RESUMO
We previously demonstrated that chotosan (CTS), a traditional herbal formula called Kampo medicine, improves diabetes-induced cognitive deficits. In the present study, we investigated the antidepressant-like effects of CTS in mice. The administration of CTS (1.0 g/kg, for 3 days) decreased the immobility time in the forced-swim test, and this decrease was prevented by the prior administration of sulpiride (an antagonist of D2/3 receptors) and WAY100635 (an antagonist of 5-HT1A receptors). None of the treatments tested altered the locomotor activity of mice. These results suggest that CTS exerts antidepressant-like effects through changes in the serotonergic and dopaminergic systems.
Assuntos
Antidepressivos/farmacologia , Dopaminérgicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Medicina Kampo , Serotoninérgicos/farmacologia , Animais , Modelos Animais de Doenças , Fenclonina/química , Imipramina/química , Imipramina/farmacologia , Ketanserina/química , Ketanserina/farmacologia , Locomoção , Masculino , Metergolina/química , Camundongos , Piperazinas/química , Piperazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Sulpirida/química , Sulpirida/farmacologia , Natação , Ioimbina/químicaRESUMO
Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [(11)C]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [(11)C]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology.
Assuntos
Metergolina/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Receptores de Serotonina/química , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Metergolina/síntese química , Metergolina/farmacocinética , Primatas , Ligação Proteica , Compostos Radiofarmacêuticos/farmacocinética , Receptores de Serotonina/metabolismo , Distribuição TecidualRESUMO
We used the MembStruk computational procedure to predict the three-dimensional (3D) structure for the serotonin 5-HT(2C) G-protein-coupled receptor (GPCR). Using this structure, we used the MSCDock computational procedure to predict the 3D structures for bound ligand-protein complexes for agonists such as serotonin and antagonists such as ritanserin, metergoline, and methiothepin. In addition, we predicted the SAR data for a series of psilocybin analogs, both agonists and antagonists. We performed molecular dynamics (MD) on serotonin bound to 5-HT(2C) and we find the protein and binding site to be stable after 5ns. We find good agreement with the currently known experimental data and we predict a number of new mutations which could be used to validate further our predicted structures. This agreement between theory and experiment suggests that our 3D structure is sufficiently accurate for use in drug design. We also compare a preliminary prediction for 5-HT(2B) with our prediction for 5-HT(2C) and find a difference in TM5 that contributes to different serotonin binding modes in 5-HT(2B) and 5-HT(2C).