico , Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , FMRFamida/farmacologia , Fluorenos/farmacologia , Neuropeptídeo Y/farmacologia , Peptídeo YY/farmacologia , Piperazinas/farmacologia , Serotoninérgicos/farmacologia , Compostos de Espiro/farmacologia , Sulpirida/farmacologia
4.
Anim Reprod Sci ; 208: 106122, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405473

RESUMO

The vitellogenesis-inhibiting hormone (VIH), also known as gonad-inhibiting hormone, is a neuropeptide hormone in crustaceans that belongs to the crustacean hyperglycemic hormone (CHH)-family peptide. There is regulation vitellogenesis by VIH during gonad maturation in crustaceans. A full-length Scylla olivacea VIH (Scyol-VIH) was identified through reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The open reading frame consists of 378 nucleotides, which encodes a 126-amino acid precursor protein, including a 22-residue signal peptide and a 103-amino acid mature peptide in which 6 highly conserved cysteine residues are present. There was expression of the Scyol-VIH gene in immature female Scylla olivacea in the eyestalk, brain and ventral nerve cord. The Scyol-VIH gene expression was localized to the eyestalk X-organ, brain neuronal clusters 6 and 11, and in multiple neuronal clusters of the ventral nerve cord. The relative abundance of Scyol-VIH mRNA transcript in the eyestalk was relatively greater in immature stage females, then decreased as ovarian maturation progressed. Furthermore, eyestalk Scyol-VIH increased after dopamine (5 µg/g BW) injection. The present research provides fundamental information about Scyol-VIH and its potential effect in controlling reproduction.


Assuntos
Braquiúros/fisiologia , Dopamina/farmacologia , Hormônios de Invertebrado/metabolismo , Ovário/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Braquiúros/genética , Clonagem Molecular , Dopamina/administração & dosagem , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios de Invertebrado/genética , Ovário/metabolismo , Filogenia , RNA Mensageiro/genética , Serotonina/administração & dosagem , Serotonina/farmacologia , Serotoninérgicos/administração & dosagem , Serotoninérgicos/farmacologia , Maturidade Sexual , Espiperona/administração & dosagem , Espiperona/farmacologia , Fatores de Tempo
5.
Curr Neuropharmacol ; 17(12): 1098-1108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31418663

RESUMO

The association of chronic pain with depression is becoming increasingly recognized. Treating both the conditions together is essential for an effective treatment outcome. In this regard, it is important to identify a shared mechanism involved in the association of chronic pain with depression. Central serotonin (5-hydroxytryptamine; 5-HT) neurotransmission has long been known to participate in the processing of signals related to pain. It also plays a key role in the pathogenesis and treatment of depression. Although functional responses to serotonin are mediated via the activation of multiple receptor types and subtypes, the 5-HT1A subtype is involved in the processing of nociception as well as the pathogenesis and treatment of depression. This receptor is located presynaptically, as an autoreceptor, on the perikaryon and dendritic spines of serotonin-containing neurons. It is also expressed as a heteroreceptor on neurons receiving input from serotonergic neurons. This article targets the 5-HT1A receptors to show that indiscriminate activation of pre and postsynaptic 5-HT1A receptors is likely to produce no therapeutic benefits; biased activation of the 5-HT heteroreceptors may be a useful strategy for treating chronic pain and depression individually as well as in a comorbid condition.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Antidepressivos/farmacologia , Dor Crônica/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Receptor 5-HT1A de Serotonina , Serotoninérgicos/farmacologia , Analgésicos não Entorpecentes/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Dor Crônica/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo/metabolismo , Humanos , Receptor 5-HT1A de Serotonina/metabolismo , Serotoninérgicos/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-31330215

RESUMO

Anxiety disorders are serious and common mental diseases, yet there is still a need for the development of more effective anxiolytics with better safety profiles than benzodiazepines and serotonin reuptake inhibitors. The serotonergic and noradrenergic systems have reciprocal interactions and are intricately related to the pathogenesis of anxiety. In this study, the anxiolytic-like effect of the novel compound ACH-000029, 3-(2-(4-(2-methoxyphenyl) piperazine-1-yl) ethyl) quinazoline-4(3H)-one, is reported. This compound acts at selected serotonergic (5-HT1A and 5-HT1D partial agonism and 5-HT2A antagonism) and α-adrenergic (α-1A, 1B and 1D antagonism) receptors, with good selectivity over other G-protein-coupled receptors. ACH-000029 exhibited high blood-brain barrier permeation and acute anxiolytic effects in the marble burying (MB) and light-dark box (LDB) models of anxiety over the dose ranges of 8-32 mg/kg i.p. and 16-30 mg/kg p.o. The anxiolytic activity was comparable to that observed for serotonin reuptake inhibitors (paroxetine and fluoxetine) and benzodiazepines (alprazolam, diazepam and clobazam). The analysis of the whole-brain c-fos expression following oral dosing showed that ACH-000029 regulated regions highly associated with the processing of environmental stimuli and anxiety behavior, such as the amygdala, paraventricular nucleus of the thalamus, retrosplenial dorsal, pallidum, bed nuclei of the stria terminalis, and locus ceruleus. No safety concerns were identified for ACH-000029 in the functional observational battery up to 50 mg/kg i.p. and in the nonprecipitated withdrawal test up to 30 mg/kg p.o. twice daily for 20 days. This work supports the further development of ACH-000029 as a drug candidate for the treatment of anxiety disorders. The analysis of the in vitro pharmacology and brain regions regulated by this compound may also lead to the exploration of other indications within the psychiatry field.


Assuntos
Adrenérgicos/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Serotoninérgicos/farmacologia , Adrenérgicos/uso terapêutico , Animais , Ansiolíticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Serotoninérgicos/uso terapêutico
7.
Int J Neuropsychopharmacol ; 22(11): 698-709, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350882

RESUMO

BACKGROUND: This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed. METHODS: The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose). RESULTS: We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50). CONCLUSIONS: Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quimioterapia Combinada , Avaliação de Resultados em Cuidados de Saúde , Quinolonas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Serotoninérgicos/farmacologia , Tiofenos/farmacologia , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Humanos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Serotoninérgicos/administração & dosagem , Serotoninérgicos/efeitos adversos , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos
9.
ACS Chem Neurosci ; 10(7): 3094-3100, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31244057

RESUMO

Rodents exhibit natural exploratory behaviors, which can be measured by the spontaneous alternation behavior (SAB) test. Perseverance in this test induced by the 5-hydroxytryptamine 1A receptor (5-HT1AR) agonist, 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), resembles compulsive behaviors observed in humans and manifests as reduced alternation ratio. This study characterized 8-OH-DPAT-induced perseverance in the SAB test in C57BL/6JOlaHsd male mice by coadministration of WAY100635, citalopram and the 5-HT releasing agent, 3,4-methylenedioxymethamphetamine (MDMA), to deepen the understanding of 5-HT-dependent mechanisms. The 5-HT1AR mechanism of 8-OH-DPAT (1.0 mg/kg, p < 0.01) on perseverance was confirmed by coadministration of the 5-HT1AR antagonist, WAY100635 (2.0 mg/kg, p < 0.05), which attenuated the effects of 8-OH-DPAT. Such effects could also be reversed by MDMA (1.0 mg/kg, p < 0.05; 10.0 mg/kg, p < 0.001) but not citalopram. These findings confirm the importance of 5-HT in regulating perseverative behavior. Future investigations are required to determine the predictive validity of the 8-OH-DPAT-disrupted SAB test as an inducible mouse model of compulsivity.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Comportamento Animal/efeitos dos fármacos , Citalopram/farmacologia , Comportamento Compulsivo , Comportamento Exploratório/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Serotoninérgicos/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Inibidores de Captação de Serotonina/farmacologia
11.
Neuroimage ; 195: 252-260, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30953835

RESUMO

One of the main limitations of pharmacological fMRI is its inability to provide a molecular insight into the main effect of compounds, leaving an open question about the relationship between drug effects and haemodynamic response. The aim of this study is to investigate the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on functional connectivity (FC) using a novel multimodal method (Receptor-Enriched Analysis of functional Connectivity by Targets - REACT). This approach enriches the resting state (rs-)fMRI analysis with the molecular information about the distribution density of serotonin receptors in the brain, given the serotonergic action of MDMA. Twenty healthy subjects participated in this double-blind, placebo-controlled, crossover study. A high-resolution in vivo atlas of four serotonin receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and its transporter (5-HTT) was used as a template in a two-step multivariate regression analysis to estimate the spatial maps reflecting the whole-brain connectivity behaviour related to each target under placebo and MDMA. Results showed that the networks exhibiting significant changes after MDMA administration are the ones informed by the 5-HTT and 5-HT1A distribution density maps, which are the main targets of this compound. Changes in the 5-HT1A-enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT2A-enriched maps correlated with the spiritual experience subscale of the Altered States of Consciousness Questionnaire. By enriching the rs-fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, we showed that MDMA effects on FC can be understood through the distribution of its main targets. This result supports the ability of this method to characterise the specificity of the functional response of the brain to MDMA binding to serotonergic receptors, paving the way to the definition of a new fingerprint in the characterization of new compounds and potentially to a further understanding to the response to treatment.


Assuntos
Encéfalo/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Serotoninérgicos/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Adulto Jovem
12.
Neuropharmacology ; 161: 107615, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31028773

RESUMO

The transporters for dopamine (DAT) and serotonin (SERT) are important targets in the treatment of psychiatric disorders including major depression, anxiety and attention-deficit hyperactivity disorder. Drugs acting at these transporters can act as inhibitors or as releasers. In addition, it has been recently appreciated that some compounds are less efficacious releasers than amphetamine. Thus, they are classified as partial releasers. Compounds can act on both SERT and DAT or display exquisite selectivity for either SERT or DAT, but the structural basis for selectivity is poorly understood. The trifluoromethyl-substitution of methcathinone in the para-position has been shown to dramatically shift the selectivity of methcathinone (MCAT) towards SERT. Here, we examined MCAT, para-trifluoromethyl-methcathinone (pCF3MCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF3-substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the pCF3group, but not of other substituents with larger van der Waal's volume, lipophilicity or polarity, converted the DAT-selective MCAT into a SERT-selective partial releaser. Electrophysiological and superfusion experiments, together with kinetic modelling, showed that pCF3MCAT, but not MCAT, trapped a fraction of SERTs in an inactive state by occupying the S2-site. These findings define a new mechanism of action for partial releasers, which is distinct from the other two known binding modes underlying partial release. Our observations highlight the fact that the substrate permeation pathway of monoamine transporters supports multiple binding modes, which can be exploited for drug design. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.


Assuntos
Propiofenonas/farmacologia , Serotoninérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Sítios de Ligação , Simulação por Computador , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Células HEK293 , Humanos , Cinética , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
13.
J Physiol ; 597(9): 2565-2589, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30919966

RESUMO

KEY POINTS: 5-HT increases the excitability of brainstem and spinal motoneurons, including the jaw-closing motoneurons, by depolarizing the membrane potential and decreasing the medium-duration afterhyperpolarization. In this study, we focused on how 5-HT enhances postsynaptic glutamatergic responses in the dendrites of the jaw-closing motoneurons. We demonstrate that 5-HT augments glutamatergic signalling by enhancing the function of the GluN2A-containing NMDA receptor (NMDAR) through the activation of 5-HT2A receptors (5-HT2A Rs) and Src kinase. To enhance glutamatergic responses, activation of the 5-HT2A Rs must occur within ∼60 µm of the location of the glutamate responses. 5-HT inputs to the jaw-closing motoneurons can significantly vary their input-output relationship, which may contribute to wide-range regulation of contractile forces of the jaw-closing muscles. ABSTRACT: Various motor behaviours are modulated by 5-HT. Although the masseter (jaw-closing) motoneurons receive both glutamatergic and serotonergic inputs, it remains unclear how 5-HT affects the glutamatergic inputs to the motoneuronal dendrites. We examined the effects of 5-HT on postsynaptic responses evoked by single- or two-photon uncaging of caged glutamate (glutamate responses) to the dendrites of masseter motoneurons in postnatal day 2-5 rats of either sex. Application of 5-HT induced membrane depolarization and enhanced the glutamate-response amplitude. This enhancement was mimicked by the 5-HT2A receptor (5-HT2A R) agonist and was blocked by the 5-HT2A/2C R antagonist. However, neither the 5-HT2B R nor the 5-HT2C R agonists altered glutamate responses. Blockade of the NMDA receptors (NMDARs), but not AMPA receptors, abolished the 5-HT-induced enhancement. Furthermore, the selective antagonist for the GluN2A subunit abolished the 5-HT-induced enhancement. 5-HT increased GluN2A phosphorylation, while the Src kinase inhibitor reduced the 5-HT-induced enhancement and GluN2A phosphorylation. When exposure to the 5-HT2A R agonist was targeted to the dendrites, the enhancement of glutamate responses was restricted to the loci of the dendrites near the puff loci. Electron microscopic immunohistochemistry revealed that both the NMDARs and the 5-HT2A Rs were close to each other in the same dendrite. These results suggest that activation of dendritic 5-HT2A Rs enhances the function of local GluN2A-containing NMDARs through Src kinase. Such enhancement of the glutamate responses by 5-HT may contribute to wide-range regulation of contractile forces of the jaw-closing muscles.


Assuntos
Dendritos/metabolismo , Ácido Glutâmico/metabolismo , Arcada Osseodentária/fisiologia , Neurônios Motores/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Dendritos/fisiologia , Arcada Osseodentária/inervação , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Contração Muscular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Serotoninérgicos/farmacologia , Potenciais Sinápticos , Quinases da Família src/metabolismo
14.
Neuropharmacology ; 151: 13-20, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30922893

RESUMO

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term effects is unclear. Sensitization to certain behavioral drug effects is a common rodent model used to assess long-lasting neurobiological adaptations induced by acute drug treatments. Nine independent experiments were undertaken to investigate if and how mice sensitize to the prosocial effects of MDMA. When treated with 7.8 mg/kg MDMA and paired every other day for a week, MDMA-induced social interaction increased precipitously across treatment sessions. This previously unreported phenomenon was investigated and found to be heavily influenced by a social context and 5-HT2AR activation. Social sensitization did not appear to develop if mice were administered MDMA in isolation, and pretreatment with MDL100907, a selective 5-HT2AR antagonist, inhibited the development of social sensitization. However, when MDL100907 was administered to mice that had already been sensitized, it did not attenuate social interaction, suggesting that 5-HT2AR activity may be necessary for the development of social sensitization but not the expression of MDMA-induced social behavior. Additional investigation is warranted to further explore the phenomenon of social sensitization and to determine the underlying neurobiological mechanisms.


Assuntos
Comportamento Animal/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Serotoninérgicos/farmacologia , Comportamento Social , Animais , Fluorbenzenos/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacologia , Antagonistas da Serotonina/farmacologia
15.
J Psychopharmacol ; 33(3): 355-363, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30665313

RESUMO

BACKGROUND: While (±)-3,4-methylenedioxymethamphetamine (MDMA) primarily induces serotonin release, it also affects dopamine and noradrenaline transmission. It is, however, unclear what role each of these neurotransmitters play in the behavioural profile of MDMA. METHODS: In this study we used the drug discrimination (DD) and the acoustic startle (ASR) paradigms to examine the behaviour of rats with and without a genetic deletion of the serotonin transporter SERT (SERT-/- and SERT+/+ rats). In DD, rats were trained to respond on different levers following an injection of 1.5 mg/kg MDMA, or saline. After acquisition, they were given a challenge dose of 0.5 mg/kg amphetamine (AMPH). In the ASR paradigm, SERT+/+ and SERT-/- rats were given 0, 5 or 10 mg/kg MDMA. RESULTS: In DD, significantly fewer SERT-/- rats acquired MDMA discrimination. When the acquirers were challenged with AMPH, SERT+/+ showed partial, while SERT-/- rats showed full generalisation to MDMA. In the ASR paradigm, MDMA significantly reduced prepulse inhibition and startle habituation in SERT+/+ rats, while having no effect in SERT-/- rats. CONCLUSION: Together these data suggest that in wildtype rats the interoceptive cues of MDMA are primarily mediated by serotonin and to a lesser extent by dopamine and noradrenaline, while the effects in the startle paradigm are almost exclusively mediated via serotonin. Together, these data contribute to our understanding of the complex pharmacodynamics of MDMA.


Assuntos
Comportamento Animal/efeitos dos fármacos , Alucinógenos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Animais , Discriminação Psicológica/efeitos dos fármacos , Dopamina/metabolismo , Deleção de Genes , Técnicas de Inativação de Genes , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Serotonina/metabolismo , Serotoninérgicos/farmacologia
16.
Behav Brain Res ; 357-358: 88-97, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-29246772

RESUMO

Our previous study found that serotonin 1A receptor (5-HT1aR) is an endogenous suppressor of nNOS expression in the hippocampus, which accounts for anxiolytic effect of fluoxetine. However, the precise molecular mechanism remains unknown. By using 8-OH-DPAT, a selective 5-HT1aR agonist, NAN-190, a selective 5-HT1aR antagonist, and U0126, an Extracellular Regulated Protein Kinases (ERK) phosphorylation inhibitor, we investigated the role of ERK in 5-HT1aR-nNOS pathway. Western blots analysis demonstrated that 5-HT1aR activation up-regulated the level of phosphorylated ERK (P-ERK) beginning at 5 min and down-regulated the expression of nNOS beginning at 20 min. Meanwhile, blockage of 5-HT1aR resulted in a decrease in P-ERK beginning at 20 min and caused an increase in nNOS expression beginning at 6 h. Although U0126 itself did not alter nNOS expression and activity, NO level, and anxiety-related behaviors, the treatment totally reversed 8-OH-DPAT-induced reduction in nNOS expression and function, and anxiolytic effect. Besides, our data showed that ERK phosphorylation was essential for 5-HT1aR activation-induced cAMP responsive element binding protein (CREB) phosphorylation, hippocampal neurogenesis and synaptogenesis of newborn neuron. Our study suggests a crucial role of ERK phosphorylation in the regulation of nNOS expression by 5-HT1aR, which is helpful for understanding the mechanism of 5-HT1aR-based anxiolytic treatment.


Assuntos
Ansiedade/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Animais Recém-Nascidos , Ansiedade/tratamento farmacológico , Adaptação à Escuridão/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Serotoninérgicos/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sacarose/administração & dosagem
17.
Behav Brain Res ; 357-358: 39-47, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-28662893

RESUMO

Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2 h) or chronic restraint (2 h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10 mg/kg) or saline was performed twice daily (12-12 h interval), for 7 consecutive days. EPM test was conducted 24 h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.


Assuntos
Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/lesões , Norepinefrina/metabolismo , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Estresse Psicológico , 5,7-Di-Hidroxitriptamina/farmacologia , Análise de Variância , Animais , Desipramina/farmacologia , Modelos Animais de Doenças , Tolerância a Medicamentos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Serotoninérgicos/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
18.
Psychosom Med ; 81(1): 34-40, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30188382

RESUMO

OBJECTIVE: Central nervous system (CNS) serotonin (5-HT) exerts both excitatory and inhibitory effects on the sympathetic nervous system (SNS) in animals. In this study, we examine the effects of tryptophan enhancement and depletion on plasma catecholamine levels in humans. METHODS: The total sample consisted of 164 healthy men and women who were tested for 2 days. Seventy-nine participants were randomized to a tryptophan enhancement condition and 85 to a tryptophan depletion condition. Both protocols consisted of a "sham day," followed by an "active day." Blood samples for assessment of plasma norepinephrine and epinephrine levels were collected before and after tryptophan enhancement/depletion. Data were analyzed using general linear models. Separate analyses were conducted for each study arm and for each measure. RESULTS: In the depletion condition, both epinephrine (F(5,330) = 2.69, p = .021) and norepinephrine (F(5,335) = 2.79, p = .018) showed small increases on active versus "sham" depletion days. There were also significant day by time interactions for epinephrine (F(3,171) = 39.32, p < .0001) and norepinephrine (F(3,195) = 31.09, p < .0001) levels in the enhancement arm. Tryptophan infusion resulted in a marked increase in epinephrine (Premean = 23.92 (12.23) versus Postmean = 81.57 (62.36)) and decrease in norepinephrine (Premean = 257.2 (106.11) versus Postmean = 177.04 (87.15)), whereas levels of both catecholamines were stable on the "sham day." CONCLUSIONS: CNS 5-HT exerts both inhibitory and excitatory effects on SNS activity in humans, potentially due to stimulation of CNS 5-HT receptors that have shown to have inhibitory (5-HT1A) and excitatory (5-HT1A and/or 5-HT2) SNS effects in animal models.


Assuntos
Epinefrina/sangue , Norepinefrina/sangue , Serotoninérgicos/farmacologia , Serotonina/metabolismo , Sistema Nervoso Simpático/metabolismo , Triptofano/farmacologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Serotoninérgicos/administração & dosagem , Triptofano/administração & dosagem
19.
Acta Neuropsychiatr ; 31(1): 27-35, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30223911

RESUMO

OBJECTIVE: To evaluate brexpiprazole adjunctive to antidepressant therapies (ADTs) as maintenance treatment in patients with major depressive disorder with inadequate response to ADT, utilising a novel study design. METHODS: The study comprised an 8-week prospective treatment period with open-label ADT with double-blind placebo treatment and a 24-week randomised treatment period. Investigators and patients were blinded to treatment periods, randomisation criteria, and timing of randomisation. Patients with early response to open-label ADT were withdrawn at Week 6. Patients fulfilling criteria for inadequate response were randomised to ADT+brexpiprazole 1-3 mg/day, or ADT+placebo. The primary endpoint was full remission: Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤10 and ≥50% decrease from randomisation (i.e. baseline) in MADRS total score for at least 8 consecutive weeks. RESULTS: The primary efficacy analysis failed to show a statistically significant difference between the proportions of patients on ADT+brexpiprazole (21.4%) and ADT+placebo (24.9%) achieving full remission; odds ratio: 0.83; p=0.2641. The secondary endpoint of change from baseline to Week 6 in MADRS total score showed no difference between ADT+brexpiprazole and ADT+placebo (-0.4; p=0.3259). The most frequent treatment-emergent adverse event (TEAE) in patients receiving ADT+brexpiprazole was weight increased (9.5% vs. 5.0% in ADT+placebo). The incidence of TEAEs leading to withdrawal in the randomised treatment period was 6.3% in the ADT+brexpiprazole group and 3.4% in the ADT+placebo group. CONCLUSION: Adjunctive brexpiprazole did not differentiate from ADT+placebo on the primary endpoint of full remission. A number of design elements in this previously untried study design may have contributed to the study result. Brexpiprazole was well tolerated.


Assuntos
Antidepressivos/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Quinolonas/farmacologia , Serotoninérgicos/farmacologia , Tiofenos/farmacologia , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Transtorno Depressivo Maior , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Serotoninérgicos/administração & dosagem , Serotoninérgicos/efeitos adversos , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Adulto Jovem
20.
Physiol Behav ; 199: 343-350, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529341

RESUMO

Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Serotoninérgicos/farmacologia , Animais , Sinais (Psicologia) , Medo , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Long-Evans
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