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1.
Artigo em Inglês | MEDLINE | ID: mdl-32479008

RESUMO

Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.


Assuntos
Clozapina/farmacologia , Maleato de Dizocilpina/toxicidade , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/induzido quimicamente
2.
J Pharmacol Sci ; 142(1): 26-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786058

RESUMO

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light-dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D1 receptor antagonist) or sulpiride (dopamine D2/D3 receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D1 receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Sesquiterpenos Policíclicos/farmacologia , Receptores Dopaminérgicos/metabolismo , Animais , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Flumazenil/farmacologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Sulpirida/farmacologia
3.
Molecules ; 24(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731603

RESUMO

The presence of dominant active compounds in standardised methanol extract from the leaves of Stizolophus balsamita (S. balsamita) was examined using HPLC with a diode-array detector. The extract and three dominant parthenolide derivatives were tested with Serotonin Research ELISA for their ability to inhibit the serotonin release from platelets. The antiserotonin effect of the extract was compared with that of parthenolide, a compound with proven antiserotonin and antimigraine effects. This study aimed to evaluate the ability of natural parthenolide derivatives to inhibit serotonin release from platelets. Izospiciformin, stizolin and stizolicin were analysed along with the standardised alcohol extract of S. balsamita leaves, which also contained four other parthenolide derivatives. All the analysed substances were found to inhibit serotonin release from platelets as compared with the control sample, which had 100% of serotonin released. Izospiciformin had the most significant impact (97.98% serotonin release inhibition). The effect of the methanol extract of S. balsamita on the serotonin release inhibition was also statistically significant.


Assuntos
Asteraceae/química , Plaquetas/metabolismo , Extratos Vegetais , Folhas de Planta/química , Antagonistas da Serotonina , Serotonina/metabolismo , Sesquiterpenos , Animais , Feminino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia
4.
Bull Exp Biol Med ; 168(2): 193-198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776959

RESUMO

Stimulation of the serotoninergic system (5-hydroxytryptophan, 50 mg/kg; fluoxetine, 3 mg/kg) induced a significant increase in HR and a reduction in the amplitude of all waves of the heart rhythm variability. Stimulation of the dopaminergic system (L-DOPA and amantadine, 20 mg/kg each) resulted in a moderate increase in HR and amplitudes of low-frequency (LF) and very-low-frequency (VLF) waves of the heart rhythm variability. Successive blockade of nicotinic (hexamethonium, 7 mg/kg) and muscarinic cholinergic receptors (atropine, 1 mg/kg) leads to a significant decrease in the variability of cardiointervals (almost to complete levelling) both under control conditions and after stimulation of the neurotransmitter systems. Serotonin receptor blockade (promethazine, 2 mg/kg) did not affect HR, but reduced the amplitude of LF- and VLF-waves. Under conditions of serotoninergic system stimulation, the blockade of serotonin receptors was followed by a significant HR acceleration without changes in heart rhythm variability; blockade of dopamine receptors (sulpiride, 1 mg/kg) induced HR acceleration and increase in the amplitude of LF- and VLF-waves; blockade of dopamine receptors under conditions of dopamine system stimulation was followed by a significant increase in HR and a decrease in the amplitude of all waves of the heart rhythm variability. It can be hypothesized that serotonin- and dopaminergic systems affect the heart rhythm via cardiomyocyte receptors and via modulation of activity of the adrenergic and cholinergic systems. The effects of serotonin- and dopaminergic systems can be considered as synergic in the CNS, and antagonistic at the periphery.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Neurotransmissores/farmacologia , Receptores de Neurotransmissores/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Animais , Colina/antagonistas & inibidores , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Ratos , Receptores Dopaminérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
5.
Eur J Pharmacol ; 864: 172718, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586629

RESUMO

Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.


Assuntos
Defecação/efeitos dos fármacos , Diarreia/complicações , Diarreia/fisiopatologia , Síndrome do Intestino Irritável/complicações , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Diarreia/tratamento farmacológico , Diarreia/psicologia , Medo/efeitos dos fármacos , Medo/psicologia , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/uso terapêutico , Estresse Psicológico/psicologia
6.
Eur J Med Chem ; 183: 111705, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581003

RESUMO

5-HT7 receptors are the most recently discovered serotonergic receptors, for which numerous physiological implications in the central and the peripheral nervous systems as well as the endocrine system are described. A current public health challenge is to propose new and more efficient treatments against neuropsychiatric disorders such as epilepsy or Alzheimer's disease. In this context, 5-HT7 receptors represent an interesting target for the treatment and prevention of those pathologies, as an alternative or in association with other medicines. Thus, numerous chemical series of agonists and antagonists have been developed. Some of these molecules have shown a therapeutic potential in various in vivo studies. This review aims to present an overview of 5-HT7 receptors and of the medicinal chemistry programs that led to the identification of new, potent and selective 5-HT7 receptors ligands. Structure-activity relationships studies based on molecular docking and pharmacophoric approaches are also described.


Assuntos
Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Humanos , Ligantes , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 183: 111690, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526973

RESUMO

The present paper describes the synthesis and the binding properties for the serotonergic 5-HT7 and 5-HT1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT7R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT7R (Ki = 9.08 and 0.85 nM, respectively) and selectivity over the 5-HT1AR (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT7R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured Ki, further validating the quality of the models.


Assuntos
Pirimidinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
8.
J Biochem Mol Toxicol ; 33(9): e22378, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332906

RESUMO

This study was performed to investigate the effect of ondansetron, a serotonin receptor (5-HT3) antagonist, in the alleviation of diclofenac-induced kidney injuries. NMRI mice were randomly divided into six groups and treated with (A) untreated control group, (B) diclofenac (100 mg/kg), (C) ondansetron (1 mg/kg), (D to F) ondansetron (0.1, 0.5, and 1 mg/kg, respectively) and diclofenac (100 mg/kg) for last 3 days of experiment. The oxidative stress tests strongly demonstrated the negative synergistic effects of diclofenac and ondansetron, regarding the observation of dose-dependent enhancement of malondialdehyde concentration, and reduction of glutathione content, and superoxide dismutase and catalase activity. Histopathological analyses revealed dose-dependent tubular epithelial cells degeneration, outstanding mononuclear cells infiltration, clear necrosis at the papillary region of kidney, dilation, and vascular hyperemia in mice kidney tissues treated with ondansetron and diclofenac. Conclusively, these findings suggested the possible ondansetron-diclofenac interaction through the induction of oxidative stress.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Diclofenaco/toxicidade , Rim/efeitos dos fármacos , Ondansetron/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Catalase/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Glutationa/metabolismo , Rim/patologia , Camundongos , Ondansetron/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Superóxido Dismutase/metabolismo
9.
Neuron ; 103(4): 686-701.e8, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31248729

RESUMO

The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.


Assuntos
Camundongos/fisiologia , Núcleos da Rafe/fisiologia , Serotonina/fisiologia , Sono/fisiologia , Peixe-Zebra/fisiologia , Animais , Nível de Alerta/genética , Nível de Alerta/fisiologia , Buspirona/farmacologia , Ritmo Circadiano/fisiologia , Fenclonina/farmacologia , Homeostase , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética , Quipazina/farmacologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Serotonina/biossíntese , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Privação do Sono/genética , Privação do Sono/fisiopatologia , Triptofano Hidroxilase/deficiência , Triptofano Hidroxilase/genética , Vigília/genética , Vigília/fisiologia , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética
10.
Arch Pharm (Weinheim) ; 352(7): e1900041, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162703

RESUMO

Serotonin 5-HT6 receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT 6 antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT 6 antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT 6 antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT 6 receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K i and K b values against 5-HT 6 receptors of 41.8 and 74 nM, respectively, an IC 50 value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents.


Assuntos
Antioxidantes/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Humanos , Modelos Moleculares , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Triazinas/antagonistas & inibidores
11.
Sex Med Rev ; 7(4): 575-586, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31196764

RESUMO

INTRODUCTION: Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss. AIM: To understand possible mechanisms by which flibanserin may produce weight loss. METHODS: A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management. MAIN OUTCOME MEASURES: Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss. RESULTS: Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT2A receptors and factors such as improved mood and improved sleep. CONCLUSION: Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586.


Assuntos
Benzimidazóis/efeitos adversos , Antagonistas da Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Nível de Alerta/efeitos dos fármacos , Benzimidazóis/farmacologia , Ingestão de Energia/efeitos dos fármacos , Feminino , Humanos , Libido/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
12.
Metab Brain Dis ; 34(5): 1313-1324, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31177357

RESUMO

The present study investigated a possible antidepressant-like effect of ((4-tert-butylcyclohexylidene)methyl) (4-methoxystyryl) sulfide (BMMS) by using the forced swimming test (FST) and the tail suspension test (TST) in Swiss mice. The contribution of serotoninergic, glutamatergic and nitrergic systems in the antidepressant-like activity of BMMS was evaluated. We also examined the involvement of monoamine oxidase (MAO)-A, MAO-B and Na+, K+-ATPase activities in prefrontal cortex of mice. BMMS, (0.1-10 mg/kg, intragastrically (i.g.)) and fluoxetine (32 mg/kg, i.g.) decreased the immobility time in the FST and TST. The anti-immobility effect of BMMS (10 mg/kg, i.g.) in the TST was prevented by the pretreatment of mice with WAY100635 (0.1 mg/kg, subcutaneously (s.c.), a 5-HT1A receptor antagonist), ketanserin (5 mg/kg, intraperitoneal (i.p.), a 5-HT2A/2C receptor antagonist), and partially blocked by ondansetron (1 mg/kg, i.p., a 5-HT3 receptor antagonist). The anti-immobility effect of BMMS (10 mg / kg, i.g.) was not avoided by pretreatment with MK-801 (0.01 mg/kg, s.c. a non-competitive N-methyl D-Aspartate (NMDA) receptor) in the TST. Pretreatment with L-arginine (500 mg/kg, i.p., a nitric oxide precursor) reversed partially the reduction in the immobility time elicited by BMMS (10 mg/kg, i.g.) in TST. BMMS altered Na+,K+-ATPase and MAO-A activities in prefrontal cortex of mice, but was not able to change the MAO-B activity. In conclusion, BMMS exerted an antidepressant-like effect in mice and serotonergic and nitrergic systems are involved in the antidepressant-like action of compound. BMMS modulated MAO-A and Na+, K+- ATPase activities in prefrontal cortex of mice.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Óxido Nítrico/metabolismo , Serotonina/metabolismo , Estirenos/farmacologia , Sulfetos/farmacologia , Animais , Antidepressivos/uso terapêutico , Arginina/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Elevação dos Membros Posteriores , Masculino , Camundongos , Monoaminoxidase/metabolismo , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Antagonistas da Serotonina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Estirenos/uso terapêutico , Sulfetos/uso terapêutico
13.
Bull Exp Biol Med ; 167(1): 1-6, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177445

RESUMO

Administration of 5-HT receptor antagonist to snails trained in conditioned food aversion prior to reminding of the conditioning stimulus caused amnesia. At the early period of amnesia (day 3), injections of protein synthesis inhibitor cycloheximide without reminder or reminder alone were ineffective. At the same time, injections of the inhibitor combined with reminder led to memory recovery; this effect in most animals persisted for at least 10 days. In the rest snails, aversive responses to presentations of the conditioning stimulus persisted for 2 days. Cycloheximide injection and reminder in 10 days after induction of amnesia did not affect its development or caused a transient memory recovery (2 days). We hypothesized that amnesia is an active process unfolding in time. One of mechanism of this process is reminder-induced and protein synthesis-depended reactivation of amnesia. Inhibitor of protein synthesis disturbed this reactivation and led to recovery of the initial memory of conditioned food aversion.


Assuntos
Amnésia/tratamento farmacológico , Amnésia/etiologia , Cicloeximida/uso terapêutico , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Metiotepina/farmacologia , Inibidores da Síntese de Proteínas/uso terapêutico , Antagonistas da Serotonina/farmacologia , Animais , Caramujos
14.
Pharmacol Res ; 146: 104310, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31229563

RESUMO

Acacetin, a natural flavonoid, possesses broad spectrum of pharmacological and biochemical activities, such as neuroprotection, antinociception and inhibition of monoamine oxidase. The current work aimed to investigate the antidepressant-like activity of acacetin in mice and explore the underlying mechanism(s). Chronic, but not acute, acacetin treatment (5, 15 or 45 mg/kg, p.o., once per day for three weeks) exerted in mice dose-dependently antidepressant-like activity, assessed by forced swim test (FST) and tail suspension test (TST). Although acacetin-treated mice showed normal circadian hypothalamo-pituitary-adrenal (HPA) axis activity, their endocrine responsivity to both acute restraint stress and intracerebroventricular injection of corticotropin-releasing factor (CRF) was buffered. The acacetin-triggered antidepressant-like activities are serotonergically dependent, since its impacts on behavior and stress responsivity were totally abolished by chemical depletion of brain serotonin by PCPA. Consistently, acacetin-treated mice showed escalated levels of brain monoamines especially serotonin and depressed activity of monoamine oxidase. Moreover, the acacetin-evoked anti-depression was preferentially counteracted by co-administration of 5-HT1A receptor antagonist WAY-100635, but potentiated by 5-HT1A receptor agonist 8-OH-DPAT and sub-effective dose of serotonergic antidepressant fluoxetine, suggesting a pivotal engagement of 5-HT1A related serotonergic system. In vitro, acacetin (1-100 nM) increased the Emax of 8-OH-DPAT. Collectively, these findings confirm that chronic acatetin administration to mice engenders antidepressant-like efficacy on both behavior and stress axis responsivity, with serotonergic system that preferentially couples with 5-HT1A receptors being critically involved.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Flavonas/farmacologia , Serotonina/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Animais , Depressão/metabolismo , Fluoxetina/farmacologia , Elevação dos Membros Posteriores/fisiologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Natação/fisiologia
15.
Eur J Med Chem ; 178: 740-751, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229876

RESUMO

This research has provided the most active 5-HT6R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT6R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT6R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7-24) was synthesized and examined on their affinities for 5-HT6R and selectivity, in respect to the 5-HT1AR, 5-HT2AR, 5-HT7R and dopamine D2 receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT6R antagonist (Ki = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT6R. Surprisingly, an introduction of SO2 caused a drastic decrease of the 5-HT6R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro.


Assuntos
Processamento de Imagem Assistida por Computador , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Ligantes , Locomoção/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Ratos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 179: 1-15, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31229883

RESUMO

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT6R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT6R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT6R and very high selectivity over 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Desenho de Fármacos , Imidazóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Células Cultivadas , Disfunção Cognitiva/induzido quimicamente , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Escopolamina/administração & dosagem , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
17.
Mol Brain ; 12(1): 29, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935412

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.


Assuntos
Memória de Curto Prazo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/efeitos adversos , Comportamento Social , Sinapses/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Feminino , Fluoxetina/efeitos adversos , Interneurônios/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sinapses/efeitos dos fármacos
18.
Psychopharmacology (Berl) ; 236(3): 1015-1029, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30980094

RESUMO

RATIONALE: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. OBJECTIVE: Direct-acting 5-HT2A/2C receptor agonists and antagonists and D1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT2A/2C and D1-3 receptor antagonists were examined in both groups. METHODS: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline. RESULTS: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. CONCLUSIONS: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.


Assuntos
Alcaloides/farmacologia , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Metanfetamina/análogos & derivados , Antagonistas da Serotonina/farmacologia , Animais , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Condicionamento Operante/fisiologia , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Drogas Ilícitas/farmacologia , Ketanserina/farmacologia , Masculino , Metanfetamina/farmacologia , Psicotrópicos/farmacologia , Ratos , Ratos Sprague-Dawley
19.
Biomol Concepts ; 10(1): 51-61, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30956225

RESUMO

The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, this study was performed to investigate the effect of Zn on the expression of morphine-induced conditioned place preference (CPP) in male rats. We used an unbiased CPP paradigm for investigating the effect of Zn. The intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations of Zn (5-20 mg/kg, i.p., and 10 nmol/rat, respectively) with or without morphine did not induce conditioned place aversion (CPA) or CPP during acquisition phase. However, the same i.p. and i.c.v. administrations of Zn induced morphine-like CPP in the expression phase. Pre-treatment with dopamine receptor antagonists (SCH23390, sulpiride, and haloperidol) and serotonin receptor antagonists (WAY100135, ketanserin, and ondansetron) reversed the enhancement effect of Zn on the expression of morphine-induced CPP (especially 20mg/kg, i.p. and 10 nmol/rat, i.c.v.). These findings suggest that acute i.p. and i.c.v administration of Zn might enhance the rewarding properties of morphine through involvement with dopaminergic and serotonergic neuronal systems.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Morfina/farmacologia , Antagonistas da Serotonina/farmacologia , Zinco/farmacologia , Animais , Benzazepinas/farmacologia , Haloperidol/farmacologia , Ketanserina/farmacologia , Masculino , Ondansetron/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Wistar , Recompensa , Sulpirida/farmacologia
20.
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
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