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1.
Biol Pharm Bull ; 44(10): 1445-1457, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34349049

RESUMO

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg-1, per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.


Assuntos
Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Privação Materna , Ocitocina/análogos & derivados , Hormônio Adrenocorticotrópico/sangue , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Masculino , Teste de Campo Aberto/efeitos dos fármacos , Ocitocina/sangue , Ocitocina/uso terapêutico , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Ocitocina/sangue
2.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299230

RESUMO

The precise neural mechanisms underlying the pathogenesis of depression are largely unknown, though stress-induced brain inflammation and serotonergic plasticity are thought to be centrally involved. Moreover, we previously demonstrated that neuropeptide FF receptor 2 (NPFFR2) overexpression provokes depressive-like behaviors in mice. Here, we assess whether NPFFR2 is involved in priming of depressive-like behaviors and downregulation of serotonergic 1A receptor (5HT1AR) after lipopolysaccharide (LPS) treatment. The forced swimming test (FST) and sucrose preference test (SPT) were used to quantify depressive-like phenotypes in wild-type (WT) and NPFFR2-knockout (KO) mice. A single dose of LPS (i.p. 1 mg/kg) readily caused increases in toll-like receptor 4 and tumor necrosis factor-α along with decreases in 5-HT1AR mRNA in the ventral hippocampus of WT mice. Furthermore, LPS treatment of WT mice increased immobility time in FST and decreased sucrose preference in SPT. In contrast, none of these effects were observed in NPFFR2-KO mice. While WT mice injected with lentiviral 5-HT1AR shRNA in the ventral hippocampus displayed an unaltered response after LPS challenge, LPS-challenged NPFFR2-KO mice displayed a profound decrease in sucrose preference when pretreated with 5-HT1AR shRNA. Taken together, these results suggest that NPFFR2 modulates LPS-induced depressive-like behavioral phenotypes by downregulating 5HT1AR in the ventral hippocampus.


Assuntos
Depressão/genética , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Neuropeptídeos/genética , Animais , Comportamento Animal/fisiologia , Depressão/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/genética , Receptores de Neuropeptídeos/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208700

RESUMO

Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin's effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/77 receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system.


Assuntos
Chalconas/farmacologia , Neuralgia/tratamento farmacológico , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Chalconas/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos
4.
Curr Sports Med Rep ; 20(7): 345-350, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34234089

RESUMO

ABSTRACT: Cannabidiol and other cannabinoids are being used more frequently for sports medicine-related conditions. This review will help sports medicine clinicians answer questions that their athletes and active patients have about the potential effectiveness of cannabinoids on common sports medicine conditions. In the article, the authors compare cannabidiol and delta-9-tetrahydrocannabinol effects, noting the difference on the endocannabinoid and nonendocannabinoid receptors. The theoretical benefits of these two compounds and the current legality in the United States surrounding cannabidiol and delta-9-tetrahydrocannabinol use also are addressed.


Assuntos
Canabidiol/uso terapêutico , Canabinoides/uso terapêutico , Medicina Esportiva , Desempenho Atlético , Concussão Encefálica/tratamento farmacológico , Canabidiol/efeitos adversos , Canabidiol/metabolismo , Canabinoides/efeitos adversos , Canabinoides/metabolismo , Cannabis/química , Cannabis/classificação , Dor Crônica/tratamento farmacológico , Dronabinol/metabolismo , Dronabinol/uso terapêutico , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Humanos , Maconha Medicinal , Osteoartrite/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Canabinoides/metabolismo , Canais de Cátion TRPV/metabolismo , Estados Unidos
5.
Elife ; 102021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34080539

RESUMO

Consolation is a common response to the distress of others in humans and some social animals, but the neural mechanisms underlying this behavior are not well characterized. By using socially monogamous mandarin voles, we found that optogenetic or chemogenetic inhibition of 5-HTergic neurons in the dorsal raphe nucleus (DR) or optogenetic inhibition of serotonin (5-HT) terminals in the anterior cingulate cortex (ACC) significantly decreased allogrooming time in the consolation test and reduced sociability in the three-chamber test. The release of 5-HT within the ACC and the activity of DR neurons were significantly increased during allogrooming, sniffing, and social approaching. Finally, we found that the activation of 5-HT1A receptors in the ACC was sufficient to reverse consolation and sociability deficits induced by the chemogenetic inhibition of 5-HTergic neurons in the DR. Our study provided the first direct evidence that DR-ACC 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability.


Assuntos
Comportamento Animal , Núcleo Dorsal da Rafe/fisiologia , Giro do Cíngulo/fisiologia , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Comportamento Social , Animais , Arvicolinae , Núcleo Dorsal da Rafe/metabolismo , Feminino , Asseio Animal , Giro do Cíngulo/metabolismo , Masculino , Atividade Motora , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Optogenética , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Fatores de Tempo
6.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071269

RESUMO

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30-180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.


Assuntos
Analgésicos Opioides/química , Destreza Motora/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Vortioxetina/farmacologia , Analgesia/métodos , Analgésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Diazepam/farmacologia , Fenclonina/química , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Naloxona/química , Dor/tratamento farmacológico , Fentolamina/química , Piperazinas/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , alfa-Metiltirosina/química
7.
Psychopharmacology (Berl) ; 238(8): 2147-2154, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33829309

RESUMO

RATIONALE: Preclinical and clinical reports suggest that ferulic acid (FA), a plant-derived phenylpropanoid, is effective against mental health problems such as agitation, anxiety, and irritability in humans, without causing adverse side effects. However, the mechanism of action is unknown. OBJECTIVE: The aim of the study is to investigate the mechanism underlying the ameliorative effects of FA on mental health problems such as agitation, anxiety, and irritability, using in vivo behavioral analysis, in vitro pharmacological analysis, and in silico binding analysis. METHODS: The effects of FA (10 mg/kg, 50 mg/kg, and 250 mg/kg) on hyperactivity and aggressive behaviors of isolation-reared mice were examined. The effects of FA (50 mg/kg and 250 mg/kg) on extracellular levels of monoamines such as serotonin (5-HT), dopamine, and noradrenaline were analyzed by in vivo microdialysis. The effects of FA (10-13-10-6 M) on 5-HT1A and 5-HT2A receptors were analyzed using a luciferase reporter gene assay. Binding of FA to the mouse 5-HT1A receptor was evaluated by in silico analysis. RESULTS: The behavioral analysis showed that administration of FA (50 mg/kg) 1 h before experiments significantly alleviated hyperactivity and aggressive behaviors in isolation-reared mice. These alleviative effects were abolished by pretreatment with the 5-HT1A receptor antagonist WAY-100635 (1 mg/kg). In vivo microdialysis analysis showed that FA (50 mg/kg) did not change extracellular monoamine levels in the prefrontal cortex of mice. The luciferase reporter gene assay indicated that FA activated 5-HT1A receptors, but not 5-HT2A receptors, in a dose-dependent manner. The maximal response of 5-HT1A receptors to FA was weaker than that to 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), a 5-HT1A receptor full agonist. In silico binding analysis showed that FA binds to the orthosteric site of 5-HT1A receptors. CONCLUSION: Taken together, these results suggest that FA ameliorates agitation-, anxiety-, and irritability-like behaviors such as hyperactivity and aggressive behaviors in isolation-reared mice via 5-HT1A receptor partial agonist activity. These findings support the efficacy of FA on mental health problems that have been suggested in preclinical and clinical practice.


Assuntos
Ácidos Cumáricos/uso terapêutico , Agonismo Parcial de Drogas , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Isolamento Social/psicologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ácidos Cumáricos/farmacologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Microdiálise/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
8.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672070

RESUMO

Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.


Assuntos
Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Animais , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Ocitocina/metabolismo
9.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652672

RESUMO

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a-i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a-i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a-i and 7a-i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d.


Assuntos
Piridinas , Receptor 5-HT1A de Serotonina , Agonistas do Receptor 5-HT1 de Serotonina , Animais , Células CHO , Cricetulus , Humanos , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia
10.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668469

RESUMO

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD's therapeutic outcomes.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade , Canabidiol/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Transtornos do Humor , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/patologia , Humanos , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Transtornos do Humor/patologia , Receptor 5-HT1A de Serotonina/metabolismo , Canais de Cátion TRPV/metabolismo
11.
Eur J Med Chem ; 214: 113243, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582388

RESUMO

We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit ß-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.


Assuntos
Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
12.
Artigo em Inglês | MEDLINE | ID: mdl-33429076

RESUMO

Endocytosis and intracellular trafficking constitute important regulatory features associated with G protein-coupled receptor (GPCR) function. GPCR endocytosis involves several remodeling events at the plasma membrane orchestrated by a concerted interplay of a large number of proteins and membrane lipids. Although considerable literature exists on the protein framework underlying GPCR endocytosis, the role of membrane lipids in this process remains largely unexplored. In order to explore the role of membrane cholesterol (an essential and important lipid in higher eukaryotes) in GPCR endocytosis, we monitored the effect of acute cholesterol depletion using methyl-ß-cyclodextrin (MßCD) on endocytosis and intracellular trafficking of the serotonin1A receptor, an important neurotransmitter GPCR. Our results show that the serotonin1A receptor exhibits agonist-induced clathrin-mediated endocytosis with a concentration-dependent inhibition in internalization with increasing concentrations of MßCD, which was restored upon cholesterol replenishment. Interestingly, subsequent to internalization under these conditions, serotonin1A receptors were re-routed toward lysosomal degradation, instead of endosomal recycling observed under normal conditions, thereby implicating membrane cholesterol in modulation of intracellular trafficking of the receptor. This raises the possibility of a novel cholesterol-dependent role of intracellular sorting proteins in GPCR trafficking. These results differ from our previous observations on the endocytosis of the serotonin1A receptor upon statin-induced chronic cholesterol depletion, in terms of endocytic pathway. We conclude that analysis of complex cellular trafficking events such as GPCR endocytosis under acute and chronic cholesterol depletion conditions should be carried out with caution due to fundamental differences underlying these processes.


Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Endocitose , Receptor 5-HT1A de Serotonina/metabolismo , Células HEK293 , Humanos , Transporte Proteico
13.
Horm Behav ; 127: 104878, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148500

RESUMO

Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.


Assuntos
Agressão/fisiologia , Hierarquia Social , Mesocricetus/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Arginina/metabolismo , Arginina Vasopressina/metabolismo , Cricetinae , Feminino , Hipotálamo Anterior/metabolismo , Masculino , Mesocricetus/metabolismo , Mesocricetus/psicologia , Ocitocina/metabolismo , Ligação Proteica , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Serotonina/metabolismo , Caracteres Sexuais , Comportamento Social
14.
J Ethnopharmacol ; 267: 113619, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33248185

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The aerial parts of Tilia americana var. mexicana (Malvaceae, formerly Tiliaceae) or "sirimo" are used in Mexican traditional medicine for the relief of mild symptoms of mental stress, commonly referred to as "nerve diseases". Individuals use this plant to fall asleep, to calm states of nervous excitement, headaches, mood disorders, and general discomfort. Recent studies indicated that fractions standardized in their flavonoid content possess antidepressant activity in behavioral assays in mice. The present study aims to focus on the evaluation of the antidepressant effect of the mixture of two flavonoids (FMix), and its interaction with serotonergic drugs. Also, the pharmacological effect of the products of the metabolism of aglycone, quercetin, was evaluated in mice subjected to forced swimming test (FST) and open field test (OFT). MATERIALS AND METHODS: A methanol-soluble extract obtained from leaves of Tilia americana was fractionated in an open column chromatographic separation. One of the fractions contained FMix wich is constituted of the mixture of quercetin 4'-O-rhamnoside (1, 47%) y isoquercitrin (2, 53%). The mice were divided into the several following groups: FMix (0.01, 0.1, 0.5, 1.0, and 2 mg/kg); FMix (1.0 mg/kg) and agonist DOI (2.0 mg/kg); FMix (1.0 mg/kg) and antagonist ketanserin (KET, 0.03 mg/kg) of 5-HT2A receptors; FMix (1.0 mg/kg) and selective agonist 8-OH-DPAT (8-OH, 0.01 mg/kg); FMix (1.0 mg/kg) and antagonist WAY100635 (WAY, 0.5 mg/kg) of 5HT1 receptors; Phloroglucinol (PHL); 3,4-dihydroxy-phenyl acid (DOPAC); p-hydroxyphenyl acetic acid (p-HPAA); and m-hydroxyphenyl acetic acid (m-HPAA) were tested in FST or OFT. RESULTS: FMix induced dependent-dose antidepressant activity and, at the highest dose administered, a sedative effect was also observed. The 8-OH-DPAT, or the DOI, or the KET combination with FMix (1.0 mg/kg) induced a higher antidepressant effect than compounds alone; there was no effect exerted with WAY. The activity on OFT increased only with the FMix and KET combination. At the same time, the products of the aglycone metabolism of quercetin, that is, DOPAC and p-HPAA, decreased the immobility time of the mice in FST at 1.0 mg/kg, and a dose-curve was formed for these. CONCLUSION: The antidepressant effect of FMix could depend, at least in part, on the degradation products of quercetin and with a possible action mode through interaction with the serotoninergic system.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/prevenção & controle , Extratos Vegetais/farmacologia , Quercetina/análogos & derivados , Neurônios Serotoninérgicos/efeitos dos fármacos , Tilia , Animais , Antidepressivos/isolamento & purificação , Antidepressivos/metabolismo , Biotransformação , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Quercetina/isolamento & purificação , Quercetina/metabolismo , Quercetina/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Tilia/química
15.
Bioorg Chem ; 106: 104487, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33339667

RESUMO

Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T1 or T2 contrast. This work reports the synthesis and evaluation of 5-HT1A targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT1A-antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multi-step synthesis led to the MPP conjugated DO3AM with 60% yield. CEST-related physicochemical parameters were evaluated after loading DO3AM-MPP with paramagnetic MRI active lanthanides: Gadolinium (Gd-DO3AM-MPP) and Europium (Eu-DO3AM-MPP). Luminescence lifetime measurements with Eu-DO3AM-MPP and computational DFT studies using Gd-DO3AM-MPP revealed the coordination of one water molecule (q = 1.43) with metal-water distance (rM-H2O) of 2.7 Å and water residence time (τm) of 0.23 ms. The dissociation constant of Kd 62 ± 0.02 pM as evaluated from fluorescence quenching of 5-HT1A (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT1A. Insights of the docked pose reflect the importance of NH2 (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT1A. Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM-1s-1 with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT1A. The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT1A receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT1A receptors.


Assuntos
Meios de Contraste/farmacologia , Imageamento por Ressonância Magnética , Propiofenonas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/síntese química , Meios de Contraste/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Propiofenonas/química , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/química , Relação Estrutura-Atividade
16.
Adv Exp Med Biol ; 1264: 29-45, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33332002

RESUMO

Cannabis can synthetize more than 400 compounds, including terpenes, flavonoids, and more than 100 phytocannabinoids. The main phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabis-based products are used as medicines in several countries. In this text, we present an overview of the main neurochemical mechanisms of action of the phytocannabinoids, especially THC and CBD. We also reviewed the indications and adverse effects of the main cannabis-based medicinal products. THC acts as a partial agonist at cannabinoid 1/2 receptors (CB1/2). It is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and changes in perceptions. THC can also produce dysphoria, anxiety, and psychotic symptoms. THC is used therapeutically in nausea and vomiting due to chemotherapy, as an appetite stimulant, and in chronic pain. CBD acts as a noncompetitive negative allosteric modulator of the CB1 receptor, as an inverse agonist of the CB2 receptor, and as an inhibitor of the reuptake of the endocannabinoid anandamide. Moreover, CBD also activates 5-HT1A serotonergic receptors and vanilloid receptors. Its use in treatment-resistant epilepsy syndromes is approved in some countries. CBD does not produce the typical effects associated with THC and has anxiolytic and antipsychotic effects. Some of the most common adverse effects of CBD are diarrhea, somnolence, nausea, and transaminase elevations (with concomitant use of antiepileptics). The mechanisms of action involved in both the therapeutic and adverse effects of the phytocannabinoids are not fully understood, involving not only the endocannabinoid system. This "promiscuous" pharmacology could be responsible for their wide therapeutic spectrum.


Assuntos
Canabidiol/farmacologia , Cannabis/química , Dronabinol/farmacologia , Canabidiol/efeitos adversos , Dronabinol/efeitos adversos , Humanos , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Canais de Cátion TRPV/metabolismo
17.
Neurosci Lett ; 743: 135555, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352288

RESUMO

Stress enhances cocaine craving. We recently reported that acute restraint stress increases cocaine conditioned place preference (CPP) in mice; however, the underlying mechanisms remain unclear. This study aimed to examine the role of serotonergic transmission in the medial prefrontal cortex (mPFC) in cocaine CPP enhancement by acute restraint stress, which increases extracellular serotonin (5-HT) levels in the mPFC. Intra-mPFC infusion of the selective serotonin reuptake inhibitor (S)-citalopram prior to the test session significantly increased the cocaine CPP score under non-stressed conditions. This is indicative of the substantial role of increased mPFC 5-HT levels in cocaine CPP enhancement. Moreover, intra-mPFC and systemic administration of the 5-HT1A receptor antagonist WAY100635 immediately before restraint stress exposure significantly attenuated stress-induced cocaine CPP enhancement. Our findings suggest that enhanced serotonergic transmission via 5-HT1A receptors in the mPFC is involved in acute stress-induced augmentation of rewarding memory of cocaine; moreover, the 5-HT1A receptor could be a therapeutic target for stress-induced cocaine craving.


Assuntos
Cocaína/administração & dosagem , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Recompensa , Estresse Psicológico/metabolismo , Animais , Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Infusões Intraventriculares , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Piridinas/administração & dosagem , Restrição Física/efeitos adversos , Restrição Física/psicologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Estresse Psicológico/psicologia
18.
Int J Mol Sci ; 22(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374481

RESUMO

Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.


Assuntos
Canabidiol/farmacologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Canabinoides/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Humanos , Metanfetamina , Piperidinas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Recidiva , Recompensa , Autoadministração , Canais de Cátion TRPV/metabolismo
19.
Int J Mol Sci ; 21(22)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233644

RESUMO

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73-110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Córtex Cerebral/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia , Animais , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos CBA , Receptor 5-HT1A de Serotonina/metabolismo
20.
Sci Rep ; 10(1): 20698, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244123

RESUMO

Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson's disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.


Assuntos
Astrócitos/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Mirtazapina/farmacologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/farmacologia , Astrócitos/metabolismo , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Feminino , Masculino , Metalotioneína/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Gravidez , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
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