RESUMO
We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.
Assuntos
Ansiolíticos/farmacologia , Piridinas/farmacologia , Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Tiofenos/farmacologia , Animais , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Células Cultivadas , Citalopram/farmacologia , Diazepam/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Isoindóis/farmacologia , Masculino , Piperazinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Ratos , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Tiofenos/uso terapêuticoRESUMO
We studied the influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobility in naive rats during forced-swim testing. However, chronic, 14-day forced-swim stress testing blocked the immobility-decreasing effect induced by a single administration of imipramine. When imipramine was administered for 14 days concurrently with forced-swim stress testing, immobility was shortened significantly. From the viewpoint of imipramine's effect, these findings suggest that chronic forced-swim stress testing in rats may be an effective animal model for depression.