Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.694
Filtrar
1.
Adv Exp Med Biol ; 1191: 121-140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002926

RESUMO

Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets: serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes. Close translational collaboration between fundamental academic and discovery research will lead to badly needed breakthroughs in the search for new anxiolytics.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/fisiopatologia , Ansiedade/fisiopatologia , Descoberta de Drogas , Neurotransmissores/metabolismo , Pesquisa Médica Translacional , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Humanos
2.
Adv Exp Med Biol ; 1191: 169-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002929

RESUMO

This chapter describes the various animal models that seem relevant to the development of anxiolytic drugs, as well as the human models of induced anxiety, or more precisely the panic inducers including cholecystokinin. It is also mentioned the theoretical model of Deakin and Graeff which seems to keep all its relevance. The knock animals are evoked as relevant tools as well as a new optogenetic technique that needs to be used in this field.


Assuntos
Ansiolíticos , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Modelos Animais de Doenças , Descoberta de Drogas , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Colecistocinina/efeitos adversos , Humanos , Optogenética
3.
Planta Med ; 86(1): 26-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31711251

RESUMO

Kava, the extract of the roots of Piper methysticum, has been traditionally consumed in the South Pacific islands for its natural relaxing property. Epidemiological data suggests that kava consumption may reduce human cancer risk, and in vitro and in vivo models suggest chemopreventive potential against carcinogen-induced tumorigenesis. Therefore, knowledge about its molecular mechanisms and responsible ingredient(s) for these beneficial properties will better guide kava's use for the management of these disorders. Psychological stress typically results in increased production of stress hormones, such as norepinephrine (NE), which activate adrenergic receptors (ARs). Psychological stress has also been associated with increased cancer incidence and poor clinical outcomes in cancer patients. Mechanistically, binding of NE to ARs induces intracellular calcium influx, which activates downstream signaling pathways involved in both stress and cancer development. In this study, we characterized the effect of kava and its components, 3 fractions and 6 major kavalactones, on NE-induced intracellular calcium influx in H1299, a human non-small cell lung carcinoma cell line. Results show that kava extract effectively inhibits NE-mediated intracellular calcium influx in H1299 cells, potentially through antagonizing ß-AR signaling. This inhibitory activity is recapitulated by the major kavalactones in kava. Among the 6 major kavalactones, DHK demonstrated the best potency. Taken together, our study suggests a novel mechanism through which kava and its ingredients potentially offer the anxiolytic and cancer-preventive activity.


Assuntos
Ansiolíticos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Cálcio/metabolismo , Kava/química , Lactonas/farmacologia , Neoplasias Pulmonares/prevenção & controle , Extratos Vegetais/farmacologia , Ansiolíticos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Humanos , Lactonas/isolamento & purificação , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/psicologia , Norepinefrina/antagonistas & inibidores , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico
4.
Braz J Med Biol Res ; 52(11): e8899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664307

RESUMO

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.


Assuntos
Ansiedade/psicologia , Comportamento Animal/fisiologia , Pesquisa Comportamental/instrumentação , Comportamento Exploratório/fisiologia , Medo/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Ansiolíticos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/farmacologia , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Modelos Animais , Pentilenotetrazol/farmacologia , Ratos Wistar , Fatores de Tempo
5.
Expert Opin Investig Drugs ; 28(11): 1003-1012, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607187

RESUMO

Introduction: Generalized anxiety disorder (GAD) is a common and disabling psychiatric condition that affects 3% of the population and exacts significant costs to society if untreated. There are numerous treatment options available, but all have side effects, and none are reliably effective; hence, there is a significant need for new medications.Areas covered: The authors reviewed clinical Phase II and III studies listed on the clinicaltrials.gov and clinicaltrialsregister.eu websites, 2007-present. Additional information was gathered from the study sponsor websites and Pubmed. The categories of mechanisms investigated include: modulators of GABAergic or glutamatergic activity; modulators of monoaminergic systems including serotonin, norepinephrine, and dopamine; and modulators of neuropeptide corticotropin release factor.Expert opinion: There are few investigational drugs in the later stages of clinical development. Challenges include high placebo response rates, enrollment of symptomatic volunteers with minimal depressive and anxiety comorbidity, and the lack of a unifying pathophysiological model. Drug developers should consider implementing trial designs such as sequential parallel comparison design to enhance signal detection. Inclusion of depressive comorbidity may also enhance signal detection by reducing placebo-responsivity. More studies examining glutamate-mediated neuroplasticity in GAD are needed.


Assuntos
Ansiolíticos/administração & dosagem , Transtornos de Ansiedade/tratamento farmacológico , Drogas em Investigação/administração & dosagem , Animais , Ansiolíticos/farmacologia , Transtornos de Ansiedade/fisiopatologia , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Projetos de Pesquisa
6.
Planta Med ; 85(14-15): 1136-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31539917

RESUMO

Monoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.


Assuntos
Ansiolíticos/farmacologia , Kava/química , Lactonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/efeitos dos fármacos , Humanos , Lactonas/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Raízes de Plantas/química
7.
Transl Psychiatry ; 9(1): 185, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383851

RESUMO

Depressive symptoms are often accompanied by cognitive impairments and recurrent depressive episodes are discussed as a potential risk for dementia. Especially, stressful life events are considered a potent risk factor for depression. Here, we induced recurrent stress-induced depressive episodes over the life span of rats, followed by cognitive assessment in the symptom-free period. Rats exposed to stress-induced depressive episodes learned faster than control rats. A high degree of stress-induced depressive-like behavior early in the paradigm was a predictor of improved cognitive performance, suggesting induction of resilience. Subsequently, exposure to lorazepam prior to stress-induced depressive episodes and cognitive testing in a nonaversive environment prevented the positive effect. This indicates a beneficial effect of the stress-associated situation, with the existence of individual coping abilities. Altogether, stress may in some have a beneficial effect, yet for those individuals unable to tackle these aversive events, consecutive unpleasant episodes may lead to worse cognitive performance later in life.


Assuntos
Comportamento Animal/fisiologia , Cognição/fisiologia , Depressão/psicologia , Resiliência Psicológica , Estresse Psicológico/psicologia , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Lorazepam/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Recidiva
8.
Biol Pharm Bull ; 42(8): 1268-1274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366864

RESUMO

Increasing evidence shows depression relevant to oxidative stress and inflammation. Anti-inflammatory strategies or antioxidants have led to the development of new antidepressants. Brazilin is a natural product from the Chinese traditional medicine Caesalpinia sappan L., exerting anti-inflammatory, antioxidant, anti-platelet concentration, and anti-cancer effects. While the antidepressant effect of brazilin is largely unknown. In present study, we investigated the effects of brazilin on H2O2-induced oxidative injury in PC12 cells and on depression- and anxiety-like behaviors of chronically mild stressed (CMS)-induced depression mice. It was found that brazilin pre-treatment (both 10 and 20 µM) significantly increased cell viability and decreased cell apoptosis in H2O2-treated PC12 cells. Furthermore, repetitive administration of brazilin to CMS-induced depression mice by intraperitoneal injection (10 mg/kg) made the mice significantly lose their latency of feeding in novelty-suppressed feeding test (NSF), have more the sucrose preference in sucrose preference test (SPT), and more time spent in the central zone without affecting their crossing activity in open field test (OFT). These results suggested that brazilin can play a role in antidepressant and anxiolytic-like behaviors for CMS-induced depression mice probably through inhibiting the oxidative stress. Therefore, brazilin is worth to be further explored for treating depressive and anxiety disorders.


Assuntos
Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Benzopiranos/uso terapêutico , Depressão/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzopiranos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Masculino , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos
9.
Pharmacol Biochem Behav ; 185: 172761, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31425712

RESUMO

Alcohol use is frequently associated with mood disorders. Similarly, individuals suffering from these disorders have a higher risk of developing alcoholism. Several reports have implicated orexin signaling in different behaviors related to alcohol consumption, whereas antagonists block these actions. However, the involvement of orexin-1-receptor (Orx1R) in ethanol-induced anxiolysis remains relatively unexplored. The purpose of this study was to investigate whether intra-accumbal inhibition of Orx1R blocks the anxiolytic-like effect of ethanol and to determine if ethanol administration modifies orexin-A content and Orx1R expression in the nucleus accumbens (NAc). The elevated-plus-maze test (EPM-test) was used to measure anxiety; orexin-A content and Orx1R expression were determined by enzyme-immunoassay and western blot, respectively. The results showed that the pretreatment with a selective antagonist of Orx1R, SB-334867 (SB, 3 µg/side), prevents the anxiolytic-like behavior induced by acute ethanol (2.5 g/kg). SB-334867 per se had no effect on anxiety levels. Pretreatment with SB-334867 followed by ethanol (SB + Et) increased orexin-A content and Orx1R levels in the NAc in comparison to the groups that only received ethanol (V + Et) or SB-334867 (SB + S). Ethanol treatment significantly augmented Orx1R expression but not the peptide content. The increase in orexin-A observed in SB + Et animals could be due in part to the inhibition of Orx1R, since SB-334867 prevents the binding of orexin-A to the receptor. This increase in orexin-A may, in turn, induce an up-regulation of receptor. Other possible explanations were discussed. In general, these findings suggest that orexin-A contributes largely to expression of ethanol-induced anxiolytic-like effect through the signaling of Orx1R in the NAc.


Assuntos
Ansiolíticos/farmacologia , Benzoxazóis/farmacologia , Etanol/farmacologia , Naftiridinas/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ureia/análogos & derivados , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Benzoxazóis/administração & dosagem , Etanol/administração & dosagem , Modelos Lineares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/administração & dosagem , Núcleo Accumbens/metabolismo , Antagonistas dos Receptores de Orexina/administração & dosagem , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia
10.
Adv Exp Med Biol ; 1155: 801-819, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468449

RESUMO

Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance. By increasing chloride concentration through GABA-ARs, taurine serves as an effective inhibitory compound for maintaining appropriate levels of brain excitability. Considering this pharmacological mechanism of taurine facilitated inhibition through the GABA-AR, the present pilot study sought to explore the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random assignments to either solutions of Saline, Taurine, or Taurine Derived compounds (i.e., TD-101, TD-102, or TD-103) to assess the rats' responsiveness to each drug in mitigating the developmental Pb2+-exposure through the GABAergic system. Long Evans Hooded rats were assessed using an Open Field (OF) test for preliminary locomotor assessment. Approximately 24-h after the OF, the same rats were exposed to the Elevated Plus Maze (EPM) and were given an i.p. injection of 43 mg/Kg of the Saline, Taurine, or TD drugs 15-min prior to testing. Each rat was tested using the random assignment method for each pharmacological condition, which was conducted using a triple-blind procedure. The OF data revealed that locomotor activity was unaffected by Pb2+-exposure with no gender differences observed. However, Pb2+-exposure induced an anxiogenic response in the EPM, which interestingly, was ameliorated in a gender-specific manner in response to taurine and TD drugs. Female rats exhibited more anxiogenic behavior than the male rats; and as such, exhibited a greater degree of anxiety that were recovered in response to Taurine and its derivatives as a drug therapy. The results from the present psychopharmacological pilot study suggests that Taurine and its derivatives could provide useful data for further exploring the pharmacological mechanisms and actions of Taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for treating anxiety and other associated mood disorders.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Chumbo/efeitos adversos , Exposição Materna/efeitos adversos , Taurina/farmacologia , Animais , Feminino , Masculino , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Distribuição Aleatória , Ratos , Ratos Long-Evans
11.
Adv Exp Med Biol ; 1155: 905-921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468456

RESUMO

Taurine is abundant in various tissues including the brain, muscle, heart, spleen, liver and kidney with various physiological functions. Since taurine is produced by cysteine sulfinic acid decarboxylase (CSAD) in the liver and kidney, taurine-deficient mice without CSAD have been investigated for abnormal physiological functions such as retinal development, immune, pancreatic and liver function. In this study, the behavioral effects and abnormal brain development caused by low taurine in the developing brain were examined. In neonatal brains of homozygous CSAD knockout mice (HO), taurine was reduced by 85%, compared to wild-type mice (WT). Taurine was reduced by 35% in the brains of 2 month-old HO, compared to WT. Anxiety, motor coordination and autistic-like behaviors were evaluated at 2 months of age using five behavioral tests: elevated plus maze, open field, social approach, marble burying and accelerating rotarod. Mice were tested from 3 groups including WT, HO and HO with oral treatment of 0.2% taurine in the drinking water (HOT). HOT were born from HO dams treated with taurine from before pregnancy and were continuously treated with taurine in the drinking water after weaning. The taurine levels in the brain and plasma of HOT were restored to WT at 2 months of age. Taurine-deficiency did not lead to changes in autistic-like behaviors as the HO were not significantly different from WT in marble burying and social approach. However, taurine-deficiency increased anxiety-like behavior in HO in the elevated plus maze and open field, compared to WT. Taurine treatment significantly restored the HOT to WT levels of anxiety-like behavior in the elevated plus maze. However, changes in exploratory activity in the open field were not improved with taurine treatment. There was a slight difference in motor ability as the WT mice stayed on the accelerating rotarod longer that the HO and HOT, but the difference was significant in the HOT during the first trial only, compared to WT.These data support hypothesis that taurine is essential for the emotional development of the brain. First, taurine is remarkably low in the neonatal brain of HO, compared to the adult brain of HO. Second, taurine treatment in HO partially improves anxiety-like behavior to WT.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Taurina/farmacologia , Animais , Comportamento Animal , Camundongos , Camundongos Knockout
12.
Biol Pharm Bull ; 42(9): 1575-1580, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257273

RESUMO

Cedrol has been reported to be effective in reducing anxiety of male mice. The limited application of females in animal models of anxiety makes it difficult to systematically investigate new drug substitutes with potential anxiolytic activity. In the present study, we investigated the behavioral response of female ICR mice to cedrol after intraperitoneal (i.p.) administration using the elevated plus maze (EPM) and the light-dark box (LDB) test, followed by determination of neurochemical changes in brain. The data suggested that cedrol at dose of 1200-1600 mg·kg-1 exhibited anxiolytic activity on the female mice, as reflected by greater percentage of entries into the open arms and time spent in the open arms in the EPM, and greater transitions between chambers and percentage of time spent in the light chamber in the LDB. Cedrol increased the level of 5-hydroxytryptamine (5-HT), decreased the level of dopamine (DA), reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and increased the ratio of 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, compared with the control group, indicative of an anxiolytic-like effect on female mice via the 5-HTnergic or DAnergic pathways.


Assuntos
Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Neurotransmissores/metabolismo , /uso terapêutico , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Feminino , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-31318691

RESUMO

Background The 5HT4 receptor agonists are antidepressants with a unique mode of action. Many studies have been done on investigational drugs, and mosapride has been shown to have a 5HT3 antagonistic property. In this study, we assessed the potential anxiolytic and antidepressant effects of mosapride on Wistar albino rats. Methods The rats were randomly assigned to two models containing 4 groups of 6 animals each. In the anxiety model, four groups included 0.5 mL of 0.5% carboxymethyl cellulose (CMC), mosapride 1.5 mg/kg, mosapride 3 mg/kg and diazepam 2 mg/kg. They were dosed for 5 days. On the 3rd day, the elevated plus maze (EPM) was conducted, and on the 5th day, the open field (OF) tests were conducted. In the depression model, four groups included 0.5 mL of 0.5% CMC, mosapride 1.5 mg/kg, mosapride 3 mg/kg and imipramine 30 mg/kg. After 3 days of dosing, the forced swim test (FST) was conducted, followed by a washout period of 1 month. Then, the rats were subjected to chronic unpredictable stress with sucrose preference. Results Compared with the control, the mosapride-treated animals showed significant anxiolytic behavior at both high and low doses in the EPM and OF tests. In the FST, both high and low doses of mosapride reduced immobility. The climbing behavior was prominent at a high dose of mosapride, whereas swimming was prominent at a low dose. In the chronic stress model, both doses of mosapride preserved sucrose preference comparable to imipramine. Conclusion These findings suggest that mosapride has anxiolytic and antidepressant activities at clinically used doses.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Benzamidas/farmacologia , Depressão/tratamento farmacológico , Morfolinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Estresse Psicológico/tratamento farmacológico , Natação/fisiologia
14.
Pharmacol Biochem Behav ; 184: 172740, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31326461

RESUMO

BACKGROUND: Alcohol use disorder is a serious illness marked by uncontrollable drinking and a negative withdrawal state when not using. Alcohol is one of the most commonly used drugs among adolescent populations. Given that adolescence is a unique developmental stage during which alcohol has long-term effects on future drug-taking behavior; it is essential to understand how early exposure to ethanol during adolescence may affect the abuse liability of the drug later in life. Our studies focused on characterizing how exposure to alcohol in adolescence alters later adult alcohol dependence behaviors, by using well-established mouse models of ethanol drinking. We hypothesized that early exposure to ethanol leads to increased ethanol intake in adults and other behavioral phenotypes that may lead to dependence. METHODS: We investigated the impact of ethanol drinking in early adolescent C57BL/6J mice using a modified Drinking in the Dark (DID) model. RESULTS: Our results showed that exposure to ethanol during adolescence enhanced ethanol intake in adulthood in the DID, and the 2-bottle choice drinking paradigms. In contrast, adult exposure of alcohol did not enhance later alcohol intake. We also conducted tests for ethanol behavioral sensitivity such as loss of righting reflex and anxiety-related behaviors to further elucidate the relationship between adolescent ethanol exposure and enhanced ethanol intake in adult mice. CONCLUSIONS: Overall, our results suggest that adolescence is a critical period of sensitivity and binge drinking that can lead to lasting changes in ethanol intake in adulthood. Further research will be required in order to more fully examine the neurochemical mechanisms underlying the lasting changes in adulthood.


Assuntos
Alcoolismo/psicologia , Ansiolíticos/farmacologia , Bebedeira/psicologia , Etanol/farmacologia , Fatores Etários , Animais , Ansiolíticos/administração & dosagem , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Concentração Alcoólica no Sangue , Comportamento de Escolha , Estudos de Coortes , Etanol/administração & dosagem , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reflexo de Endireitamento/efeitos dos fármacos
15.
J Agric Food Chem ; 67(50): 13790-13808, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31148444

RESUMO

Essential oils are usually used in aromatherapy to alleviate anxiety symptoms. In comparison to traditional drugs, essential oils have fewer side effects and more diversified application ways, including inhalation. This review provides a comprehensive overview of studies on anxiolytic effects of essential oils in preclinical and clinical trials. Most of the essential oils used in clinical studies have been proven to be anxiolytic in animal models. Inhalation and oral administration were two common methods for essential oil administration in preclinical and clinical trials. Massage was only used in the clinical trials, while intraperitoneal injection was only used in the preclinical trails. In addition to essential oils that are commonly used in aromatherapy, essential oils from many folk medicinal plants have also been reported to be anxiolytic. More than 20 compounds derived from essential oils have shown an anxiolytic effect in rodents, while two-thirds of them are alcohols and terpenes. Monoamine neurotransmitters, amino acid neurotransmitters, and the hypothalamic-pituitary-adrenal axis are thought to play important roles in the anxiolytic effects of essential oils.


Assuntos
Ansiolíticos/química , Óleos Voláteis/química , Óleos Vegetais/química , Animais , Ansiolíticos/farmacologia , Aromaterapia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Óleos Voláteis/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia
16.
J Ethnopharmacol ; 241: 112006, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31153863

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Montanoa tomentosa Cerv. (MT) is a native plant from Mexico used in traditional medicine as a remedy for reproductive impairments and relaxing effects. In previous studies, it has been shown that the endocrine state could modify the antianxiety-like actions of anxiolytic compounds. Although women are the primary user of MT, no studies have evaluated the potential impact of the endocrine milieu on its anti-anxiety actions. AIMS OF THE STUDY: Ascertain the antianxiety effects of M. tomentosa in rats with different hormonal conditions, and to analyze the participation of the GABAA receptor in ovariectomized rats treated with MT. MATERIALS AND METHODS: The animal model of anxiety used was the elevated plus-maze (EPM). Rats' endocrine conditions were: a) Low hormone levels (rats in diestrus I and II phases); b) High hormone levels (proestrus/estrus phases); c) No hormones (ovariectomized rats); and d) Rats under progesterone withdrawal (PW). To evaluate the participation of the GABAA receptor in the anxiolytic-like action of MT the antagonist picrotoxin was used. RESULTS: Results showed that MT induced dose-dependent anxiolytic-like actions in rats with low hormone level conditions. Also, MT reduced anxiety-like behavior in female rats under PW, in contrast to diazepam which was ineffective. MT's anxiolytic-like effect was blocked by picrotoxin, suggesting the participation of the GABAA receptor complex. However, increased anxiety-like behavior was observed in rats with a high hormone level condition and low doses of MT. CONCLUSIONS: Beneficial anxiolytic-like actions of MT are observed under low hormone conditions, particularly in the PW challenge (a condition that can be related to a premenstrual period). Furthermore, the participation of the GABAA receptor is evidenced. However, hormonal variations could induce the opposite effects, hence women should be cautious.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Montanoa , Extratos Vegetais/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiedade/sangue , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Feminino , Locomoção/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta , Progesterona/sangue , Ratos Wistar , Receptores de GABA-A/fisiologia
17.
J Ethnopharmacol ; 239: 111923, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31034951

RESUMO

Ethnopharmacological relevance Senna septemtrionalis (Viv.) H.S. Irwin & Barneby (Fabaceae) is a shrub empirically used as diuretic, and for the treatment of neurological disorders. These pharmacological effects have not been previously evaluated. AIM OF THE STUDY: To evaluate the diuretic and CNS effects of a standardized ethanol extract of Senna septemtrionalis aerial parts (SSE). MATERIALS AND METHODS: Gas chromatography mass spectrometry was used to perform a chemical analysis with SSE. In all tests, SSE was evaluated from 10 to 100 mg/kg p.o. The diuretic activity of SSE was assessed in mice individually placed in metabolic cages. After 6 h, the urine volume and the electrolyte excretion (Na and K) were measured. The role of prostaglandins and nitric oxide was assessed administrating mice with indomethacin and N(ω)-nitro-L-arginine methyl ester (L-NAME), prior the administration of 100 mg/kg SSE. The sedative effects of SSE were analyzed with the pentobarbital-induced sleeping time test. The effects of SSE on motor coordination in mice were evaluated with the rotarod test. The antidepressant-like activity of SSE was analyzed with the forced swimming test (FST) and the tail suspension test (TST). The role of 5-HT2 receptor, α1-and α2-adrenoceptors, or muscarinic receptors was assessed administrating mice with cyproheptadine, prazosin, yohimbine, and atropine, respectively, prior the administration of 100 mg/kg SSE in the FST. The anxiolytic-like activity of SSE (10-100 mg/kg p.o.) was assessed using the light-dark test (LDB), the elevated plus maze test (EPM), the cylinder exploratory test, and the open field test (OFT). The anticonvulsant effect of SSE (1-100 mg/kg) was evaluated in mice administered with different convulsant agents: strychnine, pentylenetetrazol (PTZ), isoniazid (INH) or yohimbine. RESULTS: The main compound found in SSE was D-pinitol (42.2%). SSE (100 mg/kg) increased the urinary volume (2.67-fold), as well as the excretion of Na (5.60-fold) and K (7.2-fold). The co-administration of SSE with L-NAME or indomethacin reverted the diuretic activity shown by SSE alone. SSE lacked sedative effects and did not affect motor coordination in mice. SSE (100 mg/kg) showed higher and similar antidepressant-like effect, compared to 20 mg/kg fluoxetine, in the FST and TST, respectively. The co-administration of SSE with yohimbine reverted the antidepressant-like activity shown by SSE alone. SSE (100 mg/kg) showed anxiolytic-like activity in the four models of anxiety, with similar activity with 1.5 mg/kg clonazepam. The seizure-protective effect of SSE was ED50 = 73.9 ±â€¯8.4 mg/kg (INH) and 40.4 ±â€¯5.2 mg/kg (yohimbine). CONCLUSION: The diuretic effects of SSE involve the possible contribution of prostaglandins and nitric oxide. SSE showed moderate anxiolytic and anticonvulsant effects, whereas the participation of α2-adrenoceptors is probably associated in the antidepressant-like effects of SSE.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Diuréticos/farmacologia , Extratos Vegetais/farmacologia , Senna (Planta) , Animais , Ansiolíticos/química , Anticonvulsivantes/química , Antidepressivos/química , Antioxidantes/química , Comportamento Animal/efeitos dos fármacos , Diuréticos/química , Etanol/química , Dose Letal Mediana , Masculino , Camundongos Endogâmicos BALB C , Componentes Aéreos da Planta , Extratos Vegetais/química , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Solventes/química
18.
J Am Soc Mass Spectrom ; 30(7): 1199-1203, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30949967

RESUMO

In this paper, drug-drug chemical interactions between two different aromatic compounds were studied by mass spectrometry. Specifically, we examined non-covalent complexes (NCX) between paclitaxel, a chemotherapeutic compound, and medications widely used in palliative care for depression, psychosis, and anxiety. It is unknown whether psychotropic medications directly interact with paclitaxel. Here, we use a simple and rapid electrospray ionization mass spectrometry in vitro assay, which has been predictive in the case of neuropeptides, to measure the relative strength of non-covalent interactions. This chemical interaction is most likely due to the overlap of aromatic rings of π-orbitals between paclitaxel and five commonly used medications: diazepam, clonozepam, sertraline, fluoxetine, and haloperidol. Molecular modeling illustrates that differences in the stability of the NCXs are likely due to the distance between the aromatic rings present in both the paclitaxel and antidepressant medications. Graphical Abstract.


Assuntos
Ansiolíticos/química , Antidepressivos/química , Antineoplásicos Fitogênicos/química , Paclitaxel/química , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Diazepam/química , Diazepam/farmacologia , Interações de Medicamentos , Fluoxetina/química , Fluoxetina/farmacologia , Haloperidol/química , Haloperidol/farmacologia , Humanos , Modelos Moleculares , Paclitaxel/farmacologia , Sertralina/química , Sertralina/farmacologia , Espectrometria de Massas por Ionização por Electrospray/métodos
19.
Psychopharmacology (Berl) ; 236(10): 2959-2973, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30963194

RESUMO

RATIONALE: Converging evidence suggests that neuroimmunity plays an important role in the pathophysiology of anxiety. Interleukin (IL)-4 is a key cytokine regulating neuroimmune functions in the central nervous system. More efficient anxiolytics with neuro-immune mechanisms are urgently needed. OBJECTIVE: To determine whether 3'-deoxyadenosine (3'-dA) exerts an anxiolytic effect and to examine the role of IL-4 in the anxiolytic effect of 3'-dA in mice. METHODS: We investigated the effects of 3'-dA on anxiety-like behaviors using elevated plus maze (EPM) or light-dark box (LDB) tests after 45 min or 5 days of treatment. Expression of IL-4, IL-10, IL-1ß, TNF-α, and IL-6 in the prefrontal cortex (PFC) was detected by Western blot and/or double immunostaining. Intracerebroventricular injection of RIL-4Rα (an IL-4-specific inhibitor) and intraperitoneal injection of 3'-dA or imipramine were co-administered, followed by EPM test. RESULTS: 3'-dA exhibited a stronger and faster anxiolytic effect than imipramine in behavioral tests. Furthermore, 3'-dA enhanced IL-4 expression after 45 min or 5 days, TNF-α and IL-1ß expression decreased significantly after a 5-day treatment with 3'-dA, and IL-10 expression increased after a 5-day treatment with 3'-dA or imipramine in the PFC. IL-4 was expressed in neurons and in some astrocytes and microglia. IL-4 expression showed a strong positive correlation with reduced anxiety behaviors. RIL-4Rα completely blocked the anxiolytic effects induced by 3'-dA and imipramine. CONCLUSIONS: This study identifies a novel and common anxiolytic IL-4 signaling pathway and provides an innovative drug with a novel neuro-immune mechanism for treating anxiety disorder.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Desoxiadenosinas/uso terapêutico , Interleucina-4/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/psicologia , Desoxiadenosinas/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Transdução de Sinais/fisiologia
20.
Dokl Biochem Biophys ; 484(1): 17-20, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012004

RESUMO

On the basis of the first dipeptide ligand of TSPO, N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23), which was obtained by us earlier, we synthesized a new dipeptide, N-phenylpropionyl-L-tryptophanyl-L-leucine amide (GD-102). GD-102 exhibited anxiolytic activity in the open field test in BALB/c mice and in the elevated plus maze test in ICR mice. The minimum effective dose of GD-102 was one order of magnitude lower than that of GD-23. Compound PK11195, a selective antagonist of TSPO, completely blocked the anxiolytic activity of GD-102, which testified to the involvement of TSPO in the realization of the anxiolytic effect of GD-102. The results were confirmed by molecular docking data.


Assuntos
Ansiolíticos/química , Dipeptídeos/química , Simulação de Acoplamento Molecular , Receptores de GABA/química , Ansiolíticos/farmacologia , Dipeptídeos/farmacologia , Humanos , Receptores de GABA/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA